Next Article in Journal
Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D
Next Article in Special Issue
The Role of Eosinophil-Derived Neurotoxin and Vascular Endothelial Growth Factor in the Pathogenesis of Eosinophilic Asthma
Previous Article in Journal
Preclinical Large Animal Porcine Models for Cardiac Regeneration and Its Clinical Translation: Role of hiPSC-Derived Cardiomyocytes
Previous Article in Special Issue
The Anti-Inflammatory Peptide TnP Is a Candidate Molecule for Asthma Treatment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 12
Issue 7
10.3390/cells12071091
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Asthma: The Use of Animal Models and Their Translational Utility

by
Jane Seymour Woodrow
1,*,
M. Katie Sheats
2,
Bethanie Cooper
2 and
Rosemary Bayless
2
1
Department of Clinical Studies, New Bolton Center, College of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA
2
Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA
*
Author to whom correspondence should be addressed.
Cells 2023, 12(7), 1091; https://doi.org/10.3390/cells12071091
Submission received: 10 March 2023 / Revised: 27 March 2023 / Accepted: 31 March 2023 / Published: 5 April 2023
(This article belongs to the Special Issue Asthma: Pathogenesis, Diagnosis, and Treatment)
Review Reports Versions Notes

Abstract

:
Asthma is characterized by chronic lower airway inflammation that results in airway remodeling, which can lead to a permanent decrease in lung function. The pathophysiology driving the development of asthma is complex and heterogenous. Animal models have been and continue to be essential for the discovery of molecular pathways driving the pathophysiology of asthma and novel therapeutic approaches. Animal models of asthma may be induced or naturally occurring. Species used to study asthma include mouse, rat, guinea pig, cat, dog, sheep, horse, and nonhuman primate. Some of the aspects to consider when evaluating any of these asthma models are cost, labor, reagent availability, regulatory burden, relevance to natural disease in humans, type of lower airway inflammation, biological samples available for testing, and ultimately whether the model can answer the research question(s). This review aims to discuss the animal models most available for asthma investigation, with an emphasis on describing the inciting antigen/allergen, inflammatory response induced, and its translation to human asthma.

1. Introduction

Asthma is a heterogeneous disease that is common in humans, affecting 1–18% of the population in various countries [1]. Asthma is characterized by chronic airway inflammation, airway remodeling, bronchial hyperreactivity, and partially reversible airflow obstruction [2,3,4,5]. The long-term goals of asthma management are aimed at controlling symptoms so that the individual can maintain normal activities, as well as avoid exacerbations, persistent airflow obstruction, and asthma-related death. Treatment primarily relies on antigen avoidance and medications such as corticosteroid and bronchodilator therapies. The treatment and management of asthma have become more individualized, especially as the disease itself is so heterogeneous. Understanding the pathophysiology of asthma is therefore critical to individualized medicine and the achievement of long-term management goals. Asthma in humans can be defined by endotype and/or phenotype. While there are multiple asthma phenotypes, the endotype is broadly divided into T2 high and non-T2 [6]. The T2-high asthma endotype involves allergy-mediated responses that involve eosinophils, interleukin (IL)-4, IL-5, IL-13, IgE, thymic stromal lymphopoietin (TSLP), leukotrienes, and prostaglandin D2 (PGD2) [7,8]. The T2-low or non-T2 asthma endotype is seen with airway neutrophilia or paucigranulocytic inflammation and is thought to be a mixture of Th1 and Th17 immune responses. Discrete divisions between these endotypes do not exist in every patient, hence the heterogenous disease process. With the greater availability of optimized animal models, the T2-high endotype has been more extensively researched, is better characterized, and has more biological therapy options including those that target IgE, eosinophils, IL-4, IL-5, and TSLP [9,10].
Animal models have been and continue to be essential for the discovery of molecular pathways driving the pathophysiology of asthma and for the discovery of novel therapeutic approaches. The use of cell lines can help to establish basic pathways in vitro, but these approaches cannot replicate intricate in vivo interactions. With the use of animal models, significant advances have been made toward the better understanding and treatment of the T2-high asthma endotype. The non-T2 asthma endotype, on the other hand, is less well characterized and has comparatively few treatments. Part of this lack of understanding is due to the fewer relevant animal models available for research. Recently, there have been several reviews about animal models of asthma [11,12,13,14,15]. This review article aims to summarize the available animal models used for asthma research and to describe their translational relevance to human asthma. Special emphasis is placed on naturally occurring animal models of asthma and how veterinarians, physicians, and researchers can be collaborative in our overall goal of better defining asthma pathophysiology, diagnosis, and treatment. This review article is not aimed at critically evaluating the specific protocols, especially those in mice, used to investigate asthma and is not a meta-analysis of data derived from animal models of asthma. The search strategy used for this review included using databases PubMed (1946 to present), CAB abstracts (1910 to present), and Google Scholar (1995 to present). Keywords included asthma, airway, inflammation, animal model, mouse, murine, rat, rabbit, sheep, ovine, guinea pig, dog, cat, horse, non-human primate, and human in various combinations. The primary literature and review articles were included.

2. Inducible Animal Models of Asthma

Most animal species, other than humans, cats, and horses, do not develop asthma naturally or spontaneously. Therefore, most animal species used to research and model asthma require human intervention to mimic the disease. The species most used in disease models is the mouse due to its short gestation, multiple inbred strains, ease of gene manipulation, and availability of reagents. A variety of models could be used depending on the research question of interest, including, mice, rats, guinea pigs, rabbits, ferrets, dogs, sheep, and non-human primates. Inducible models of asthma typically require abnormal sensitization routes and the use of adjuvants for an adequate immune response. Additionally, inducible models are not useful for longitudinal studies or to study aspects of asthma related to chronicity as most of the animal models undergo desensitization.

2.1. Mice

Mice are the most widely used animal model for the investigation of many diseases, including asthma. In 1994, a mouse model of allergic pulmonary inflammation was described using chicken ovalbumin (OVA) [16]. Benefits of mouse models include the availability of genetically engineered transgenic or gene-knockout strains, short gestation (20–30 days), and readily available species-specific reagents. Decades of research in mice have greatly enhanced our understanding of asthma and especially that of the T2-high asthma endotype [17,18,19]. OVA is inexpensive, has well-described MHCI and MHCII epitopes, and there are genetically engineered transgenic mice available for investigating OVA-specific responses. Other allergens, which can be argued are more natural stimulants of T2-high asthma development or exacerbation, are house dust mites (HDMs), fungal elements such as Alternaria alternata, pollen, and cockroach extracts [20,21,22,23,24,25]. Because OVA is not an important allergen in human asthma, these other allergens offer more clinical and pathophysiological relevance. Humans with asthma are noted to display exaggerated asthmatic episodes upon inhalation of HDMs [26]. In mouse models, chronic exposure to HDMs may replicate some aspects of chronicity and airway remodeling, as well as be useful for assessing treatments [27,28,29]. Additionally, the route of administration of the sensitizers is also variable in mice depending on the model, from intraperitoneal, subcutaneous, intra-tracheal, and aerosolized. Intraperitoneal and subcutaneous routes are least similar to the spontaneous development of asthma, which is due to chronic airway exposure to the antigen. Important viral pathogens that have been associated with asthma exacerbations in humans are influenza, rhinovirus, and respiratory syncytial virus, and mouse models have been useful for studying the impact of viral infections on asthma pathology [30,31,32,33,34,35].
The non-T2 asthma endotype and chronic asthma have been more difficult to study with the use of mouse models, as mice become tolerant to antigen exposure. The various mouse strains, sensitization, challenge methods, and type of asthma modeled (acute versus chronic) have been reviewed extensively, with a few specified here [29,36,37,38,39,40]. Many of the models available are acute, and the longest duration for a chronic model is approximately 12 weeks. When evaluating the response to the allergen challenge, many are T2-high asthma models, even when used chronically. This emphasizes the limited ability to investigate the pathophysiology of non-T2 asthma, especially in a chronic model, using a mouse model. Table 1 summarizes common mouse models of asthma. When evaluating the mouse strains used, most commonly BALB/c or C57BL/6 mice are used. BALB/c mice are IgE-high responders/Th2 immune responders, while C57BL/6 mice are skewed more to a Th1 immune response and are low-IgE producers [41,42,43,44,45]. Humanized mouse models can also be utilized, which allows for the investigation of various components of the human immune system [46,47,48]. Non-T2 asthma mouse models are limited, but neutrophilic airway inflammation has been able to be developed [38,49,50]. Most of the non-T2 asthma models rely on adoptive transfer of specifically differentiated Th cells. The inflammation though is short-lived, making longitudinal studies of either eosinophilic or neutrophilic airway inflammation impossible in the mouse. Additional important differences between mouse asthma models and naturally occurring human asthma include the transience of methacholine-induced AHR post-allergen exposure in mice, the desensitization that occurs with repeated allergen exposure in mice, and the variable need for IgE and mast cells in mice [14,37,40,51].
Table 1. Mouse models of asthma, acute versus chronic.
Table 1. Mouse models of asthma, acute versus chronic.
StrainAllergenSensitizationExposure/ChallengePulmonary InflammationReferences
BALB/cOVAOVA (IP) on 7 alternate daysOVA aerosol for 8 consecutive daysAcute[52,53]
BALB/cOVAOVA (IP) on 7 alternate daysOVA (IT) on day 42 for 3 days, each 3 days apartAcute[54]
BALB/cOVAOVA + AlOH3 (IP) on day 0 and OVA (IP) on day 10OVA aerosol on days 17 and 24Acute[55]
BALB/cOVAOVA + AlOH3 (IP) on days 0 and 52 × OVA inhalations, each 4 h apart on day 17Acute[56]
BALB/cOVAOVA + alum (IP) on days 0 and 14OVA (IN) on days 14, 25, 26, and 27Acute[57]
BALB/cOVAOVA + AlOH3 (IP) on days 0 and 14OVA aerosol on days 28–30Acute[58,59]
BALB/cOVAOVA/alum (IP) on days 0 and 12OVA aerosol on days 18–23Acute[60,61,62]
BALB/cOVAOVA + alum (IP) on days 0 and 14OVA aerosol on days 28–30 and 72 days after last challengeAcute[63]
BALB/cOVA + LPSOVA-specific Th1 (IV)Day 1 OVA (IN) daily for 4 days, last treatment day LPS (IN)Acute[49]
BALB/cOVAOVA (IT) on day −1, day 0 Th17 retro-orbitalDay 1–3 daily OVA (IT)Acute[50]
C57BL/6HDMDer p 1 + AlOH3 (IP) on day 0HDM aerosol on day 14 for 7 consecutive daysAcute[64]
C57BL/6OVA + LPSOVA + LPS (OP) on days 0 and 7OVA (OP) on days 14–16Acute[65]
A/JBla g 2 and Der f 1Ova + AlOH3 (IP) on days 0 and 7Allergen oro-tracheal on day 14Acute[66]
C57BL/6OVAOVA-DCs (IT) on day 0OVA aerosol on day 14–20Acute[67]
CB.17 SCIDDptHuman PBMCs (IP)Dpt aerosols 1×/day for 4 consecutive days starting day 14Acute[46]
NOD/SCIDHDMHuman PBMCs (IP)Dpt (IT) on days 1, 3, 7Acute[47]
BALB/cOVAOva + AlOH3 (IP) on days 0 and 5OVA aerosol 3 days/week, starting day 17, for 6 weeksChronic[56]
BALB/cOVAOVA + alum (IP) on days 7 and 21OVA exposure 3 days/week, for up to 8 weeksChronic[68]
BALB/cOVAOVA + alum (IP) on days 0 and 14OVA (IN) on days 14, 27, 28, 47, 61, and 73–75Chronic[69]
BALB/cOVAOVA + aluminum potassium sulphate (IP) on days 1 and 11OVA (IN) on days 11, 19, 20, 33, 34, 47, 48, 61, 62, 75, 76, 89, 90Chronic[70]
BALB/cOVAOVA + alum (IP) on days 0 and 12OVA aerosol on days 18–23 and then 3 days/week for up to 8 weeks starting on day 26Chronic[62]
BALB/cOVAOVA + alum (SC) on days 0, 7, 14, 21OVA (IN) on days 27, 29, 31, and then 2×/week for 3 monthsChronic[71]
BALB/cHDMNAHDM (IN) 5 days/week for up to 7 weeksChronic[27]
BALB/cHDMNAHDM (IN) 5 days/week for up to 5 weeksChronic[28]
IP = intraperitoneal, IN = intranasal, IT = intratracheal, SC = subcutaneous, IV = intravenous, OP = oropharyngeal aspiration, NA = not applicable.
In addition to the previously mentioned benefits of reagent and assay availability and the variety of genetically engineered transgenic mice, terminal mouse asthma studies also allow for easy tissue collection. Lung function testing is also available in the mouse and recent advancements have made it possible to assess lung function longitudinally, rather than terminally [72,73,74,75]. Like other inducible models, the pathophysiologic relevance of murine asthma models to naturally occurring human asthma has been questioned. Murine asthma models are also limited in their ability to model the chronicity of human asthma. Anatomically, mice have monopodial branching of the bronchi while humans have dichotomous branching; mice have zero to one respiratory bronchioles while humans have several generations; the airway cartilage is limited to the trachea in mice while it extends from the trachea to the distal bronchioles in humans [76]. The airway inflammation of mice in asthma models may also more similarly reflect allergic alveolitis than asthma, and the roles of eosinophils and mast cells vary between mice and men. Mouse eosinophils, in OVA-induced airway inflammation, do not have significant degranulation [77]. Additionally, both histamine and serotonin play a role in AHR in mice and are released from mast cells, while serotonin’s role in human AHR is unclear [78]. While limitations and differences exist, mouse models of asthma are likely to remain the most used animal model for investigating the pathophysiology and molecular pathways of asthma. Complimentary studies in naturally occurring animal models of asthma could be used to further validate and support the relevance of findings in inducible models such as mice.

2.2. Guinea Pigs

Asthma is not a naturally occurring disease in guinea pigs, but the immediate hypersensitivity reaction of the lungs has been appreciated for some time in guinea pigs [79]. The use of OVA as a sensitizer for the study of T2-high asthma is common in inducible animal models, such as mice and rats. Guinea pigs can also be sensitized to ovalbumin, or other stimulants, to induce IgE-mediated airway mechanisms that replicate a response similar to the asthma phenotype of humans that involves eosinophilia and increased airway responsiveness [80,81,82,83,84,85]. OVA can be delivered via various routes for sensitization, including peritoneal, subcutaneous, and aerosolized. Low-dose OVA, 10 µg, has been shown to induce early asthmatic responses (EARs) with the production of IgE and IgG1 [86,87]. A larger dose of OVA, 100 µg, can induce both EAR and late asthmatic responses (LARs) [86,87,88,89]. Aerosol sensitization, more physiologically like naturally occurring asthma, with low-dose OVA induces EAR and LAR with IgE and IgG1 production and high-dose OVA induces EAR, airway eosinophilia, and airway hypersensitivity [90,91,92]. The use of the allergen house dust mite (HDM) has also been shown to induce airway hyperresponsiveness, eosinophilia, and the recruitment of mast cells, which, in repeated intranasal HDM exposure, additionally caused airway wall hyperplasia [93].
The acute, allergic hypersensitivity reactions in the airway of asthmatic humans, such as airway smooth muscle contraction, eosinophil infiltrate, airway hyperresponsiveness, and mucus production, are mediated in part by activation of the histamine H1 receptor and leukotriene cysteinyl leukotriene (cysLT)-1 receptor [94,95,96,97]. These receptor activations are also appreciated in guinea pigs [98,99,100]. Given the similarities, guinea pigs have been used to develop drugs used in the treatment of asthma. Leukotriene receptor antagonists, such as Montelukast, were developed by the use of guinea pig models [101,102,103,104,105,106,107,108]. A phosphodiesterase (PDE3/4) inhibitor, ensifentrine, aimed at relaxing airway smooth muscle was also developed in guinea pigs and its function was confirmed in humans [109,110,111].
While there are similarities and proven benefits of guinea pigs as a research model for asthma, there are differences worth acknowledging. Guinea pigs have an elongated soft palate and, as a result, are obligate nasal breathers [112]. They have seven lung lobes, three right and two left, and two accessory lobes. They have a dichotomous branching of the bronchial tree, as do humans, although guinea pig and human branching differ slightly, with guinea pigs having fewer bifurcations. The parenchyma of the lung lacks connective tissue and is therefore more fragile than human lung. The alveoli contain many macrophages, but phagocytosis appears to be primarily via neutrophils that move into the alveoli. Chronicity is not a feature of induced asthma in guinea pigs, as they become tolerant to the allergens used and do not display nonspecific hypersensitivity [113,114]. Additionally, bronchoconstriction in the guinea pig asthma models appears to be mediated by primarily by histamine, which may have limited translational relevance to human asthma patients in which antihistamines have limited efficacy [115]. Logistic limitations for guinea pigs as an animal model are a longer gestation (60–75 days) compared to mice and less reagent availability. There has been an effort to develop more guinea pig assays, identify translatable markers, and review the availability of monoclonal antibodies to make research more viable in this species [116,117,118,119,120,121].

2.3. Rabbits

Rabbits were among the first animal models for asthma research. Rabbits are phylogenetically more similar to primates than other rodents. Similarities between induced asthma in rabbits and humans include bronchoconstriction, airway obstruction, and airway hyperresponsiveness [122,123]. Rabbit models of asthma require antigen sensitization within 24 h of birth for the development of late-phase airway responses when later challenged; however, this is not necessary if only investigating early-phase airway responses [122,124,125,126,127,128]. IgE is the primary anaphylactic antibody response for rabbits. Additionally, rabbits have both heterophils, which are analogous to human neutrophils, and eosinophils; special staining is required to differentiate these cells from one another [129]. Lung function testing can be performed for more objective measurements, and histamine or methacholine can be used for evaluating airway responsiveness [130,131,132]. Asthma treatments such as corticosteroids, PDE4 inhibitors, bronchodilators, and others of various routes of delivery have variable effectiveness in rabbit models [133]. A factor that may influence the deposition/distribution of air and particles in the lung is the fact that rabbits have monopodial branching, different from humans. Rabbits also lack submucosal glands and goblet cells appear to be less numerous than those in humans [134]. Limitations to their use is reagent availability, the low number of transgenic lines, and increased cost.

2.4. Sheep

A model of maternal allergic asthma in sheep was recently developed as a method to investigate the impacts of the intrauterine environment on asthma in both mothers and offspring [135,136,137,138]. Immune consequences of the allergic airway inflammation of humans are replicated in sheep, including IgE-related responses, the recruitment of eosinophils and lymphocytes, locally activated mast cells, and mucus production [139,140,141]. Both early- and late-phase allergic airway responses have been noted in sheep models [142,143]. Allergic airway inflammatory responses in sheep have been utilized for evaluating novel airway treatments, such as Montelukast and tryptase inhibitors [108,144]. However, not all novel therapeutics extrapolate to humans, for example, inhibitors of platelet-activating factors are effective in sheep, but not humans with asthma [145]. Multiple studies have also utilized sheep for the investigation of Th2-driven asthma using HDM and to study the impact of chronic lower airway inflammation on lung function and airway remodeling [140,143,146,147,148]. Lung function testing can be performed on sheep for additional objective data analysis [149]. Sheep lobes are also well separated by tissue septa, making it easier to apply different treatments to localized areas [150]. Airway branching in sheep, similar to other large mammals and humans, is dichotomous [150,151]. Additionally, large volumes of blood can be collected from sheep, compared to other inducible models. Compared to rodent models though, the cost of sheep as a translation asthma model is relatively high.

2.5. Rats

Rat asthma models most commonly use OVA for sensitization and the strain most utilized is the Brown Norway rat [152,153,154,155]. There are also models described using HDM as an antigen [156]. The HDM model has been used more recently for evaluation of treatments in the area of angiogenesis [157,158]. OVA, in combination with LPS, has been used to model eosinophilic, neutrophilic, and lymphocytic airway inflammation and lung remodeling [159]. Rats produce IgE; display hyperreactivity to methacholine, acetylcholine, and serotonin; accumulate neutrophils, lymphocytes, and eosinophils in BALF; show elevations in Th2 cytokines similar to allergic asthma in humans [160,161,162,163]. Rats have a weak bronchoconstriction response and require high levels of antigen/agonist exposure to elicit this response. Regarding treatments, beta2-receptor agonists (such as salbutamol) and steroids (dexamethasone and budesonide) are effective in rat models [164,165,166].

2.6. Dogs

Dogs develop allergic diseases, but atopic dermatitis is much more common than asthma; therefore, it is not feasible to use dogs as a naturally occurring animal model of asthma. However, an inducible model of asthma in dogs has been reported. Several studies have been performed in dogs being naturally or actively sensitized with Ascaris suum larvae investigating the role of the vagus and phrenic nerve, COX responses, and airway responses to molecules such as histamine, prostaglandins, and acetylcholine [167,168,169,170,171,172,173,174,175,176]. Ragweed-sensitized beagles are another popular model used to study mechanisms of asthma [177,178,179,180,181]. Interestingly, in dogs, neutrophilic airway inflammation is more common than eosinophilic inflammation following allergen challenge [182,183,184,185,186]. Additionally, dogs have the unique ability to develop prolonged airway hypersensitivity, up to 5 months, to A. suum [187]. Advantages of dogs as an animal model include its size and ability to collect large sample volumes, but reagents specific for dogs are limited compared to reagents for mice and humans.

2.7. Nonhuman Primates

Models of asthma in nonhuman primates have been utilized, primarily in rhesus monkeys and macaques [188,189,190,191,192,193,194,195]. Sensitizers most commonly used have been Ascaris extract, HDMs, and birch pollen allergens, all of which induce a Th2 immune response. Benefits of using nonhuman primates include genetic and physiological similarities to humans, including the ability to be upright and bipedal. Pulmonary lung function testing and bronchoscopy can also be performed [196]. In the case that nonhuman primates are euthanized for other reasons, precision-cut lung slices could be used for ex vivo modeling to investigate bronchoconstriction, including the response to therapies [197]. Access to reagents is easier in nonhuman primates compared to other large animal models. Disadvantages of using nonhuman primate models include high cost and ethical concerns.

3. Naturally Occurring Animal Models of Asthma

Animals that develop asthma spontaneously allow for the investigation of asthma development and pathophysiology in a ‘real-world’ scenario. Longitudinal studies, chronic asthma changes, and the heterogeneity of asthma can be investigated in these models. Translational clinical studies could also be pursued through collaborations with veterinarians. Both cats and horses develop asthma naturally. Cats develop T2-high asthma, while horses have T2-high and non-T2 asthma subtypes.

3.1. Cats

Cats are one of the species that naturally develop asthma. Characteristics of feline asthma are very similar to humans, including features such as eosinophilic airway inflammation, bronchoconstriction, and airway remodeling [198,199,200,201]. While the exact pathophysiology of feline asthma is not well understood, it is believed to be an allergic-type etiology [202,203,204,205,206,207,208]. In support of allergy-mediated etiology, allergen-specific immunotherapy and allergen avoidance can help control clinical signs [203,206,209]. There can be an overlap to other diseases such as bronchitis and the limitation of not being able to perform lung function testing to evaluate for reversible airway obstruction after inhalation of a bronchodilator potentially leads to the confusion of asthma and bronchitis [210]. While clinical studies can be performed in naturally occurring cases of asthma in cats, there are also models that use specific antigen exposures such as with HDM and Bermuda grass [205]. A type 2 immune response profile has been identified in peripheral blood mononuclear cells and BALF cells in cats with asthma. An experimental induction of asthma in cats has also been used to evaluate microbiome changes of the airway, both in acute and chronic stages [211].
In addition to being a naturally occurring model, feline asthma has additional translational relevance because cats live in the same environment as humans and may be responding to similar airway antigens. Both humans and cats have alveolarized respiratory bronchioles, but these bronchioles continue for several generations in humans, while cats only have one generation [212,213]. Well-developed submucosal glands and ciliated epithelial cells of the airway appear to be comparable between humans and cats; therefore, they may have similar mucociliary clearance. Histologic changes seen in human asthma, such as airway wall inflammation, epithelial cell hyperplasia and desquamation, hypertrophy and hyperplasia of airway smooth muscle, and hypertrophy of submucosal glands, are appreciated in cats, except for a thickened basement membrane [205,214,215]. Similarities also exist in the non-adrenergic, non-cholinergic inhibitory nervous system control over airway diameter [216,217,218]. Cats display an airway hyperresponsiveness to methacholine and reversibility to bronchoconstriction with beta agonists, similar to humans [201]. Whole-body plethysmography can be performed in cats [219]. While a similar type 2 immune response and associated cell types, cytokines and chemokines, are seen in humans and cats with asthma, differences in histamine response exist, with cats displaying both dilation and constriction. Additionally, cysLT do not play an important role in cats as it does in human asthma [220,221,222,223].

3.2. Horses

Horses are an additional species that develop asthma naturally. Currently, equine asthma (EA) includes two categories: mild to moderate equine asthma (mEA) and severe equine asthma (sEA). Unlike human asthma, the term ‘severe’ for EA is used to describe a greater degree of lower airway inflammation and severity of clinical signs but does not necessarily mean the asthma is difficult to manage or treat. Equine asthma is a chronic inflammatory lung disease with characteristics similar to human asthma, including enhanced bronchial reactivity; chronic, partially reversible airflow obstruction; pulmonary remodeling; lower airway inflammation [224,225,226]. Equine asthma prevalence is not clearly defined, but some studies suggest that up to 80% of horses may have mEA and up to 17% may have sEA [227,228,229,230,231]. A 2016 consensus statement by the American College of Veterinary Medicine defined two categories of equine asthma (EA), mEA and sEA, and the diagnosis of each [224]. The diagnosis of asthma is based on history, clinical signs, physical examination, bronchoalveolar lavage fluid (BALF) cytology, and lung function tests, depending on availability. Clinical signs supportive of sEA include cough; increased respiratory rate and effort at rest; poor performance/exercise intolerance; increased tracheal mucus, crackles, and/or wheezes on lung auscultation; serous, mucoid, or mucopurulent nasal discharge. By contrast, clinical signs of mEA are primarily linked to athletic performance and can include cough, decreased performance, or prolonged respiratory recovery following exercise. Importantly, horses with mEA do not have respiratory abnormalities at rest. BALF is routinely collected for EA diagnosis. For mEA, consistent cytologic findings include mild to moderate increases in % neutrophils (5–20%), mast cells (>2%), eosinophils (>1%), or a combination of cell types. For sEA, cytology shows a marked increase in % neutrophils (>20–25%). Cultures and complete blood count are often used to rule-out pneumonia. The term paucigranulocytic inflammation is not widely used in veterinary medicine, but anecdotal evidence supports the relevance of this term for a subset of severely asthmatic horses.
Asthma immune responses in both horses and humans have been broadly characterized by a Type 2 immune response, termed Type 2 high; or a mixed immune response, termed Type 2 low or non-type 2 [8,232]. The cytokine profiles of mEA and sEA, either at the protein or mRNA level, indicate a Th1, Th2, Th17, or mixed immune response, depending on the study [233,234,235,236,237,238,239,240,241,242,243,244,245]. Generally, samples from horses with mEA are most often a T2-high endotype, and samples from horses with sEA indicate a non-T2 endotype. Benefits of using the horse as a translational asthma model have been suggested by several review articles [246,247,248,249]. While the pathophysiology of both human and equine asthma is still being defined, they appear to have similarities regarding airway inflammation, remodeling, responses, clinical signs, and response to therapy. Horses display both acute and long-term airway responses. Because they are large animals, it is relatively easy to obtain large volumes of blood and airway lavage (tracheal and bronchial). In research settings, endobronchial brushings and/or biopsy samples, lung function testing, and even lung biopsies are frequently collected [250,251,252]. Due to the prevalence of EA and the importance and popularity of horses as performance athletes and companion animals, there is a need in veterinary medicine for improved treatments and diagnostics for EA. As a result, lung function testing, which has been technically difficult to perform in an ambulatory setting, has advanced to include portable testing options [253,254,255,256,257,258].
The primary trigger for EA is organic dust. Some asthmatic horses are sensitive to organic dust in barns and/or hay and experience worsening symptoms when housed indoors. Other asthmatic horses are sensitive to the organic dusts encountered in pasture environments during hot and humid conditions. This type of asthma is referred to as Equine Pasture Asthma (EPA) and is most commonly diagnosed in subtropical climates such as the southeastern United States. For either type of asthma, antigen avoidance is the most effective treatment for decreasing lower airway inflammation and symptoms. Therefore, horses who worsen indoors experience symptom relief when kept out of the barn environment and are fed soaked or steamed hay or a hay-alternative diet [259]; horses who worsen on a summer pasture experience symptom relief when moved indoors to a temperature-regulated environment [232]. In addition to environmental management, and as a necessary treatment during acute asthma exacerbation, horses with asthma are routinely treated with inhaled or systemic corticosteroids and bronchodilators [238,243,260,261,262,263]. There is also a demonstrated benefit to daily omega-3 supplementation in horses with sEA [264].
Like asthma in humans, asthma in horses is heterogenous with different clinical presentations (i.e., phenotypes) and immunopathogeneses (i.e., endotypes) [265]. Studies in horses with mEA provide variable evidence for the roles of mast cells, eosinophils and neutrophils, and Th2-high and Th2-low cytokines, suggesting that horses with mEA could be used as a translational model for several different human asthma endotypes. By contrast, studies in horses with sEA primarily show evidence for a mixed cytokine response (Th1/Th2/Th17) and consistent airway neutrophilia, suggesting translational relevance of sEA for non-allergic and/or neutrophilic asthma in humans [249,265]. Recent studies using differential gene expression analysis show striking similarities between the transcriptomic profiles of sEA and severe neutrophilic asthma in humans [266,267]. One of these studies also showed a significant upregulation of miR-142-3p and miR-223 in lung tissue samples from asthmatic horses vs. controls. These two miRNAs have also been shown to promote airway inflammation and obstruction in severe neutrophilic asthma in humans [266]. Historically, neutrophilic asthma in humans has been less well researched and understood, partially due to a lack of relevant animal models. This is despite neutrophilic asthma in humans being associated with greater morbidity and mortality [268,269]. While mouse models of neutrophilic asthma are now available [270], and have been used to identify novel biomarkers and therapeutic approaches [271,272], horses are another potentially useful translational model for this important asthma endotype. Like asthma in humans, sEA is a chronic disease that leads to structural changes in the lung that mirror changes in humans with asthma [225,273]. With environmental management, asthmatic horses can be maintained in remission and exacerbation can be induced when needed by feeding dusty/moldy hay or nebulizing hay dust extract (HDE). Clinical signs, blood samples, and airway samples including tracheal and bronchial lavage, brushings, biopsies, and pulmonary function can all be used for investigations of novel molecular pathways, identifications of new therapeutic targets, or when conducting short- or long-term clinical trials. For clinicians and researchers lacking equine expertise or facilities, it is possible to collaborate with veterinary clinician scientists who are already conducting translational and comparative research using EA as a model. Samples can also be requested from an Equine Respiratory Tissue Biobank (http://asthmeequin.com/en/facilities/, accessed on 22 September 2022). Equine asthma is an important spontaneous animal model of asthma with demonstrated value for future translational research.

4. Approach to Asthma Research

Using inducible animal models of asthma allows for large-scale research and increases the statistical power of the results. Mice are commonly the first in vivo model utilized due to gestation length, litter size, homogenous genetics, availability of transgenic mice, ease of terminal studies, cost, and access to species-specific reagents. While defining the pathophysiology of T2-high asthma and the development of novel therapeutics have greatly benefited from mouse models, non-T2 asthma research has been left behind. To define molecular pathways, the combination of in vitro, ex vivo, and mouse models are best utilized. The transgenic mice available for use enable specific aspects of a cellular pathway to be investigated. A step-up approach is likely best used when defining the pathophysiology of asthma and developing novel therapeutics. Findings in mice can be validated in other mouse models of asthma, such as other outbred strains or humanized mouse models, and once validated, the findings can be further investigated in more anatomically similar models. Finally, the hypothesized pathophysiology of asthma and novel therapeutics can be evaluated in naturally occurring cases of asthma, such as in cats and horses. One Health and fostering collaboration lend the opportunity to expand our research knowledge and ability to advance our understanding of asthma etiology, phenotypes, endotypes, diagnosis, and treatment. Both cat and horse owners are looking for more individualized medicine to best treat and manage their animal’s disease. Clinical research studies in veterinary species are common and veterinary patients are a group of animals with naturally developing disease in which physicians and basic researchers could collaborate. Longitudinal studies and features of asthma related to chronicity can be investigated in these naturally occurring models. Advanced research techniques are utilized in clinical trials in veterinary species and further collaboration can help establish similarities and differences in cats, horses, and humans with asthma. Additionally, horses offer a unique aspect for investigation as many horses are athletes, with athletic abilities spanning from local shows to Olympic/International events.

5. Conclusions

Asthma is a lifelong disease and requires constant medical management. Asthma puts a large economic burden on the individual and the country. In the United States alone in 2013, the estimated total cost of asthma, including costs due to missed work and mortality, was USD 81.9 billion [274]. A better understanding of the pathophysiology of asthma in humans by utilizing animal models of asthma is aimed at improving diagnostics and treatments. Depending on the research question and budget, a certain animal model of asthma may be more applicable for use. Naturally occurring animal models of asthma have the benefit of investigating the aspect of chronicity, collecting longitudinal data, and evaluating novel treatments. As summarized in Table 2, there are various pros and cons to each animal model of asthma and, ultimately, it is up to the researcher to determine which model is most appropriate to answer the research question.
Table 2. Animal Models of Asthma.
Table 2. Animal Models of Asthma.
AnimalStimuliPredominant Cell Type, ImmunopathologyCharacteristics Shared with Human AsthmaStrengthsLimitations
Inducible Models
Mouse
[17,18,19,37,275]
OVA +/− LPS, HDM,
Cockroach,
Alternaria alternata antigen, pollen		Eosinophils, Neutrophils
Th2-high and Th2-low asthma models are available, depending on sensitization/challenge conditions		Bronchoconstriction
Airway hyperresponsiveness
Goblet cell hyperplasia/↑ Mucus production
Airway smooth muscle hypertrophy
Subepithelial fibrosis		Low cost
Transgenic or gene-knockout strains
Short gestation length
Wide availability of mouse-specific reagents and assays		Lack of ability to model chronicity due to tolerance
Limited/indirect measures of pulmonary function, generally requires anesthesia
Guinea Pig
[85,276]
OVA, HDMEosinophils, Neutrophils
Th2-high asthma, IgE-mediated		Bronchoconstriction,
Airway hyperresponsiveness,
Goblet cell hyperplasia/↑ Mucus production
Subepithelial fibrosis		Low costNeutrophils are the primary phagocytes within alveoli (vs. alveolar macrophages)
Lack of ability to model chronicity due to tolerance
Rabbit
[122,123,277,278,279]		OVA,
Alternaria tenuis antigen		Eosinophils
Th2-high asthma, IgE-mediated		Bronchoconstriction,
Airway hyperresponsiveness		Low costSensitization can occur within 24 h of birth to optimize early and late airway responses
Rabbits have heterophils instead of neutrophils
Sheep
[140,143,146,147,280,281,282,283,284]		HDM,
Ascaris suum antigen		Eosinophils
Th2-high asthma, IgE-mediated		Bronchoconstriction
Airway hyperresponsiveness
↑ airway collagen deposition
↑ bronchial smooth muscle thickness
Goblet cell hyperplasia/↑ Mucus production		Similar placental physiology to humans
Body size and anatomy allow pulmonary function assessment in conscious animals and large BAL fluid volume/cell number
Lifespan is amenable to modeling chronic asthma		Cost
Limited species-specific assays and antibodies
Rat
[152,153,154]		OVA, HDMEosinophils
Th2-high asthma, IgE-mediated		Bronchoconstriction,
Airway hyperresponsiveness,
Goblet cell hyperplasia/↑ Mucus production		Low cost
Transgenic or gene-knockout strains
Short gestation length
Availability of rat-specific reagents and assays		Weak bronchoconstriction
Require high levels of antigen exposure
Limited/indirect measures of pulmonary function, generally requires anesthesia
Dog
[285]		Ascaris suum antigen,
Ragweed antigen,
Ozone		Neutrophils, Eosinophils
IgE-mediated		Airway hyperresponsivenessRelative low cost among other large animal modelsLimited species-specific assays and antibodies
Public concerns with laboratory testing on companion animals
Nonhuman Primates
[286,287,288]		Ozone,
Ascaris suum antigen, HDM, Pollen, Tobacco smoke
Eosinophil
Th2-high asthma, IgE-mediated		Bronchoconstriction
Airway hyperresponsiveness
↑ Mucus production
Subepithelial fibrosis
Upright, bipedal stance mirrors human posture to a greater extent than other quadruped species
Greater overlap in airway transcriptome between rhesus macaques and humans
Similarities in immune system compared to humans, many anti-human antibodies and reagents are cross-reactive with monkey antigens 		Cost,
Ethics of research involving nonhuman primates
Naturally Occurring Models
Cat
[205]		Dust/dust mites,
Smoke (tobacco or fireplace),
Pollen,
Household chemicals		Eosinophils
Th2-high asthma, IgE-mediated		Bronchoconstriction
Airway remodeling		Indoor client-owned cats have similar environmental exposures to their owners
Feline patients (no per diem fee) represent a recruitable population for testing novel therapeutics 		Limited species-specific assays and antibodies
Horse
[289,290]		Organic dust,
Lipopolysaccharide,
Fungal spores (e.g., Aspergillus sp.),
Pollen		Neutrophils, Mast cells,
Eosinophils, Mixed
Th2-low and Th2-high asthma		Bronchoconstriction
Airway hyperresponsiveness
Airway remodeling
Mucus production
Bronchial angiogenesis		Spontaneous disease with similar triggers
Pulmonary function testing can be performed at rest and during exercise
Repeated collection of airway samples (large volume/cell recovery) and flexible bronchoscopy and long lifespan enable extended longitudinal studies (years )
Equine patients (no per diem fee) represent a recruitable population for testing novel therapeutics 		Cost
Limited species-specific assays and antibodies

Author Contributions

Conceptualization, J.S.W.; data curation, J.S.W., M.K.S., B.C., R.B.; writing—original draft preparation, J.S.W.; writing—review and editing, J.S.W., M.K.S., B.C., R.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2022. Available online: www.ginasthma.org (accessed on 22 September 2022).
  2. Haley, K.J.; Sunday, M.E.; Wiggs, B.R.; Kozakewich, H.P.; Reilly, J.J.; Mentzer, S.J.; Sugarbaker, D.J.; Doerschuk, C.M.; Drazen, J.M. Inflammatory cell distribution within and along asthmatic airways. Am. J. Respir. Crit. Care Med. 1998, 158, 565–572. [Google Scholar] [CrossRef] [PubMed]
  3. Carter, P.M.; Heinly, T.L.; Yates, S.W.; Lieberman, P.L. Asthma: The irreversible airways disease. J. Investig. Allergol. Clin. Immunol. 1997, 7, 566–571. [Google Scholar] [PubMed]
  4. Paré, P.D.; Roberts, C.R.; Bai, T.R.; Wiggs, B.J. The functional consequences of airway remodeling in asthma. Monaldi Arch. Chest Dis. 1997, 52, 589–596. [Google Scholar] [PubMed]
  5. Vignola, A.M.; Chanez, P.; Campbell, A.M.; Souques, F.; Lebel, B.; Enander, I.; Bousquet, J. Airway inflammation in mild intermittent and in persistent asthma. Am. J. Respir. Crit. Care Med. 1998, 157, 403–409. [Google Scholar] [CrossRef] [PubMed]
  6. McDowell, P.J.; Heaney, L.G. Different endotypes and phenotypes drive the heterogeneity in severe asthma. Allergy 2020, 75, 302–310. [Google Scholar] [CrossRef]
  7. Licari, A.; Castagnoli, R.; Brambilla, I.; Marseglia, A.; Tosca, M.A.; Marseglia, G.L.; Ciprandi, G. Asthma Endotyping and Biomarkers in Childhood Asthma. Pediatr. Allergy Immunol. Pulmonol. 2018, 31, 44–55. [Google Scholar] [CrossRef] [PubMed]
  8. Kuruvilla, M.E.; Lee, F.E.; Lee, G.B. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clin. Rev. Allergy Immunol. 2019, 56, 219–233. [Google Scholar] [CrossRef]
  9. Schoettler, N.; Strek, M.E. Recent Advances in Severe Asthma: From Phenotypes to Personalized Medicine. Chest 2020, 157, 516–528. [Google Scholar] [CrossRef] [PubMed]
  10. Papapostolou, N.; Makris, M. Allergic Asthma in the Era of Personalized Medicine. J. Pers. Med. 2022, 12, 1162. [Google Scholar] [CrossRef]
  11. Bates, J.H.; Rincon, M.; Irvin, C.G. Animal models of asthma. Am. J. Physiol. Cell. Mol. Physiol. 2009, 297, L401–L410. [Google Scholar] [CrossRef]
  12. Shin, Y.S.; Takeda, K.; Gelfand, E.W. Understanding asthma using animal models. Allergy Asthma Immunol. Res. 2009, 1, 10–18. [Google Scholar] [CrossRef] [PubMed]
  13. Chapman, D.G.; Tully, J.E.; Nolin, J.D.; Janssen-Heininger, Y.M.; Irvin, C.G. Animal models of allergic airways disease: Where are we and where to next? J. Cell. Biochem. 2014, 115, 2055–2064. [Google Scholar] [CrossRef] [PubMed]
  14. Mullane, K.; Williams, M. Animal models of asthma: Reprise or reboot? Biochem. Pharm. 2014, 87, 131–139. [Google Scholar] [CrossRef] [PubMed]
  15. Aun, M.V.; Bonamichi-Santos, R.; Arantes-Costa, F.M.; Kalil, J.; Giavina-Bianchi, P. Animal models of asthma: Utility and limitations. J. Asthma Allergy 2017, 10, 293–301. [Google Scholar] [CrossRef] [PubMed]
  16. Kung, T.T.; Jones, H.; Adams, G.K., 3rd; Umland, S.P.; Kreutner, W.; Egan, R.W.; Chapman, R.W.; Watnick, A.S. Characterization of a murine model of allergic pulmonary inflammation. Int. Arch. Allergy Immunol. 1994, 105, 83–90. [Google Scholar] [CrossRef] [PubMed]
  17. Brusselle, G.G.; Kips, J.C.; Tavernier, J.H.; van der Heyden, J.G.; Cuvelier, C.A.; Pauwels, R.A.; Bluethmann, H. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin. Exp. Allergy 1994, 24, 73–80. [Google Scholar] [CrossRef] [PubMed]
  18. Gavett, S.H.; Chen, X.; Finkelman, F.; Wills-Karp, M. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am. J. Respir. Cell Mol. Biol. 1994, 10, 587–593. [Google Scholar] [CrossRef] [PubMed]
  19. Lukacs, N.W.; Strieter, R.M.; Chensue, S.W.; Kunkel, S.L. Interleukin-4-dependent pulmonary eosinophil infiltration in a murine model of asthma. Am. J. Respir. Cell Mol. Biol. 1994, 10, 526–532. [Google Scholar] [CrossRef] [PubMed]
  20. Wimmer, M.; Alessandrini, F.; Gilles, S.; Frank, U.; Oeder, S.; Hauser, M.; Ring, J.; Ferreira, F.; Ernst, D.; Winkler, J.B.; et al. Pollen-derived adenosine is a necessary cofactor for ragweed allergy. Allergy 2015, 70, 944–954. [Google Scholar] [CrossRef]
  21. Yee, M.C.; Nichols, H.L.; Polley, D.; Saifeddine, M.; Pal, K.; Lee, K.; Wilson, E.H.; Daines, M.O.; Hollenberg, M.D.; Boitano, S.; et al. Protease-activated receptor-2 signaling through β-arrestin-2 mediates Alternaria alkaline serine protease-induced airway inflammation. Am. J. Physiol. Cell. Mol. Physiol. 2018, 315, L1042–L1057. [Google Scholar] [CrossRef]
  22. Yasuda, Y.; Nagano, T.; Kobayashi, K.; Nishimura, Y. Group 2 Innate Lymphoid Cells and the House Dust Mite-Induced Asthma Mouse Model. Cells 2020, 9, 1178. [Google Scholar] [CrossRef] [PubMed]
  23. Arizmendi, N.G.; Abel, M.; Puttagunta, L.; Asaduzzaman, M.; Davidson, C.; Karimi, K.; Forsythe, P.; Vliagoftis, H. Mucosal exposure to cockroach extract induces allergic sensitization and allergic airway inflammation. Allergy Asthma Clin. Immunol. 2011, 7, 22. [Google Scholar] [CrossRef] [PubMed]
  24. Tjota, M.Y.; Hrusch, C.L.; Blaine, K.M.; Williams, J.W.; Barrett, N.A.; Sperling, A.I. Signaling through FcRγ-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses. J. Allergy Clin. Immunol. 2014, 134, 706–713.e708. [Google Scholar] [CrossRef] [PubMed]
  25. Oeder, S.; Alessandrini, F.; Wirz, O.F.; Braun, A.; Wimmer, M.; Frank, U.; Hauser, M.; Durner, J.; Ferreira, F.; Ernst, D.; et al. Pollen-derived nonallergenic substances enhance Th2-induced IgE production in B cells. Allergy 2015, 70, 1450–1460. [Google Scholar] [CrossRef]
  26. McAllen, M.K.; Assem, E.S.; Maunsell, K. House-dust mite asthma. Results of challenge tests on five criteria with Dermatophagoides pteronyssinus. Br. Med. J. 1970, 2, 501–504. [Google Scholar] [CrossRef]
  27. Johnson, J.R.; Wiley, R.E.; Fattouh, R.; Swirski, F.K.; Gajewska, B.U.; Coyle, A.J.; Gutierrez-Ramos, J.C.; Ellis, R.; Inman, M.D.; Jordana, M. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am. J. Respir. Crit. Care Med. 2004, 169, 378–385. [Google Scholar] [CrossRef] [PubMed]
  28. Ulrich, K.; Hincks, J.S.; Walsh, R.; Wetterstrand, E.M.; Fidock, M.D.; Sreckovic, S.; Lamb, D.J.; Douglas, G.J.; Yeadon, M.; Perros-Huguet, C.; et al. Anti-inflammatory modulation of chronic airway inflammation in the murine house dust mite model. Pulm. Pharmacol. Ther. 2008, 21, 637–647. [Google Scholar] [CrossRef]
  29. Nials, A.T.; Uddin, S. Mouse models of allergic asthma: Acute and chronic allergen challenge. Dis. Model. Mech. 2008, 1, 213–220. [Google Scholar] [CrossRef] [PubMed]
  30. Barends, M.; de Rond, L.G.; Dormans, J.; van Oosten, M.; Boelen, A.; Neijens, H.J.; Osterhaus, A.D.; Kimman, T.G. Respiratory syncytial virus, pneumonia virus of mice, and influenza A virus differently affect respiratory allergy in mice. Clin. Exp. Allergy 2004, 34, 488–496. [Google Scholar] [CrossRef] [PubMed]
  31. Ravanetti, L.; Dijkhuis, A.; Sabogal Pineros, Y.S.; Bal, S.M.; Dierdorp, B.S.; Dekker, T.; Logiantara, A.; Adcock, I.M.; Rao, N.L.; Boon, L.; et al. An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model. Allergy 2017, 72, 737–753. [Google Scholar] [CrossRef] [PubMed]
  32. Doorley, L.A.; LeMessurier, K.S.; Iverson, A.R.; Palipane, M.; Samarasinghe, A.E. Humoral immune responses during asthma and influenza co-morbidity in mice. Immunobiology 2017, 222, 1064–1073. [Google Scholar] [CrossRef] [PubMed]
  33. Mahmutovic Persson, I.; Menzel, M.; Ramu, S.; Cerps, S.; Akbarshahi, H.; Uller, L. IL-1β mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation. Respir. Res. 2018, 19, 16. [Google Scholar] [CrossRef] [PubMed]
  34. Kantor, D.B.; Stenquist, N.; McDonald, M.C.; Schultz, B.J.; Hauptman, M.; Smallwood, C.D.; Nelson, K.A.; Perzanowski, M.S.; Matsui, E.C.; Phipatanakul, W.; et al. Rhinovirus and serum IgE are associated with acute asthma exacerbation severity in children. J. Allergy Clin. Immunol. 2016, 138, 1467–1471.e1469. [Google Scholar] [CrossRef] [PubMed]
  35. Hu, X.; Li, X.; Hu, C.; Qin, L.; He, R.; Luo, L.; Tang, W.; Feng, J. Respiratory Syncytial Virus Exacerbates OVA-mediated asthma in mice through C5a-C5aR regulating CD4(+)T cells Immune Responses. Sci. Rep. 2017, 7, 15207. [Google Scholar] [CrossRef] [PubMed]
  36. Akkoc, T.; O′Mahony, L.; Ferstl, R.; Akdis, C.; Akkoc, T. Mouse Models of Asthma: Characteristics, Limitations and Future Perspectives on Clinical Translation. Adv. Exp. Med. Biol. 2022, 1376, 119–133. [Google Scholar]
  37. Alessandrini, F.; Musiol, S.; Schneider, E.; Blanco-Pérez, F.; Albrecht, M. Mimicking Antigen-Driven Asthma in Rodent Models-How Close Can We Get? Front. Immunol. 2020, 11, 575936. [Google Scholar] [CrossRef]
  38. Maltby, S.; Tay, H.L.; Yang, M.; Foster, P.S. Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation. Respirology 2017, 22, 874–885. [Google Scholar] [CrossRef]
  39. Persson, C.G.; Erjefält, J.S.; Korsgren, M.; Sundler, F. The mouse trap. Trends Pharmacol. Sci. 1997, 18, 465–467. [Google Scholar] [CrossRef]
  40. Kumar, R.K.; Foster, P.S. Are mouse models of asthma appropriate for investigating the pathogenesis of airway hyper-responsiveness? Front. Physiol. 2012, 3, 312. [Google Scholar] [CrossRef] [PubMed]
  41. Bousquet, J.; Jeffery, P.K.; Busse, W.W.; Johnson, M.; Vignola, A.M. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2000, 161, 1720–1745. [Google Scholar] [CrossRef] [PubMed]
  42. Birrell, M.A.; Battram, C.H.; Woodman, P.; McCluskie, K.; Belvisi, M.G. Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways. Respir. Res. 2003, 4, 3. [Google Scholar] [CrossRef]
  43. McMillan, S.J.; Lloyd, C.M. Prolonged allergen challenge in mice leads to persistent airway remodelling. Clin. Exp. Allergy 2004, 34, 497–507. [Google Scholar] [CrossRef]
  44. Herz, U.; Renz, H.; Wiedermann, U. Animal models of type I allergy using recombinant allergens. Methods 2004, 32, 271–280. [Google Scholar] [CrossRef]
  45. Van Hove, C.L.; Maes, T.; Cataldo, D.D.; Guéders, M.M.; Palmans, E.; Joos, G.F.; Tournoy, K.G. Comparison of acute inflammatory and chronic structural asthma-like responses between C57BL/6 and BALB/c mice. Int. Arch. Allergy Immunol. 2009, 149, 195–207. [Google Scholar] [CrossRef] [PubMed]
  46. Duez, C.; Tsicopoulos, A.; Janin, A.; Tillie-Leblond, I.; Thyphronitis, G.; Marquillies, P.; Hamid, Q.; Wallaert, B.; Tonnel, A.B.; Pestel, J. An in vivo model of allergic inflammation: Pulmonary human cell infiltrate in allergen-challenged allergic Hu-SCID mice. Eur. J. Immunol. 1996, 26, 1088–1093. [Google Scholar] [CrossRef] [PubMed]
  47. Perros, F.; Hoogsteden, H.C.; Coyle, A.J.; Lambrecht, B.N.; Hammad, H. Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy 2009, 64, 995–1002. [Google Scholar] [CrossRef] [PubMed]
  48. Shultz, L.D.; Ishikawa, F.; Greiner, D.L. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 2007, 7, 118–130. [Google Scholar] [CrossRef] [PubMed]
  49. Yang, M.; Kumar, R.K.; Foster, P.S. Pathogenesis of steroid-resistant airway hyperresponsiveness: Interaction between IFN-gamma and TLR4/MyD88 pathways. J. Immunol. 2009, 182, 5107–5115. [Google Scholar] [CrossRef] [PubMed]
  50. McKinley, L.; Alcorn, J.F.; Peterson, A.; Dupont, R.B.; Kapadia, S.; Logar, A.; Henry, A.; Irvin, C.G.; Piganelli, J.D.; Ray, A.; et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 2008, 181, 4089–4097. [Google Scholar] [CrossRef]
  51. Epstein, M.M. Do mouse models of allergic asthma mimic clinical disease? Int. Arch. Allergy Immunol. 2004, 133, 84–100. [Google Scholar] [CrossRef]
  52. Hessel, E.M.; Zwart, A.; Oostveen, E.; Van Oosterhout, A.J.; Blyth, D.I.; Nijkamp, F.P. Repeated measurement of respiratory function and bronchoconstriction in unanesthetized mice. J. Appl. Physiol. 1985 1995, 79, 1711–1716. [Google Scholar] [CrossRef] [PubMed]
  53. Janssen, E.M.; van Oosterhout, A.J.; Nijkamp, F.P.; van Eden, W.; Wauben, M.H. The efficacy of immunotherapy in an experimental murine model of allergic asthma is related to the strength and site of T cell activation during immunotherapy. J. Immunol. 2000, 165, 7207–7214. [Google Scholar] [CrossRef] [PubMed]
  54. Blyth, D.I.; Wharton, T.F.; Pedrick, M.S.; Savage, T.J.; Sanjar, S. Airway subepithelial fibrosis in a murine model of atopic asthma: Suppression by dexamethasone or anti-interleukin-5 antibody. Am. J. Respir. Cell Mol. Biol. 2000, 23, 241–246. [Google Scholar] [CrossRef]
  55. Choi, I.W.; Sun, K.; Kim, Y.S.; Ko, H.M.; Im, S.Y.; Kim, J.H.; You, H.J.; Lee, Y.C.; Lee, J.H.; Park, Y.M.; et al. TNF-alpha induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A(2) activation. J. Allergy Clin. Immunol. 2005, 116, 537–543. [Google Scholar] [CrossRef] [PubMed]
  56. Fernandez-Rodriguez, S.; Ford, W.R.; Broadley, K.J.; Kidd, E.J. Establishing the phenotype in novel acute and chronic murine models of allergic asthma. Int. Immunopharmacol. 2008, 8, 756–763. [Google Scholar] [CrossRef] [PubMed]
  57. Henderson, W.R., Jr.; Lewis, D.B.; Albert, R.K.; Zhang, Y.; Lamm, W.J.; Chiang, G.K.; Jones, F.; Eriksen, P.; Tien, Y.T.; Jonas, M.; et al. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J. Exp. Med. 1996, 184, 1483–1494. [Google Scholar] [CrossRef] [PubMed]
  58. Hamelmann, E.; Cieslewicz, G.; Schwarze, J.; Ishizuka, T.; Joetham, A.; Heusser, C.; Gelfand, E.W. Anti-interleukin 5 but not anti-IgE prevents airway inflammation and airway hyperresponsiveness. Am. J. Respir. Crit. Care Med. 1999, 160, 934–941. [Google Scholar] [CrossRef]
  59. Tomkinson, A.; Duez, C.; Cieslewicz, G.; Pratt, J.C.; Joetham, A.; Shanafelt, M.C.; Gundel, R.; Gelfand, E.W. A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J. Immunol. 2001, 166, 5792–5800. [Google Scholar] [CrossRef]
  60. Lloyd, C.M.; Gonzalo, J.A.; Nguyen, T.; Delaney, T.; Tian, J.; Oettgen, H.; Coyle, A.J.; Gutierrez-Ramos, J.C. Resolution of bronchial hyperresponsiveness and pulmonary inflammation is associated with IL-3 and tissue leukocyte apoptosis. J. Immunol. 2001, 166, 2033–2040. [Google Scholar] [CrossRef]
  61. McMillan, S.J.; Bishop, B.; Townsend, M.J.; McKenzie, A.N.; Lloyd, C.M. The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J. Exp. Med. 2002, 195, 51–57. [Google Scholar] [CrossRef]
  62. McMillan, S.J.; Xanthou, G.; Lloyd, C.M. Therapeutic administration of Budesonide ameliorates allergen-induced airway remodelling. Clin. Exp. Allergy 2005, 35, 388–396. [Google Scholar] [CrossRef] [PubMed]
  63. Kanehiro, A.; Ikemura, T.; Mäkelä, M.J.; Lahn, M.; Joetham, A.; Dakhama, A.; Gelfand, E.W. Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. Am. J. Respir. Crit. Care Med. 2001, 163, 173–184. [Google Scholar] [CrossRef] [PubMed]
  64. Tournoy, K.G.; Kips, J.C.; Schou, C.; Pauwels, R.A. Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness. Clin. Exp. Allergy 2000, 30, 79–85. [Google Scholar] [CrossRef] [PubMed]
  65. Immormino, R.M.; Jania, C.M.; Tilley, S.L.; Moran, T.P. Neuropilin-2 regulates airway inflammation in a neutrophilic asthma model. Immun. Inflamm. Dis. 2022, 10, e575. [Google Scholar] [CrossRef] [PubMed]
  66. Sarpong, S.B.; Zhang, L.Y.; Kleeberger, S.R. A novel mouse model of experimental asthma. Int. Arch. Allergy Immunol. 2003, 132, 346–354. [Google Scholar] [CrossRef] [PubMed]
  67. Lambrecht, B.N.; De Veerman, M.; Coyle, A.J.; Gutierrez-Ramos, J.C.; Thielemans, K.; Pauwels, R.A. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Investig. 2000, 106, 551–559. [Google Scholar] [CrossRef] [PubMed]
  68. Temelkovski, J.; Hogan, S.P.; Shepherd, D.P.; Foster, P.S.; Kumar, R.K. An improved murine model of asthma: Selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax 1998, 53, 849–856. [Google Scholar] [CrossRef] [PubMed]
  69. Henderson, W.R., Jr.; Tang, L.O.; Chu, S.J.; Tsao, S.M.; Chiang, G.K.; Jones, F.; Jonas, M.; Pae, C.; Wang, H.; Chi, E.Y. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am. J. Respir. Crit. Care Med. 2002, 165, 108–116. [Google Scholar] [CrossRef] [PubMed]
  70. Leigh, R.; Ellis, R.; Wattie, J.; Southam, D.S.; De Hoogh, M.; Gauldie, J.; O′Byrne, P.M.; Inman, M.D. Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation. Am. J. Respir. Cell Mol. Biol. 2002, 27, 526–535. [Google Scholar] [CrossRef] [PubMed]
  71. Lee, S.Y.; Kim, J.S.; Lee, J.M.; Kwon, S.S.; Kim, K.H.; Moon, H.S.; Song, J.S.; Park, S.H.; Kim, Y.K. Inhaled corticosteroid prevents the thickening of airway smooth muscle in murine model of chronic asthma. Pulm. Pharmacol. Ther. 2008, 21, 14–19. [Google Scholar] [CrossRef]
  72. McGovern, T.K.; Robichaud, A.; Fereydoonzad, L.; Schuessler, T.F.; Martin, J.G. Evaluation of respiratory system mechanics in mice using the forced oscillation technique. J. Vis. Exp. 2013, 75, e50172. [Google Scholar]
  73. Bonnardel, E.; Prevel, R.; Campagnac, M.; Dubreuil, M.; Marthan, R.; Berger, P.; Dupin, I. Determination of reliable lung function parameters in intubated mice. Respir. Res. 2019, 20, 211. [Google Scholar] [CrossRef] [PubMed]
  74. De Vleeschauwer, S.I.; Rinaldi, M.; De Vooght, V.; Vanoirbeek, J.A.; Vanaudenaerde, B.M.; Verbeken, E.K.; Decramer, M.; Gayan-Ramirez, G.N.; Verleden, G.M.; Janssens, W. Repeated invasive lung function measurements in intubated mice: An approach for longitudinal lung research. Lab. Anim. 2011, 45, 81–89. [Google Scholar] [CrossRef] [PubMed]
  75. Glaab, T.; Braun, A. Noninvasive Measurement of Pulmonary Function in Experimental Mouse Models of Airway Disease. Lung 2021, 199, 255–261. [Google Scholar] [CrossRef]
  76. Hyde, D.M.; Miller, L.A.; Schelegle, E.S.; Fanucchi, M.V.; Van Winkle, L.S.; Tyler, N.K.; Avdalovic, M.V.; Evans, M.J.; Kajekar, R.; Buckpitt, A.R.; et al. Asthma: A comparison of animal models using stereological methods. Eur. Respir. Rev. 2006, 15, 122–135. [Google Scholar] [CrossRef]
  77. Malm-Erjefält, M.; Persson, C.G.; Erjefält, J.S. Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 2001, 24, 352–359. [Google Scholar] [CrossRef] [PubMed]
  78. De Bie, J.J.; Henricks, P.A.; Cruikshank, W.W.; Hofman, G.; Jonker, E.H.; Nijkamp, F.P.; Van Oosterhout, A.J. Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5-HT receptor antagonists in a mouse model of allergic asthma. Br. J. Pharmacol. 1998, 124, 857–864. [Google Scholar] [CrossRef]
  79. Auer, J.; Lewis, P.A. The Physiology of the Immediate Reaction of Anaphylaxis in the Guinea-Pig. J. Exp. Med. 1910, 12, 151–175. [Google Scholar] [CrossRef]
  80. Meurs, H.; Santing, R.E.; Remie, R.; van der Mark, T.W.; Westerhof, F.J.; Zuidhof, A.B.; Bos, I.S.; Zaagsma, J. A guinea pig model of acute and chronic asthma using permanently instrumented and unrestrained animals. Nat. Protoc. 2006, 1, 840–847. [Google Scholar] [CrossRef] [PubMed]
  81. Iijima, H.; Ishii, M.; Yamauchi, K.; Chao, C.L.; Kimura, K.; Shimura, S.; Shindoh, Y.; Inoue, H.; Mue, S.; Takishima, T. Bronchoalveolar lavage and histologic characterization of late asthmatic response in guinea pigs. Am. Rev. Respir. Dis. 1987, 136, 922–929. [Google Scholar] [CrossRef]
  82. Hutson, P.A.; Church, M.K.; Clay, T.P.; Miller, P.; Holgate, S.T. Early and late-phase bronchoconstriction after allergen challenge of nonanesthetized guinea pigs. I. The association of disordered airway physiology to leukocyte infiltration. Am. Rev. Respir. Dis. 1988, 137, 548–557. [Google Scholar] [CrossRef] [PubMed]
  83. Santing, R.E.; Olymulder, C.G.; Zaagsma, J.; Meurs, H. Relationships among allergen-induced early and late phase airway obstructions, bronchial hyperreactivity, and inflammation in conscious, unrestrained guinea pigs. J. Allergy Clin. Immunol. 1994, 93, 1021–1030. [Google Scholar] [CrossRef]
  84. Sanjar, S.; Aoki, S.; Kristersson, A.; Smith, D.; Morley, J. Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitized guinea-pigs: The effect of anti-asthma drugs. Br. J. Pharmacol. 1990, 99, 679–686. [Google Scholar] [CrossRef] [PubMed]
  85. Boichot, E.; Lagente, V.; Carre, C.; Waltmann, P.; Mencia-Huerta, J.M.; Braquet, P. Bronchial hyperresponsiveness and cellular infiltration in the lung of guinea-pigs sensitized and challenged by aerosol. Clin. Exp. Allergy 1991, 21, 67–76. [Google Scholar] [CrossRef]
  86. Andersson, P. Antigen-induced bronchial anaphylaxis in actively sensitized guinea-pigs. Pattern of response in relation to immunization regimen. Allergy 1980, 35, 65–71. [Google Scholar] [CrossRef] [PubMed]
  87. Smith, N.; Broadley, K.J. Optimisation of the sensitisation conditions for an ovalbumin challenge model of asthma. Int. Immunopharmacol. 2007, 7, 183–190. [Google Scholar] [CrossRef] [PubMed]
  88. Evans, R.L.; Nials, A.T.; Knowles, R.G.; Kidd, E.J.; Ford, W.R.; Broadley, K.J. A comparison of antiasthma drugs between acute and chronic ovalbumin-challenged guinea-pig models of asthma. Pulm. Pharmacol. Ther. 2012, 25, 453–464. [Google Scholar] [CrossRef]
  89. Lowe, A.P.P.; Thomas, R.S.; Nials, A.T.; Kidd, E.J.; Broadley, K.J.; Ford, W.R. Route of Administration Affects Corticosteroid Sensitivity of a Combined Ovalbumin and Lipopolysaccharide Model of Asthma Exacerbation in Guinea Pigs. J. Pharmacol. Exp. Ther. 2017, 362, 327–337. [Google Scholar] [CrossRef]
  90. Nabe, T.; Shinoda, N.; Yamada, M.; Sekioka, T.; Saeki, Y.; Yamamura, H.; Kohno, S. Repeated antigen inhalation-induced reproducible early and late asthma in guinea pigs. Jpn. J. Pharmacol. 1997, 75, 65–75. [Google Scholar] [CrossRef] [PubMed]
  91. Park, J.K.; Kim, Y.K.; Lee, S.R.; Cho, S.H.; Min, K.U.; Kim, Y.Y. Repeated exposure to low levels of sulfur dioxide (SO2) enhances the development of ovalbumin-induced asthmatic reactions in guinea pigs. Ann. Allergy Asthma Immunol. 2001, 86, 62–67. [Google Scholar] [CrossRef]
  92. Hori, M.; Iwama, T.; Asakura, Y.; Kawanishi, M.; Kamon, J.; Hoshino, A.; Takahashi, S.; Takahashi, K.; Nakaike, S.; Tsuruzoe, N. NT-702 (parogrelil hydrochloride, NM-702), a novel and potent phosphodiesterase 3 inhibitor, suppress the asthmatic response in guinea pigs, with both bronchodilating and anti-inflammatory effects. Eur. J. Pharmacol. 2009, 618, 63–69. [Google Scholar] [CrossRef]
  93. Ramos-Ramírez, P.; Noreby, M.; Liu, J.; Ji, J.; Abdillahi, S.M.; Olsson, H.; Dahlén, S.E.; Nilsson, G.; Adner, M. A new house dust mite-driven and mast cell-activated model of asthma in the guinea pig. Clin. Exp. Allergy 2020, 50, 1184–1195. [Google Scholar] [CrossRef]
  94. Adams, G.K., 3rd; Lichtenstein, L.M. Antagonism of antigen-induced contraction of guinea pig and human airways. Nature 1977, 270, 255–257. [Google Scholar] [CrossRef]
  95. Björck, T.; Dahlén, S.E. Leukotrienes and histamine mediate IgE-dependent contractions of human bronchi: Pharmacological evidence obtained with tissues from asthmatic and non-asthmatic subjects. Pulm. Pharmacol. 1993, 6, 87–96. [Google Scholar] [CrossRef]
  96. Ellis, J.L.; Hubbard, W.C.; Meeker, S.; Undem, B.J. Ragweed antigen E and anti-IgE in human central versus peripheral isolated bronchi. Am. J. Respir. Crit. Care Med. 1994, 150, 717–723. [Google Scholar] [CrossRef] [PubMed]
  97. Roquet, A.; Dahlén, B.; Kumlin, M.; Ihre, E.; Anstrén, G.; Binks, S.; Dahlén, S.E. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am. J. Respir. Crit. Care Med. 1997, 155, 1856–1863. [Google Scholar] [CrossRef] [PubMed]
  98. Lamm, W.J.; Lai, Y.L.; Hildebrandt, J. Histamine and leukotrienes mediate pulmonary hypersensitivity to antigen in guinea pigs. J. Appl. Phys. Respir Environ Exerc Phys. 1984, 56, 1032–1038. [Google Scholar] [CrossRef] [PubMed]
  99. Ressmeyer, A.R.; Larsson, A.K.; Vollmer, E.; Dahlèn, S.E.; Uhlig, S.; Martin, C. Characterisation of guinea pig precision-cut lung slices: Comparison with human tissues. Eur. Respir. J. 2006, 28, 603–611. [Google Scholar] [CrossRef] [PubMed]
  100. Yu, L.; Liu, Q.; Canning, B.J. Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways. Eur. J. Pharmacol. 2018, 822, 108–118. [Google Scholar] [CrossRef] [PubMed]
  101. Hay, D.W.; Muccitelli, R.M.; Tucker, S.S.; Vickery-Clark, L.M.; Wilson, K.A.; Gleason, J.G.; Hall, R.F.; Wasserman, M.A.; Torphy, T.J. Pharmacologic profile of SK&F 104353: A novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways. J. Pharmacol. Exp. Ther. 1987, 243, 474–481. [Google Scholar] [PubMed]
  102. Krell, R.D.; Aharony, D.; Buckner, C.K.; Keith, R.A.; Kusner, E.J.; Snyder, D.W.; Bernstein, P.R.; Matassa, V.G.; Yee, Y.K.; Brown, F.J.; et al. The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist. Am. Rev. Respir. Dis. 1990, 141 Pt 1, 978–987. [Google Scholar] [CrossRef]
  103. Krell, R.D.; Kusner, E.J.; Aharony, D.; Giles, R.E. Biochemical and pharmacological characterization of ICI 198,615: A peptide leukotriene receptor antagonist. Eur. J. Pharmacol. 1989, 159, 73–81. [Google Scholar] [CrossRef] [PubMed]
  104. Ishii, A.; Nakagawa, T.; Nambu, F.; Motoishi, M.; Miyamoto, T. Inhibition of endogenous leukotriene-mediated lung anaphylaxis in guinea pigs by a novel receptor antagonist ONO-1078. Int. Arch. Allergy Appl. Immunol. 1990, 92, 404–407. [Google Scholar] [CrossRef] [PubMed]
  105. Nakagawa, N.; Obata, T.; Kobayashi, T.; Okada, Y.; Nambu, F.; Terawaki, T.; Aishita, H. In vivo pharmacologic profile of ONO-1078: A potent, selective and orally active peptide leukotriene (LT) antagonist. Jpn. J. Pharmacol. 1992, 60, 217–225. [Google Scholar] [CrossRef] [PubMed]
  106. Yamaguchi, T.; Kohrogi, H.; Honda, I.; Kawano, O.; Sugimoto, M.; Araki, S.; Ando, M. A novel leukotriene antagonist, ONO-1078, inhibits and reverses human bronchial contraction induced by leukotrienes C4 and D4 and antigen in vitro. Am. Rev. Respir. Dis. 1992, 146, 923–929. [Google Scholar] [CrossRef] [PubMed]
  107. Malo, P.E.; Bell, R.L.; Shaughnessy, T.K.; Summers, J.B.; Brooks, D.W.; Carter, G.W. The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis. Pulm. Pharmacol. 1994, 7, 73–79. [Google Scholar] [CrossRef]
  108. Jones, T.R.; Labelle, M.; Belley, M.; Champion, E.; Charette, L.; Evans, J.; Ford-Hutchinson, A.W.; Gauthier, J.Y.; Lord, A.; Masson, P.; et al. Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist. Can. J. Physiol. Pharmacol. 1995, 73, 191–201. [Google Scholar] [CrossRef]
  109. Spina, D.; Ferlenga, P.; Biasini, I.; Moriggi, E.; Marchini, F.; Semeraro, C.; Page, C.P. The effect duration of selective phosphodiesterase inhibitors in the guinea pig. Life Sci. 1998, 62, 953–965. [Google Scholar] [CrossRef]
  110. Boswell-Smith, V.; Spina, D.; Oxford, A.W.; Comer, M.B.; Seeds, E.A.; Page, C.P. The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J. Pharmacol. Exp. Ther. 2006, 318, 840–848. [Google Scholar]
  111. Franciosi, L.G.; Diamant, Z.; Banner, K.H.; Zuiker, R.; Morelli, N.; Kamerling, I.M.; de Kam, M.L.; Burggraaf, J.; Cohen, A.F.; Cazzola, M.; et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: Findings from four clinical trials. Lancet Respir. Med. 2013, 1, 714–727. [Google Scholar] [CrossRef]
  112. Brewer, N.R.; Cruise, L.J. The Respiratory System of the Guinea Pig: Emphasis on Species Differences. Contemp. Top. Lab. Anim. Sci. 1997, 36, 100–108. [Google Scholar]
  113. Popa, V.; Douglas, J.S.; Bouhuys, A. Airway responses to histamine, acetylcholine, and antigen in sensitized guinea pigs. J. Lab. Clin. Med. 1974, 84, 225–234. [Google Scholar] [PubMed]
  114. Lewis, C.A.; Broadley, K.J. Airway hyper- or hyporeactivity to inhaled spasmogens 24 h after ovalbumin challenge of sensitized guinea-pigs. Br. J. Pharmacol. 1995, 116, 2351–2358. [Google Scholar] [CrossRef] [PubMed]
  115. Pretolani, M.; Vargaftig, B.B. From lung hypersensitivity to bronchial hyperreactivity. What can we learn from studies on animal models? Biochem. Pharmacol. 1993, 45, 791–800. [Google Scholar] [CrossRef] [PubMed]
  116. Tree, J.A.; Elmore, M.J.; Javed, S.; Williams, A.; Marsh, P.D. Development of a guinea pig immune response-related microarray and its use to define the host response following Mycobacterium bovis BCG vaccination. Infect. Immun. 2006, 74, 1436–1441. [Google Scholar] [CrossRef] [PubMed]
  117. Jain, R.; Dey, B.; Tyagi, A.K. Development of the first oligonucleotide microarray for global gene expression profiling in guinea pigs: Defining the transcription signature of infectious diseases. BMC Genom. 2012, 13, 520. [Google Scholar] [CrossRef]
  118. Gillis, P.A.; Hernandez-Alvarado, N.; Gnanandarajah, J.S.; Wussow, F.; Diamond, D.J.; Schleiss, M.R. Development of a novel, guinea pig-specific IFN-γ ELISPOT assay and characterization of guinea pig cytomegalovirus GP83-specific cellular immune responses following immunization with a modified vaccinia virus Ankara (MVA)-vectored GP83 vaccine. Vaccine 2014, 32, 3963–3970. [Google Scholar] [CrossRef]
  119. Lasco, T.M.; Gonzalez-Juarrero, M.; Saalmüller, A.; Lunney, J.K. Cross-reaction of anti-human CD monoclonal antibodies on guinea pig cells: A summary of the guinea pig section of the HLDA8 animal homologues data. Vet. Immunol. Immunopathol. 2007, 119, 131–136. [Google Scholar] [CrossRef]
  120. Schäfer, H.; Burger, R. Tools for cellular immunology and vaccine research the in the guinea pig: Monoclonal antibodies to cell surface antigens and cell lines. Vaccine 2012, 30, 5804–5811. [Google Scholar] [CrossRef]
  121. Adner, M.; Canning, B.J.; Meurs, H.; Ford, W.; Ramos Ramírez, P.; van den Berg, M.P.M.; Birrell, M.A.; Stoffels, E.; Lundblad, L.K.A.; Nilsson, G.P.; et al. Back to the future: Re-establishing guinea pig in vivo asthma models. Clin. Sci (Lond). 2020, 134, 1219–1242. [Google Scholar] [CrossRef]
  122. Shampain, M.P.; Behrens, B.L.; Larsen, G.L.; Henson, P.M. An animal model of late pulmonary responses to Alternaria challenge. Am. Rev. Respir. Dis. 1982, 126, 493–498. [Google Scholar]
  123. Minshall, E.M.; Riccio, M.M.; Herd, C.M.; Douglas, G.J.; Seeds, E.A.; McKenniff, M.G.; Sasaki, M.; Spina, D.; Page, C.P. A novel animal model for investigating persistent airway hyperresponsiveness. J. Pharmacol. Toxicol. Methods 1993, 30, 177–188. [Google Scholar] [CrossRef]
  124. Keir, S.D.; Spina, D.; Douglas, G.; Herd, C.; Page, C.P. Airway responsiveness in an allergic rabbit model. J. Pharmacol. Toxicol. Methods 2011, 64, 187–195. [Google Scholar] [CrossRef] [PubMed]
  125. Obiefuna, P.C.; Batra, V.K.; Nadeem, A.; Borron, P.; Wilson, C.N.; Mustafa, S.J. A novel A1 adenosine receptor antagonist, L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione], reduces allergic responses to house dust mite in an allergic rabbit model of asthma. J. Pharmacol. Exp. Ther. 2005, 315, 329–336. [Google Scholar] [CrossRef] [PubMed]
  126. Tiotiu, A.; Chenuel, B.; Foucaud, L.; Demoulin, B.; Demoulin-Alexikova, S.; Christov, C.; Poussel, M. Lack of desensitization of the cough reflex in ovalbumin-sensitized rabbits during exercise. PLoS ONE 2017, 12, e0171862. [Google Scholar] [CrossRef] [PubMed]
  127. Basin, S.; Valentin, S.; Demoulin-Alexikova, S.; Demoulin, B.; Foucaud, L.; Gérard, D.; Pouget, C.; Allado, E.; Chenuel, B.; Poussel, M. Impact of Inhaled Corticosteroids on the Modulation of Respiratory Defensive Reflexes During Artificial Limb Exercise in Ovalbumin-Sensitized Rabbits. Front. Physiol. 2021, 12, 804577. [Google Scholar] [CrossRef]
  128. Dos Santos Rocha, A.; Südy, R.; Peták, F.; Habre, W. Physiologically variable ventilation in a rabbit model of asthma exacerbation. Br. J. Anaesth. 2020, 125, 1107–1116. [Google Scholar] [CrossRef] [PubMed]
  129. Minshall, E.; Spina, D.; Page, C.P. Effects of neonatal immunization and repeated allergen exposure on airway responsiveness in the rabbit. J. Appl. Physiol (1985). 1996, 80, 2108–2119. [Google Scholar] [CrossRef]
  130. Zavala, D.C.; Rhodes, M.L. Selective bronchial catheterization for the study of experimental lung damage in the rabbit. Proc. Soc. Exp. Biol. Med. 1973, 144, 509–512. [Google Scholar] [CrossRef]
  131. Herd, C.M.; Donigi-Gale, D.; Shoupe, T.S.; Burroughs, D.; Yeadon, M.; Page, C.P. Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen-induced airway responses in neonatally immunized rabbits. Br. J. Pharmacol. 1994, 112, 292–298. [Google Scholar] [CrossRef]
  132. Herd, C.M.; Gozzard, N.; Page, C.P. Capsaicin pre-treatment prevents the development of antigen-induced airway hyperresponsiveness in neonatally immunised rabbits. Eur. J. Pharmacol. 1995, 282, 111–119. [Google Scholar] [CrossRef] [PubMed]
  133. Keir, S.; Page, C. The rabbit as a model to study asthma and other lung diseases. Pulm. Pharmacol. Ther. 2008, 21, 721–730. [Google Scholar] [CrossRef]
  134. Choi, H.K.; Finkbeiner, W.E.; Widdicombe, J.H. A comparative study of mammalian tracheal mucous glands. J. Anat. 2000, 197 Pt 3, 361–372. [Google Scholar] [CrossRef]
  135. Clifton, V.L.; Moss, T.J.; Wooldridge, A.L.; Gatford, K.L.; Liravi, B.; Kim, D.; Muhlhausler, B.S.; Morrison, J.L.; Davies, A.; De Matteo, R.; et al. Development of an experimental model of maternal allergic asthma during pregnancy. J. Physiol. 2016, 594, 1311–1325. [Google Scholar] [CrossRef]
  136. Clifton, V.L.; McDonald, M.; Morrison, J.L.; Holman, S.L.; Lock, M.C.; Saif, Z.; Meakin, A.; Wooldridge, A.L.; Gatford, K.L.; Wallace, M.J.; et al. Placental glucocorticoid receptor isoforms in a sheep model of maternal allergic asthma. Placenta 2019, 83, 33–36. [Google Scholar] [CrossRef]
  137. Meakin, A.S.; Morrison, J.L.; Bradshaw, E.L.; Holman, S.L.; Saif, Z.; Gatford, K.L.; Wallace, M.J.; Bischof, R.J.; Moss, T.J.M.; Clifton, V.L. Identification of placental androgen receptor isoforms in a sheep model of maternal allergic asthma. Placenta 2021, 104, 232–235. [Google Scholar] [CrossRef] [PubMed]
  138. Wooldridge, A.L.; Clifton, V.L.; Moss, T.J.M.; Lu, H.; Jamali, M.; Agostino, S.; Muhlhausler, B.S.; Morrison, J.L.; De Matteo, R.; Wallace, M.J.; et al. Maternal allergic asthma during pregnancy alters fetal lung and immune development in sheep: Potential mechanisms for programming asthma and allergy. J. Physiol. 2019, 597, 4251–4262. [Google Scholar] [CrossRef] [PubMed]
  139. Bischof, R.J.; Snibson, K.; Shaw, R.; Meeusen, E.N. Induction of allergic inflammation in the lungs of sensitized sheep after local challenge with house dust mite. Clin. Exp. Allergy 2003, 33, 367–375. [Google Scholar] [CrossRef] [PubMed]
  140. Snibson, K.J.; Bischof, R.J.; Slocombe, R.F.; Meeusen, E.N. Airway remodelling and inflammation in sheep lungs after chronic airway challenge with house dust mite. Clin. Exp. Allergy 2005, 35, 146–152. [Google Scholar] [CrossRef] [PubMed]
  141. Bischof, R.J.; Bourke, J.E.; Hirst, S.J.; Meeusen, E.N.; Snibson, K.J.; Van Der Velden, J. Measurement and impact of remodeling in the lung: Airway neovascularization in asthma. Proc. Am. Thorac. Soc. 2009, 6, 673–677. [Google Scholar] [CrossRef]
  142. Abraham, W.; Delehunt, J.; Yerger, L.; Marchette, B. Characterization of a late phase pulmonary response after antigen challenge in allergic sheep. Am. Rev. Respir. Dis. 1983, 128, 839–844. [Google Scholar]
  143. Koumoundouros, E.; Bischof, R.J.; Meeusen, E.N.; Mareels, I.M.; Snibson, K.J. Chronic airway disease: Deteriorating pulmonary function in sheep associated with repeated challenges of house dust mite. Exp. Lung Res. 2006, 32, 321–330. [Google Scholar] [CrossRef] [PubMed]
  144. Clark, J.M.; Abraham, W.M.; Fishman, C.E.; Forteza, R.; Ahmed, A.; Cortes, A.; Warne, R.L.; Moore, W.R.; Tanaka, R.D. Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. Am. J. Respir. Crit. Care Med. 1995, 152 Pt 1, 2076–2083. [Google Scholar] [CrossRef]
  145. Tomioka, K.; Garrido, R.; Ahmed, A.; Stevenson, J.S.; Abraham, W.M. YM461, a PAF antagonist, blocks antigen-induced late airway responses and airway hyperresponsiveness in allergic sheep. Eur. J. Pharmacol. 1989, 170, 209–215. [Google Scholar] [CrossRef]
  146. Van der Velden, J.; Harkness, L.M.; Barker, D.M.; Barcham, G.J.; Ugalde, C.L.; Koumoundouros, E.; Bao, H.; Organ, L.A.; Tokanovic, A.; Burgess, J.K.; et al. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma. Sci. Rep. 2016, 6, 26309. [Google Scholar] [CrossRef] [PubMed]
  147. Van der Velden, J.; Barker, D.; Barcham, G.; Koumoundouros, E.; Snibson, K. Increased vascular density is a persistent feature of airway remodeling in a sheep model of chronic asthma. Exp. Lung Res. 2012, 38, 307–315. [Google Scholar] [CrossRef] [PubMed]
  148. Bischof, R.J.; Snibson, K.J.; Van Der Velden, J.; Meeusen, E.N. Immune response to allergens in sheep sensitized to house dust mite. J. Inflamm (Lond). 2008, 5, 16. [Google Scholar] [CrossRef] [PubMed]
  149. Van der Velden, J.; Barker, D.; Barcham, G.; Koumoundouros, E.; Snibson, K. Assessment of peripheral airway function following chronic allergen challenge in a sheep model of asthma. PLoS ONE 2011, 6, e28740. [Google Scholar] [CrossRef]
  150. Kirschvink, N.; Reinhold, P. Use of alternative animals as asthma models. Curr. Drug. Targets 2008, 9, 470–484. [Google Scholar] [CrossRef] [PubMed]
  151. Scheerlinck, J.-P.Y.; Snibson, K.J.; Bowles, V.M.; Sutton, P. Biomedical applications of sheep models: From asthma to vaccines. Trends Biotechnol. 2008, 26, 259–266. [Google Scholar] [CrossRef]
  152. Kips, J.C.; Cuvelier, C.A.; Pauwels, R.A. Effect of acute and chronic antigen inhalation on airway morphology and responsiveness in actively sensitized rats. Am. Rev. Respir. Dis. 1992, 145, 1306–1310. [Google Scholar] [CrossRef] [PubMed]
  153. Misawa, M.; Chiba, Y. Repeated antigenic challenge-induced airway hyperresponsiveness and airway inflammation in actively sensitized rats. Jpn. J. Pharmacol. 1993, 61, 41–50. [Google Scholar] [CrossRef]
  154. Renzi, P.M.; al Assaad, A.S.; Yang, J.; Yasruel, Z.; Hamid, Q. Cytokine expression in the presence or absence of late airway responses after antigen challenge of sensitized rats. Am. J. Respir. Cell Mol. Biol. 1996, 15, 367–373. [Google Scholar] [CrossRef]
  155. Schneider, T.; van Velzen, D.; Moqbel, R.; Issekutz, A.C. Kinetics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model. Am. J. Respir. Cell Mol. Biol. 1997, 17, 702–712. [Google Scholar] [CrossRef] [PubMed]
  156. Gilmour, M.I.; Selgrade, M.J. A model of immune-mediated lung disease in rats sensitized to house dust mite and upregulation of immunity following exposure to nitrogen dioxide. Chest 1996, 109 (Suppl. 3), 69s. [Google Scholar] [CrossRef]
  157. Wagner, E.M.; Jenkins, J.; Schmieder, A.; Eldridge, L.; Zhang, Q.; Moldobaeva, A.; Zhang, H.; Allen, J.S.; Yang, X.; Mitzner, W.; et al. Angiogenesis and airway reactivity in asthmatic Brown Norway rats. Angiogenesis 2015, 18, 1–11. [Google Scholar] [CrossRef]
  158. Lanza, G.M.; Jenkins, J.; Schmieder, A.H.; Moldobaeva, A.; Cui, G.; Zhang, H.; Yang, X.; Zhong, Q.; Keupp, J.; Sergin, I.; et al. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat. Theranostics 2017, 7, 377–389. [Google Scholar] [CrossRef] [PubMed]
  159. Thakur, V.R.; Khuman, V.; Beladiya, J.V.; Chaudagar, K.K.; Mehta, A.A. An experimental model of asthma in rats using ovalbumin and lipopolysaccharide allergens. Heliyon 2019, 5, e02864. [Google Scholar] [CrossRef] [PubMed]
  160. Renzi, P.M.; Olivenstein, R.; Martin, J.G. Inflammatory cell populations in the airways and parenchyma after antigen challenge in the rat. Am. Rev. Respir. Dis. 1993, 147, 967–974. [Google Scholar] [CrossRef] [PubMed]
  161. Rabb, H.A.; Olivenstein, R.; Issekutz, T.B.; Renzi, P.M.; Martin, J.G. The role of the leukocyte adhesion molecules VLA-4, LFA-1, and Mac-1 in allergic airway responses in the rat. Am. J. Respir. Crit. Care Med. 1994, 149, 1186–1191. [Google Scholar] [CrossRef]
  162. Laberge, S.; Rabb, H.; Issekutz, T.B.; Martin, J.G. Role of VLA-4 and LFA-1 in allergen-induced airway hyperresponsiveness and lung inflammation in the rat. Am. J. Respir. Crit. Care Med. 1995, 151 Pt 1, 822–829. [Google Scholar] [CrossRef]
  163. Haczku, A.; Macary, P.; Haddad, E.B.; Huang, T.J.; Kemeny, D.M.; Moqbel, R.; Chung, K.F. Expression of Th-2 cytokines interleukin-4 and -5 and of Th-1 cytokine interferon-gamma in ovalbumin-exposed sensitized Brown-Norway rats. Immunology 1996, 88, 247–251. [Google Scholar] [CrossRef]
  164. Peták, F.; Wale, J.L.; Sly, P.D. Effects of salbutamol and Ro-20-1724 on airway and parenchymal mechanics in rats. J. Appl. Physiol (1985). 1999, 87, 1373–1380. [Google Scholar] [CrossRef]
  165. Elwood, W.; Lötvall, J.O.; Barnes, P.J.; Chung, K.F. Effect of dexamethasone and cyclosporin A on allergen-induced airway hyperresponsiveness and inflammatory cell responses in sensitized Brown-Norway rats. Am. Rev. Respir. Dis. 1992, 145, 1289–1294. [Google Scholar] [CrossRef] [PubMed]
  166. Tigani, B.; Hannon, J.P.; Schaeublin, E.; Mazzoni, L.; Fozard, J.R. Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen. Naunyn Schmiedebergs Arch. Pharmacol. 2003, 368, 17–25. [Google Scholar] [CrossRef] [PubMed]
  167. Gold, W.; Kessler, G.-F.; Yu, D. Role of vagus nerves in experimental asthma in allergic dogs. J. Appl. Physiol. 1972, 33, 719–725. [Google Scholar] [CrossRef] [PubMed]
  168. Krell, R.D.; Chakrin, L.W. Canine airway responses to acetylcholine, prostaglandin F2α, histamine, and serotonin after chronic antigen exposure. J. Allergy Clin. Immunol. 1976, 58, 664–675. [Google Scholar] [CrossRef] [PubMed]
  169. Hirshman, C.A.; Malley, A.; Downes, H. Basenji-Greyhound dog model of asthma: Reactivity to Ascaris suum, citric acid, and methacholine. J. Appl. Physiol. 1980, 49, 953–957. [Google Scholar] [CrossRef] [PubMed]
  170. Snapper, J.R.; Braasch, P.S.; Loring, S.H.; Ingram, R.H., Jr.; Drazen, J.M. Comparison of the responsiveness to histamine and to Ascaris suum challenge in dogs. Am. Rev. Respir. Dis. 1980, 122, 775–780. [Google Scholar] [CrossRef]
  171. Palevsky, H.; Grippi, M.; Pack, A. The effect of antigen-induced bronchoconstriction on phrenic nerve activity. Am. Rev. Respir. Dis. 1986, 133, 749–756. [Google Scholar]
  172. Kleeberger, S.; Kolbe, J.; Adkinson, N.F., Jr.; Peters, S.; Spannhake, E. Central role of cyclooxygenase in the response of canine peripheral airways to antigen. J. Appl. Physiol. 1986, 61, 1309–1315. [Google Scholar] [CrossRef]
  173. Sasaki, H.; Yanai, M.; Shimura, S.; Okayama, H.; Aikawa, T.; Sasaki, T.; Takishima, T. Late Asthmatic Response to Ascaris Antigen Challenge in Dogs Treated with Metyrapone1-3. Am. Rev. Respir. Dis. 1987, 136, 1459–1465. [Google Scholar] [CrossRef]
  174. Turner, C.R.; Spannhake, E.W. Acute topical steroid administration blocks mast cell increase and the late asthmatic response of the canine peripheral airways. Am. Rev. Respir. Dis. 1990, 141, 421–427. [Google Scholar] [CrossRef]
  175. Miyahara, T.; Shibamoto, T.; Wang, H.-G.; Koyama, S. Role of circulating blood components and thromboxane in anaphylactic vasoconstriction in isolated canine lungs. J. Appl. Physiol. 1997, 83, 1508–1516. [Google Scholar] [CrossRef] [PubMed]
  176. Wood, L.J.; Inman, M.D.; Denburg, J.A.; O′Byrne, P.M. Allergen challenge increases cell traffic between bone marrow and lung. Am. J. Respir. Cell Mol. Biol. 1998, 18, 759–767. [Google Scholar] [CrossRef]
  177. Becker, A.; Hershkovich, J.; Simons, F.; Simons, K.; Lilley, M.; Kepron, M. Development of chronic airway hyperresponsiveness in ragweed-sensitized dogs. J. Appl. Physiol. 1989, 66, 2691–2697. [Google Scholar] [CrossRef]
  178. House, A.; Celly, C.; Young, S.; Kreutner, W.; Chapman, R. Bronchoconstrictor reactivity to NKA in allergic dogs: A comparison to histamine and methacholine. Pulm. Pharmacol. Ther. 2001, 14, 135–140. [Google Scholar] [CrossRef] [PubMed]
  179. Chrusch, C.; Sharma, S.; Unruh, H.; Bautista, E.; Duke, K.; Becker, A.; Kepron, W.; Mink, S.N. Histamine H3 receptor blockade improves cardiac function in canine anaphylaxis. Am. J. Respir. Crit. Care Med. 1999, 160, 1142–1149. [Google Scholar] [CrossRef] [PubMed]
  180. Barrett, E.G.; Rudolph, K.; Bowen, L.E.; Muggenburg, B.A.; Bice, D.E. Effect of inhaled ultrafine carbon particles on the allergic airway response in ragweed-sensitized dogs. Inhal. Toxicol. 2003, 15, 151–165. [Google Scholar] [CrossRef] [PubMed]
  181. Out, T.A.; Wang, S.Z.; Rudolph, K.; Bice, D.E. Local T-cell activation after segmental allergen challenge in the lungs of allergic dogs. Immunology 2002, 105, 499–508. [Google Scholar] [CrossRef]
  182. Chung, K.; Becker, A.; Lazarus, S.; Frick, O.; Nadel, J.; Gold, W. Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs. J. Appl. Physiol. 1985, 58, 1347–1353. [Google Scholar] [CrossRef]
  183. Bice, D.E.; Degen, M.A.; Harris, D.L.; Muggenburg, B.A. Recruitment of antibody-forming cells in the lung after local immunization is nonspecific. Am. Rev. Respir. Dis. 1982, 126, 635–639. [Google Scholar] [PubMed]
  184. Bice, D.; Weissman, D.; Muggenburg, B. Long-term maintenance of localized antibody responses in the lung. Immunology 1991, 74, 215. [Google Scholar] [PubMed]
  185. Weissman, D.N.; Bice, D.E.; Muggenburg, B.A.; Haley, P.J.; Shopp, G.M.; Schuyler, M.R. Primary immunization in the canine lung. Am. Rev. Respir. Dis. 1992, 145, 6–12. [Google Scholar] [CrossRef]
  186. Wooley, M.; Wattie, J.; Ellis, R.; Lane, C.; Stevens, W.; Wooley, K.; Dahlback, M.; O′Byrne, P. Effect of an inhaled corticosteroid on airway eosinophils and allergen-induced airway hyperresponsiveness. J. Appl. Physiol. 1994, 77, 1303–1308. [Google Scholar] [CrossRef]
  187. Redman, T.K.; Rudolph, K.; Barr, E.B.; Bowen, L.E.; Muggenburg, B.A.; Bice, D.E. Pulmonary immunity to ragweed in a Beagle dog model of allergic asthma. Exp. Lung Res. 2001, 27, 433–451. [Google Scholar] [CrossRef] [PubMed]
  188. Weiszer, I.; Patterson, R.; Pruzansky, J.J. Ascaris hypersensitivity in the rhesus monkey. I. A model for the study of immediate type thypersensitity in the primate. J. Allergy 1968, 41, 14–22. [Google Scholar]
  189. Gundel, R.H.; Wegner, C.D.; Letts, L.G. Antigen-induced acute and late-phase responses in primates. Am. Rev. Respir. Dis. 1992, 146, 369–373. [Google Scholar] [CrossRef]
  190. Turner, C.R.; Andresen, C.J.; Smith, W.B.; Watson, J.W. Characterization of a primate model of asthma using anti-allergy/anti-asthma agents. Inflamm. Res. 1996, 45, 239–245. [Google Scholar] [CrossRef]
  191. Yasue, M.; Nakamura, S.; Yokota, T.; Okudaira, H.; Okumura, Y. Experimental monkey model sensitized with mite antigen. Int. Arch. Allergy Immunol. 1998, 115, 303–311. [Google Scholar] [CrossRef] [PubMed]
  192. Schelegle, E.S.; Gershwin, L.J.; Miller, L.A.; Fanucchi, M.V.; Van Winkle, L.S.; Gerriets, J.P.; Walby, W.F.; Omlor, A.M.; Buckpitt, A.R.; Tarkington, B.K.; et al. Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae). Am. J. Pathol. 2001, 158, 333–341. [Google Scholar] [CrossRef] [PubMed]
  193. Van Scott, M.R.; Hooker, J.L.; Ehrmann, D.; Shibata, Y.; Kukoly, C.; Salleng, K.; Westergaard, G.; Sandrasagra, A.; Nyce, J. Dust mite-induced asthma in cynomolgus monkeys. J. Appl. Phys. 1985 2004, 96, 1433–1444. [Google Scholar] [CrossRef] [PubMed]
  194. Patterson, R.; Harris, K.E.; Pruzansky, J.J. Induction of IgE-mediated cutaneous, cellular, and airway reactivity in rhesus monkeys by Ascaris suum infection. J. Lab. Clin. Med. 1983, 101, 864–872. [Google Scholar] [PubMed]
  195. Ferreira, F.D.; Mayer, P.; Sperr, W.R.; Valent, P.; Seiberler, S.; Ebner, C.; Liehl, E.; Scheiner, O.; Kraft, D.; Valenta, R. Induction of IgE antibodies with predefined specificity in rhesus monkeys with recombinant birch pollen allergens, Bet v 1 and Bet v 2. J. Allergy Clin. Immunol. 1996, 97 Pt 1, 95–103. [Google Scholar] [CrossRef]
  196. Plopper, C.G.; Heidsiek, J.G.; Weir, A.J.; George, J.A.; Hyde, D.M. Tracheobronchial epithelium in the adult rhesus monkey: A quantitative histochemical and ultrastructural study. Am. J. Anat. 1989, 184, 31–40. [Google Scholar] [CrossRef] [PubMed]
  197. Seehase, S.; Schlepütz, M.; Switalla, S.; Mätz-Rensing, K.; Kaup, F.J.; Zöller, M.; Schlumbohm, C.; Fuchs, E.; Lauenstein, H.D.; Winkler, C.; et al. Bronchoconstriction in nonhuman primates: A species comparison. J. Appl. Physiol (1985). 2011, 111, 791–798. [Google Scholar] [CrossRef] [PubMed]
  198. Moise, N.; Spaulding, G. Feline bronchial asthma: Pathogenesis, pathophysiology, diagnostics and therapeutic considerations. Compend. Contin. Educ. Pract. Vet. 1981, 3, 1091–1102. [Google Scholar]
  199. Howard, E.; Ryan, C. Chronic Obstructive Pulmonary Disease in the Domestic Cat; California Veterinarian: Gardena, CA, USA, 1982. [Google Scholar]
  200. Moise, N.S.; Wiedenkeller, D.; Yeager, A.E.; Blue, J.T.; Scarlett, J. Clinical, radiographic, and bronchial cytologic features of cats with bronchial disease: 65 cases (1980–1986). J. Am. Vet. Med. Assoc. 1989, 194, 1467–1473. [Google Scholar]
  201. Dye, J.A.; McKiernan, B.C.; Rozanski, E.A.; Hoffmann, W.E.; Losonsky, J.M.; Homco, L.D.; Weisiger, R.M.; Kakoma, I. Bronchopulmonary disease in the cat: Historical, physical, radiographic, clinicopathologic, and pulmonary functional evaluation of 24 affected and 15 healthy cats. J. Vet. Intern. Med. 1996, 10, 385–400. [Google Scholar] [CrossRef]
  202. Corcoran, B.M.; Foster, D.J.; Fuentes, V.L. Feline asthma syndrome: A retrospective study of the clinical presentation in 29 cats. J. Small Anim. Pr. 1995, 36, 481–488. [Google Scholar] [CrossRef]
  203. Halliwell, R.E. Efficacy of hyposensitization in feline allergic diseases based upon results of in vitro testing for allergen-specific immunoglobulin E. J. Am. Anim. Hosp. Assoc. 1997, 33, 282–288. [Google Scholar] [CrossRef]
  204. Moriello, K.A.; Stepien, R.L.; Henik, R.A.; Wenholz, L.J. Pilot study: Prevalence of positive aeroallergen reactions in 10 cats with small-airway disease without concurrent skin disease. Vet. Derm. 2007, 18, 94–100. [Google Scholar] [CrossRef] [PubMed]
  205. Norris Reinero, C.R.; Decile, K.C.; Berghaus, R.D.; Williams, K.J.; Leutenegger, C.M.; Walby, W.F.; Schelegle, E.S.; Hyde, D.M.; Gershwin, L.J. An experimental model of allergic asthma in cats sensitized to house dust mite or bermuda grass allergen. Int. Arch. Allergy Immunol. 2004, 135, 117–131. [Google Scholar] [CrossRef] [PubMed]
  206. Prost, C. Treatment of feline asthma with allergen avoidance and specific immunotherapy: Experience with 20 cats. Rev. Fr. Allergol. Immunol. Clin. 2008, 48, 409–413. [Google Scholar]
  207. Nafe, L.A.; DeClue, A.E.; Lee-Fowler, T.M.; Eberhardt, J.M.; Reinero, C.R. Evaluation of biomarkers in bronchoalveolar lavage fluid for discrimination between asthma and chronic bronchitis in cats. Am. J. Vet. Res. 2010, 71, 583–591. [Google Scholar] [CrossRef]
  208. Reinero, C.R. Advances in the understanding of pathogenesis, and diagnostics and therapeutics for feline allergic asthma. Vet. J. 2011, 190, 28–33. [Google Scholar] [CrossRef] [PubMed]
  209. Adamama-Moraitou, K.K.; Patsikas, M.N.; Koutinas, A.F. Feline lower airway disease: A retrospective study of 22 naturally occurring cases from Greece. J. Feline Med. Surg. 2004, 6, 227–233. [Google Scholar] [CrossRef] [PubMed]
  210. Grotheer, M.; Schulz, B. Feline asthma and chronic bronchitis–an overview of diagnostics and therapy. Tierarztl. Prax. Ausg. K Kleintiere Heimtiere 2019, 47, 175–187. [Google Scholar]
  211. Vientós-Plotts, A.I.; Ericsson, A.C.; McAdams, Z.L.; Rindt, H.; Reinero, C.R. Temporal changes of the respiratory microbiota as cats transition from health to experimental acute and chronic allergic asthma. Front. Vet. Sci. 2022, 9, 983375. [Google Scholar] [CrossRef]
  212. Plopper, C.G.; Hyde, D.M. Epithelial cells of the bronchiole. In Comparative Biology of the Normal Lung; Elsevier: Amsterdam, Netherlands, 2015; pp. 83–92. [Google Scholar]
  213. St George, J.; Harkema, J.R.; Hyde, D.M.; Plopper, C.G. Cell populations and structure/function relationships of cells in the airways. Toxicol. Lung 1988, 71–102. [Google Scholar]
  214. Padrid, P. Animal models of asthma. Lung Biol. Health Dis. 1996, 96, 211–233. [Google Scholar]
  215. Padrid, P.; Snook, S.; Finucane, T.; Shiue, P.; Cozzi, P.; Solway, J.; Leff, A.R. Persistent airway hyperresponsiveness and histologic alterations after chronic antigen challenge in cats. Am. J. Respir. Crit. Care Med. 1995, 151, 184–193. [Google Scholar] [CrossRef] [PubMed]
  216. Diamond, L.; O′Donnell, M. A nonadrenergic vagal inhibitory pathway to feline airways. Science 1980, 208, 185–188. [Google Scholar] [CrossRef] [PubMed]
  217. Irvin, C.G.; Boileau, R.; Tremblay, J.; Martin, R.R.; Macklem, P.T. Bronchodilatation: Noncholinergic, nonadrenergic mediation demonstrated in vivo in the cat. Science 1980, 207, 791–792. [Google Scholar] [CrossRef] [PubMed]
  218. Richardson, J.; Beland, J. Nonadrenergic inhibitory nervous system in human airways. J. Appl. Physiol. 1976, 41, 764–771. [Google Scholar] [CrossRef]
  219. Kirschvink, N.; Leemans, J.; Delvaux, F.; Snaps, F.; Clercx, C.; Gustin, P. Non-invasive assessment of airway responsiveness in healthy and allergen-sensitised cats by use of barometric whole body plethysmography. Vet. J. 2007, 173, 343–352. [Google Scholar] [CrossRef] [PubMed]
  220. Chand, N.; Eyre, P. Atypical (relaxant) response to histamine in cat bronchus. Agents Actions 1977, 7, 183–190. [Google Scholar] [CrossRef] [PubMed]
  221. Mohammed, S.; Higenbottam, T.; Adcock, J. Effects of aerosol-applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetized cats. J. Physiol. 1993, 469, 51–66. [Google Scholar] [CrossRef]
  222. Norris, C.R.; Decile, K.C.; Berghaus, L.J.; Berghaus, R.D.; Walby, W.F.; Schelegle, E.S.; Hyde, D.M.; Gershwin, L.J. Concentrations of cysteinyl leukotrienes in urine and bronchoalveolar lavage fluid of cats with experimentally induced asthma. Am. J. Vet. Res. 2003, 64, 1449–1453. [Google Scholar] [CrossRef]
  223. Reinero, C.R.; Decile, K.C.; Byerly, J.R.; Berghaus, R.D.; Walby, W.F.; Berghaus, L.J.; Hyde, D.M.; Schelegle, E.S.; Gershwin, L.J. Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma. Am. J. Vet. Res. 2005, 66, 1121–1127. [Google Scholar] [CrossRef]
  224. Couetil, L.L.; Cardwell, J.M.; Gerber, V.; Lavoie, J.P.; Leguillette, R.; Richard, E.A. Inflammatory Airway Disease of Horses--Revised Consensus Statement. J. Vet. Intern. Med. 2016, 30, 503–515. [Google Scholar] [CrossRef] [PubMed]
  225. Ferrari, C.R.; Cooley, J.; Mujahid, N.; Costa, L.R.; Wills, R.W.; Johnson, M.E.; Swiderski, C.E. Horses With Pasture Asthma Have Airway Remodeling That Is Characteristic of Human Asthma. Vet. Pathol. 2018, 55, 144–158. [Google Scholar] [CrossRef] [PubMed]
  226. Bullone, M.; Joubert, P.; Gagné, A.; Lavoie, J.P.; Hélie, P. Bronchoalveolar lavage fluid neutrophilia is associated with the severity of pulmonary lesions during equine asthma exacerbations. Equine Vet. J. 2018, 50, 609–615. [Google Scholar] [CrossRef] [PubMed]
  227. Pirie, R.S. Recurrent airway obstruction: A review. Equine Vet. J. 2014, 46, 276–288. [Google Scholar] [CrossRef] [PubMed]
  228. Hotchkiss, J.W.; Reid, S.W.; Christley, R.M. A survey of horse owners in Great Britain regarding horses in their care. Part 2: Risk factors for recurrent airway obstruction. Equine Vet. J. 2007, 39, 301–308. [Google Scholar] [CrossRef]
  229. Ivester, K.M.; Couëtil, L.L.; Moore, G.E. An observational study of environmental exposures, airway cytology, and performance in racing thoroughbreds. J. Vet. Intern. Med. 2018, 32, 1754–1762. [Google Scholar] [CrossRef]
  230. Couëtil, L.L.; Ward, M.P. Analysis of risk factors for recurrent airway obstruction in North American horses: 1,444 cases (1990-1999). J. Am. Vet. Med. Assoc. 2003, 223, 1645–1650. [Google Scholar] [CrossRef]
  231. Wasko, A.J.; Barkema, H.W.; Nicol, J.; Fernandez, N.; Logie, N.; Léguillette, R. Evaluation of a risk-screening questionnaire to detect equine lung inflammation: Results of a large field study. Equine Vet. J. 2011, 43, 145–152. [Google Scholar] [CrossRef]
  232. Couetil, L.; Cardwell, J.M.; Leguillette, R.; Mazan, M.; Richard, E.; Bienzle, D.; Bullone, M.; Gerber, V.; Ivester, K.; Lavoie, J.P.; et al. Equine Asthma: Current Understanding and Future Directions. Front. Vet. Sci. 2020, 7, 450. [Google Scholar] [CrossRef]
  233. Hughes, K.J.; Nicolson, L.; Da Costa, N.; Franklin, S.H.; Allen, K.J.; Dunham, S.P. Evaluation of cytokine mRNA expression in bronchoalveolar lavage cells from horses with inflammatory airway disease. Vet. Immunol. Immunopathol. 2011, 140, 82–89. [Google Scholar] [CrossRef]
  234. Lavoie, J.P.; Cesarini, C.; Lavoie-Lamoureux, A.; Moran, K.; Lutz, S.; Picandet, V.; Jean, D.; Marcoux, M. Bronchoalveolar lavage fluid cytology and cytokine messenger ribonucleic Acid expression of racehorses with exercise intolerance and lower airway inflammation. J. Vet. Intern. Med. 2011, 25, 322–329. [Google Scholar] [CrossRef] [PubMed]
  235. Beekman, L.; Tohver, T.; Leguillette, R. Comparison of cytokine mRNA expression in the bronchoalveolar lavage fluid of horses with inflammatory airway disease and bronchoalveolar lavage mastocytosis or neutrophilia using REST software analysis. J. Vet. Intern. Med. 2012, 26, 153–161. [Google Scholar] [CrossRef] [PubMed]
  236. Richard, E.A.; Depecker, M.; Defontis, M.; Leleu, C.; Fortier, G.; Pitel, P.H.; Courouce-Malblanc, A. Cytokine concentrations in bronchoalveolar lavage fluid from horses with neutrophilic inflammatory airway disease. J. Vet. Intern. Med. 2014, 28, 1838–1844. [Google Scholar] [CrossRef] [PubMed]
  237. Montgomery, J.B.; Husulak, M.L.; Kosolofski, H.; Dos Santos, S.; Burgess, H.; Meachem, M.D. Tumor necrosis factor-alpha protein concentrations in bronchoalveolar lavage fluid from healthy horses and horses with severe equine asthma. Vet. Immunol. Immunopathol. 2018, 202, 70–73. [Google Scholar] [CrossRef] [PubMed]
  238. Giguere, S.; Viel, L.; Lee, E.; MacKay, R.J.; Hernandez, J.; Franchini, M. Cytokine induction in pulmonary airways of horses with heaves and effect of therapy with inhaled fluticasone propionate. Vet. Immunol. Immunopathol. 2002, 85, 147–158. [Google Scholar] [CrossRef] [PubMed]
  239. Lavoie, J.P.; Maghni, K.; Desnoyers, M.; Taha, R.; Martin, J.G.; Hamid, Q.A. Neutrophilic airway inflammation in horses with heaves is characterized by a Th2-type cytokine profile. Am. J. Respir. Crit. Care Med. 2001, 164 Pt 1, 1410–1413. [Google Scholar] [CrossRef]
  240. Debrue, M.; Hamilton, E.; Joubert, P.; Lajoie-Kadoch, S.; Lavoie, J.P. Chronic exacerbation of equine heaves is associated with an increased expression of interleukin-17 mRNA in bronchoalveolar lavage cells. Vet. Immunol. Immunopathol. 2005, 105, 25–31. [Google Scholar] [CrossRef]
  241. Padoan, E.; Ferraresso, S.; Pegolo, S.; Castagnaro, M.; Barnini, C.; Bargelloni, L. Real time RT-PCR analysis of inflammatory mediator expression in recurrent airway obstruction-affected horses. Vet. Immunol. Immunopathol. 2013, 156, 190–199. [Google Scholar] [CrossRef]
  242. Tessier, L.; Cote, O.; Clark, M.E.; Viel, L.; Diaz-Mendez, A.; Anders, S.; Bienzle, D. Impaired response of the bronchial epithelium to inflammation characterizes severe equine asthma. BMC Genom. 2017, 18, 708. [Google Scholar] [CrossRef]
  243. Bond, S.L.; Hundt, J.; Leguillette, R. Effect of injected dexamethasone on relative cytokine mRNA expression in bronchoalveolar lavage fluid in horses with mild asthma. BMC Vet. Res. 2019, 15, 397. [Google Scholar] [CrossRef]
  244. Hansen, S.; Otten, N.D.; Birch, K.; Skovgaard, K.; Hopster-Iversen, C.; Fjeldborg, J. Bronchoalveolar lavage fluid cytokine, cytology and IgE allergen in horses with equine asthma. Vet. Immunol. Immunopathol. 2019, 220, 109976. [Google Scholar] [CrossRef]
  245. Hue, E.; Orard, M.; Toquet, M.P.; Depecker, M.; Couroucé, A.; Pronost, S.; Paillot, R.; Richard, E.A. Asymmetrical Pulmonary Cytokine Profiles Are Linked to Bronchoalveolar Lavage Fluid Cytology of Horses With Mild Airway Neutrophilia. Front. Vet. Sci. 2020, 7, 226. [Google Scholar] [CrossRef] [PubMed]
  246. Leclere, M.; Lavoie-Lamoureux, A.; Lavoie, J.P. Heaves, an asthma-like disease of horses. Respirology 2011, 16, 1027–1046. [Google Scholar] [CrossRef] [PubMed]
  247. Bullone, M.; Lavoie, J.P. Asthma “of horses and men”–how can equine heaves help us better understand human asthma immunopathology and its functional consequences? Mol. Immunol. 2015, 66, 97–105. [Google Scholar] [CrossRef] [PubMed]
  248. Davis, K.U.; Sheats, M.K. The Role of Neutrophils in the Pathophysiology of Asthma in Humans and Horses. Inflammation 2021, 44, 450–465. [Google Scholar] [CrossRef]
  249. Sheats, M.K.; Davis, K.U.; Poole, J.A. Comparative Review of Asthma in Farmers and Horses. Curr. Allergy Asthma Rep. 2019, 19, 50. [Google Scholar] [CrossRef] [PubMed]
  250. Relave, F.; David, F.; Leclère, M.; Alexander, K.; Bussières, G.; Lavoie, J.P.; Marcoux, M. Evaluation of a thoracoscopic technique using ligating loops to obtain large lung biopsies in standing healthy and heaves-affected horses. Vet. Surg. 2008, 37, 232–240. [Google Scholar] [CrossRef]
  251. Relave, F.; David, F.; Leclère, M.; Alexander, K.; Hélie, P.; Meulyzer, M.; Lavoie, J.P.; Marcoux, M. Thoracoscopic lung biopsies in heaves-affected horses using a bipolar tissue sealing system. Vet. Surg. 2010, 39, 839–846. [Google Scholar] [CrossRef]
  252. Lugo, J.; Stick, J.A.; Peroni, J.; Harkema, J.R.; Derksen, F.J.; Robinson, N.E. Safety and efficacy of a technique for thoracoscopically guided pulmonary wedge resection in horses. Am. J. Vet. Res. 2002, 63, 1232–1240. [Google Scholar] [CrossRef]
  253. Young, S.S.; Hall, L.W. A rapid, non-invasive method for measuring total respiratory impedance in the horse. Equine Vet. J. 1989, 21, 99–105. [Google Scholar] [CrossRef]
  254. Young, S.S.; Tesarowski, D. Respiratory mechanics of horses measured by conventional and forced oscillation techniques. J. Appl. Physiol (1985). 1994, 76, 2467–2472. [Google Scholar] [CrossRef] [PubMed]
  255. Young, S.S.; Tesarowski, D.; Viel, L. Frequency dependence of forced oscillatory respiratory mechanics in horses with heaves. J. Appl. Physiol (1985). 1997, 82, 983–987. [Google Scholar] [CrossRef] [PubMed]
  256. van Erck, E.; Votion, D.M.; Kirschvink, N.; Art, T.; Lekeux, P. Use of the impulse oscillometry system for testing pulmonary function during methacholine bronchoprovocation in horses. Am. J. Vet. Res. 2003, 64, 1414–1420. [Google Scholar] [CrossRef] [PubMed]
  257. Van Erck, E.; Votion, D.; Art, T.; Lekeux, P. Qualitative and quantitative evaluation of equine respiratory mechanics by impulse oscillometry. Equine Vet. J. 2006, 38, 52–58. [Google Scholar] [CrossRef] [PubMed]
  258. Bizzotto, D.; Paganini, S.; Stucchi, L.; Avallone, M.P.; Ramirez, E.M.; Pompilio, P.P.; Ferrucci, F.; Lavoie, J.P.; Dellacà, R.L. A portable fan-based device for evaluating lung function in horses by the forced oscillation technique. Physiol. Meas. 2022, 43, 025001. [Google Scholar] [CrossRef] [PubMed]
  259. Olave, C.J.; Ivester, K.M.; Couetil, L.L.; Burgess, J.; Park, J.H.; Mukhopadhyay, A. Effects of low-dust forages on dust exposure, airway cytology, and plasma omega-3 concentrations in Thoroughbred racehorses: A randomized clinical trial. J. Vet. Intern. Med. 2023, 37, 338–348. [Google Scholar] [CrossRef]
  260. Mainguy-Seers, S.; Lavoie, J.P. Glucocorticoid treatment in horses with asthma: A narrative review. J. Vet. Intern. Med. 2021, 35, 2045–2057. [Google Scholar] [CrossRef]
  261. Lavoie, J.P.; Bullone, M.; Rodrigues, N.; Germim, P.; Albrecht, B.; von Salis-Soglio, M. Effect of different doses of inhaled ciclesonide on lung function, clinical signs related to airflow limitation and serum cortisol levels in horses with experimentally induced mild to severe airway obstruction. Equine Vet. J. 2019, 51, 779–786. [Google Scholar] [CrossRef]
  262. Lavoie, J.P.; Leclere, M.; Rodrigues, N.; Lemos, K.R.; Bourzac, C.; Lefebvre-Lavoie, J.; Beauchamp, G.; Albrecht, B. Efficacy of inhaled budesonide for the treatment of severe equine asthma. Equine Vet. J. 2019, 51, 401–407. [Google Scholar] [CrossRef]
  263. Léguillette, R.; Tohver, T.; Bond, S.L.; Nicol, J.A.; McDonald, K.J. Effect of Dexamethasone and Fluticasone on Airway Hyperresponsiveness in Horses With Inflammatory Airway Disease. J. Vet. Intern. Med. 2017, 31, 1193–1201. [Google Scholar] [CrossRef]
  264. Nogradi, N.; Couetil, L.L.; Messick, J.; Stochelski, M.A.; Burgess, J.R. Omega-3 fatty acid supplementation provides an additional benefit to a low-dust diet in the management of horses with chronic lower airway inflammatory disease. J. Vet. Intern. Med. 2015, 29, 299–306. [Google Scholar] [CrossRef] [PubMed]
  265. Bond, S.; Leguillette, R.; Richard, E.A.; Couetil, L.; Lavoie, J.P.; Martin, J.G.; Pirie, R.S. Equine asthma: Integrative biologic relevance of a recently proposed nomenclature. J. Vet. Intern. Med. 2018, 32, 2088–2098. [Google Scholar] [CrossRef] [PubMed]
  266. Hulliger, M.F.; Pacholewska, A.; Vargas, A.; Lavoie, J.P.; Leeb, T.; Gerber, V.; Jagannathan, V. An Integrative miRNA-mRNA Expression Analysis Reveals Striking Transcriptomic Similarities between Severe Equine Asthma and Specific Asthma Endotypes in Humans. Genes 2020, 11, 1143. [Google Scholar] [CrossRef]
  267. Padoan, E.; Ferraresso, S.; Pegolo, S.; Barnini, C.; Castagnaro, M.; Bargelloni, L. Gene Expression Profiles of the Immuno-Transcriptome in Equine Asthma. Animals (Basel) 2022, 13, 4. [Google Scholar] [CrossRef]
  268. Ray, A.; Kolls, J.K. Neutrophilic Inflammation in Asthma and Association with Disease Severity. Trends Immunol. 2017, 38, 942–954. [Google Scholar] [CrossRef]
  269. Seys, S.F.; Lokwani, R.; Simpson, J.L.; Bullens, D.M.A. New insights in neutrophilic asthma. Curr. Opin. Pulm. Med. 2019, 25, 113–120. [Google Scholar] [CrossRef]
  270. Yu, Q.L.; Chen, Z. Establishment of different experimental asthma models in mice. Exp. Ther. Med. 2018, 15, 2492–2498. [Google Scholar] [CrossRef]
  271. An, T.J.; Rhee, C.K.; Kim, J.H.; Lee, Y.R.; Chon, J.Y.; Park, C.K.; Yoon, H.K. Effects of Macrolide and Corticosteroid in Neutrophilic Asthma Mouse Model. Tuberc. Respir. Dis (Seol). 2018, 81, 80–87. [Google Scholar] [CrossRef]
  272. Quoc, Q.L.; Choi, Y.; Thi Bich, T.C.; Yang, E.M.; Shin, Y.S.; Park, H.S. S100A9 in adult asthmatic patients: A biomarker for neutrophilic asthma. Exp. Mol. Med. 2021, 53, 1170–1179. [Google Scholar] [CrossRef]
  273. Herszberg, B.; Ramos-Barbon, D.; Tamaoka, M.; Martin, J.G.; Lavoie, J.P. Heaves, an asthma-like equine disease, involves airway smooth muscle remodeling. J. Allergy Clin. Immunol. 2006, 118, 382–388. [Google Scholar] [CrossRef] [PubMed]
  274. Nurmagambetov, T.; Kuwahara, R.; Garbe, P. The Economic Burden of Asthma in the United States, 2008–2013. Ann. Am. Thorac. Soc. 2018, 15, 348–356. [Google Scholar] [CrossRef] [PubMed]
  275. Fallon, P.G.; Schwartz, C. The high and lows of type 2 asthma and mouse models. J. Allergy Clin. Immunol. 2020, 145, 496–498. [Google Scholar] [CrossRef] [PubMed]
  276. Bazán-Perkins, B.; Sánchez-Guerrero, E.; Vargas, M.H.; Martínez-Cordero, E.; Ramos-Ramírez, P.; Alvarez-Santos, M.; Hiriart, G.; Gaxiola, M.; Hernández-Pando, R. Beta1-integrins shedding in a guinea-pig model of chronic asthma with remodelled airways. Clin. Exp. Allergy 2009, 39, 740–751. [Google Scholar] [CrossRef] [PubMed]
  277. Mousa, A.M.; Almatroudi, A.; Alwashmi, A.S.; Abdulmonem, W.A.; Aljohani, A.S.M.; Alhumaydhi, F.A.; Alsahli, M.A.; Alrumaihi, F.; Allemailem, K.S.; Abdellatif, A.A.H.; et al. Thyme oil alleviates Ova-induced bronchial asthma through modulating Th2 cytokines, IgE, TSLP and ROS. Biomed. Pharmacother. 2021, 140, 111726. [Google Scholar] [CrossRef] [PubMed]
  278. Nino, G.; Hu, A.; Grunstein, J.S.; McDonough, J.; Kreiger, P.A.; Josephson, M.B.; Choi, J.K.; Grunstein, M.M. G Protein βγ-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma. PLoS ONE 2012, 7, e32078. [Google Scholar] [CrossRef]
  279. Halim, N.S.S.; Ch′ng, E.S.; Kardia, E.; Ali, S.A.; Radzi, R.; Yahaya, B.H. Aerosolised Mesenchymal Stem Cells Expressing Angiopoietin-1 Enhances Airway Repair. Stem Cell Rev. Rep. 2019, 15, 112–125. [Google Scholar] [CrossRef]
  280. Liravi, B.; Piedrafita, D.; Nguyen, G.; Bischof, R.J. Dynamics of IL-4 and IL-13 expression in the airways of sheep following allergen challenge. BMC Pulm. Med. 2015, 15, 101. [Google Scholar] [CrossRef]
  281. Gatford, K.L.; Wooldridge, A.L.; Kind, K.L.; Bischof, R.; Clifton, V.L. Pre-birth origins of allergy and asthma. J. Reprod. Immunol. 2017, 123, 88–93. [Google Scholar] [CrossRef]
  282. Solèr, M.; Sielczak, M.W.; Abraham, W.M. A PAF antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep. J. Appl. Physiol (1985). 1989, 67, 406–413. [Google Scholar] [CrossRef]
  283. Solèr, M.; Sielczak, M.; Abraham, W.M. A bradykinin-antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep. Pulm. Pharmacol. 1990, 3, 9–15. [Google Scholar] [CrossRef] [PubMed]
  284. Abraham, W.M.; Burch, R.M.; Farmer, S.G.; Sielczak, M.W.; Ahmed, A.; Cortes, A. A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. Am. Rev. Respir. Dis. 1991, 143 Pt 1, 787–796. [Google Scholar] [CrossRef]
  285. Chapman, R.W. Canine models of asthma and COPD. Pulm. Pharmacol. Ther. 2008, 21, 731–742. [Google Scholar] [CrossRef]
  286. Miller, L.A.; Royer, C.M.; Pinkerton, K.E.; Schelegle, E.S. Nonhuman Primate Models of Respiratory Disease: Past, Present, and Future. ILAR J. 2017, 58, 269–280. [Google Scholar] [CrossRef] [PubMed]
  287. Abbas, A.R.; Jackman, J.K.; Bullens, S.L.; Davis, S.M.; Choy, D.F.; Fedorowicz, G.; Tan, M.; Truong, B.T.; Gloria Meng, Y.; Diehl, L.; et al. Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model. Am. J. Pathol. 2011, 179, 1667–1680. [Google Scholar] [CrossRef] [PubMed]
  288. Coffman, R.L.; Hessel, E.M. Nonhuman primate models of asthma. J. Exp. Med. 2005, 201, 1875–1879. [Google Scholar] [CrossRef] [PubMed]
  289. Bullone, M.; Lavoie, J.P. The equine asthma model of airway remodeling: From a veterinary to a human perspective. Cell Tissue Res. 2020, 380, 223–236. [Google Scholar] [CrossRef]
  290. Lange-Consiglio, A.; Stucchi, L.; Zucca, E.; Lavoie, J.P.; Cremonesi, F.; Ferrucci, F. Insights into animal models for cell-based therapies in translational studies of lung diseases: Is the horse with naturally occurring asthma the right choice? Cytotherapy 2019, 21, 525–534. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Woodrow, J.S.; Sheats, M.K.; Cooper, B.; Bayless, R. Asthma: The Use of Animal Models and Their Translational Utility. Cells 2023, 12, 1091. https://doi.org/10.3390/cells12071091

AMA Style

Woodrow JS, Sheats MK, Cooper B, Bayless R. Asthma: The Use of Animal Models and Their Translational Utility. Cells. 2023; 12(7):1091. https://doi.org/10.3390/cells12071091

Chicago/Turabian Style

Woodrow, Jane Seymour, M. Katie Sheats, Bethanie Cooper, and Rosemary Bayless. 2023. "Asthma: The Use of Animal Models and Their Translational Utility" Cells 12, no. 7: 1091. https://doi.org/10.3390/cells12071091

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop