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Editorial

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3 pages, 180 KiB

Open AccessEditorial

Airway Smooth Muscle and Asthma

by Steven An and Dale D. Tang

Cells 2023, 12(6), 882; https://doi.org/10.3390/cells12060882 - 12 Mar 2023

Viewed by 1159

Abstract

Airway smooth muscle (ASM) was first described in 1804 by Franz Daniel Reisseisen (as related by Otis (1983)) [...] Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

Research

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8 pages, 1642 KiB

Open AccessCommunication

The Bronchoprotective Effects of Dual Pharmacology, Muscarinic Receptor Antagonist and β₂ Adrenergic Receptor Agonist Navafenterol in Human Small Airways

by Joseph Antony Jude, Ian Dainty, Nikhil Karmacharya, William Jester and Reynold Panettieri

Cells 2023, 12(2), 240; https://doi.org/10.3390/cells12020240 - 06 Jan 2023

Cited by 1 | Viewed by 1473

Abstract

Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β₂ adrenergic receptor (β₂AR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is [...] Read more.

Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β₂ adrenergic receptor (β₂AR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and β₂AR agonist functions, currently in development as a COPD therapeutic. In precision-cut human lung slices (hPCLS), we investigated the bronchoprotective effect of navafenterol against two non-muscarinic contractile agonists, histamine and thromboxane A₂ (TxA₂) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and β₂AR antagonist propranolol reversed this inhibitory effect. TxA₂ analog-induced bronchoconstriction was attenuated by navafenterol pre-treatment, albeit to a lesser magnitude than that of histamine-induced bronchoconstriction. Propranolol completely reversed the inhibitory effect of navafenterol on TxA₂ analog-induced bronchoconstriction. In the presence of histamine or TxA₂ analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by β₂AR agonism of navafenterol. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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18 pages, 1994 KiB

Open AccessArticle

IL-5 and GM-CSF, but Not IL-3, Promote the Proliferative Properties of Inflammatory-like and Lung Resident-like Eosinophils in the Blood of Asthma Patients

by Jolita Palacionyte, Andrius Januskevicius, Egle Vasyle, Airidas Rimkunas, Ieva Bajoriuniene, Skaidrius Miliauskas and Kestutis Malakauskas

Cells 2022, 11(23), 3804; https://doi.org/10.3390/cells11233804 - 28 Nov 2022

Cited by 3 | Viewed by 1648

Abstract

Blood eosinophils can be described as inflammatory-like (iEOS-like) and lung-resident-like (rEOS-like) eosinophils. This study is based on the hypothesis that eosinophilopoetins such as interleukin (IL)-3 and IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) alter the proliferative properties of eosinophil subtypes and may be associated [...] Read more.

Blood eosinophils can be described as inflammatory-like (iEOS-like) and lung-resident-like (rEOS-like) eosinophils. This study is based on the hypothesis that eosinophilopoetins such as interleukin (IL)-3 and IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) alter the proliferative properties of eosinophil subtypes and may be associated with the expression of their receptors on eosinophils. We investigated 8 individuals with severe nonallergic eosinophilic asthma (SNEA), 17 nonsevere allergic asthma (AA), and 11 healthy subjects (HS). For AA patients, a bronchial allergen challenge with Dermatophagoides pteronyssinus was performed. Eosinophils were isolated from peripheral blood using high-density centrifugation and magnetic separation methods. The subtyping of eosinophils was based on magnetic bead-conjugated antibodies against L-selectin. Preactivation by eosinophilopoetins was performed by incubating eosinophil subtypes with IL-3, IL-5, and GM-CSF, and individual combined cell cultures were prepared with airway smooth muscle (ASM) cells. ASM cell proliferation was assessed using an Alamar blue assay. The gene expression of eosinophilopoetin receptors was analyzed with a qPCR. IL-5 and GM-CSF significantly enhanced the proliferative properties of iEOS-like and rEOS-like cells on ASM cells in both SNEA and AA groups compared with eosinophils not activated by cytokines (p < 0.05). Moreover, rEOS-like cells demonstrated a higher gene expression of the IL-3 and IL-5 receptors compared with iEOS-like cells in the SNEA and AA groups (p < 0.05). In conclusion: IL-5 and GM-CSF promote the proliferative properties of iEOS-like and rEOS-like eosinophils; however, the effect of only IL-5 may be related to the expression of its receptors in asthma patients. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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15 pages, 3366 KiB

Open AccessArticle

Nestin Modulates Airway Smooth Muscle Cell Migration by Affecting Spatial Rearrangement of Vimentin Network and Focal Adhesion Assembly

by Ruping Wang, Sakeeb Khan, Guoning Liao, Yidi Wu and Dale D. Tang

Cells 2022, 11(19), 3047; https://doi.org/10.3390/cells11193047 - 29 Sep 2022

Cited by 4 | Viewed by 1679

Abstract

Airway smooth muscle cell migration plays a role in the progression of airway remodeling, a hallmark of allergic asthma. However, the mechanisms that regulate cell migration are not yet entirely understood. Nestin is a class VI intermediate filament protein that is involved in [...] Read more.

Airway smooth muscle cell migration plays a role in the progression of airway remodeling, a hallmark of allergic asthma. However, the mechanisms that regulate cell migration are not yet entirely understood. Nestin is a class VI intermediate filament protein that is involved in the proliferation/regeneration of neurons, cancer cells, and skeletal muscle. Its role in cell migration is not fully understood. Here, nestin knockdown (KD) inhibited the migration of human airway smooth muscle cells. Using confocal microscopy and the Imaris software, we found that nestin KD attenuated focal adhesion sizes during cell spreading. Moreover, polo-like kinase 1 (Plk1) and vimentin phosphorylation at Ser-56 have been previously shown to affect focal adhesion assembly. Here, nestin KD reduced Plk1 phosphorylation at Thr-210 (an indication of Plk1 activation), vimentin phosphorylation at Ser-56, the contacts of vimentin filaments to paxillin, and the morphology of focal adhesions. Moreover, the expression of vimentin phosphorylation-mimic mutant S56D (aspartic acid substitution at Ser-56) rescued the migration, vimentin reorganization, and focal adhesion size of nestin KD cells. Together, our results suggest that nestin promotes smooth muscle cell migration. Mechanistically, nestin regulates Plk1 phosphorylation, which mediates vimenitn phosphorylation, the connection of vimentin filaments with paxillin, and focal adhesion assembly. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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13 pages, 2646 KiB

Open AccessArticle

Smooth Muscle Myosin Localizes at the Leading Edge and Regulates the Redistribution of Actin-regulatory Proteins during Migration

by Ruping Wang, Eylon Arbel and Dale D. Tang

Cells 2022, 11(15), 2334; https://doi.org/10.3390/cells11152334 - 29 Jul 2022

Cited by 1 | Viewed by 2028

Abstract

Airway smooth muscle cell migration plays an essential role in airway development, repair, and remodeling. Smooth muscle myosin II has been traditionally thought to localize in the cytoplasm solely and regulates cell migration by affecting stress fiber formation and focal adhesion assembly. In [...] Read more.

Airway smooth muscle cell migration plays an essential role in airway development, repair, and remodeling. Smooth muscle myosin II has been traditionally thought to localize in the cytoplasm solely and regulates cell migration by affecting stress fiber formation and focal adhesion assembly. In this study, we unexpectedly found that 20-kDa myosin light chain (MLC₂₀) and myosin-11 (MYH11), important components of smooth muscle myosin, were present at the edge of lamellipodia. The knockdown of MLC₂₀ or MYH11 attenuated the recruitment of c-Abl, cortactinProfilin-1 (Pfn-1), and Abi1 to the cell edge. Moreover, myosin light chain kinase (MLCK) colocalized with integrin β1 at the tip of protrusion. The inhibition of MLCK attenuated the recruitment of c-Abl, cortactin, Pfn-1, and Abi1 to the cell edge. Furthermore, MLCK localization at the leading edge was reduced by integrin β1 knockdown. Taken together, our results demonstrate that smooth muscle myosin localizes at the leading edge and orchestrates the recruitment of actin-regulatory proteins to the tip of lamellipodia. Mechanistically, integrin β1 recruits MLCK to the leading edge, which catalyzes MLC₂₀ phosphorylation. Activated myosin regulates the recruitment of actin-regulatory proteins to the leading edge, and promotes lamellipodial formation and migration. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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Review

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20 pages, 3079 KiB

Open AccessReview

Purification of Myosin from Bovine Tracheal Smooth Muscle, Filament Formation and Endogenous Association of Its Regulatory Complex

by Lu Wang, Isabel J. Sobieszek, Chun Y. Seow and Apolinary Sobieszek

Cells 2023, 12(3), 514; https://doi.org/10.3390/cells12030514 - 03 Feb 2023

Viewed by 1561

Abstract

Dynamic regulation of myosin filaments is a crucial factor in the ability of airway smooth muscle (ASM) to adapt to a wide length range. Increased stability or robustness of myosin filaments may play a role in the pathophysiology of asthmatic airways. Biochemical techniques [...] Read more.

Dynamic regulation of myosin filaments is a crucial factor in the ability of airway smooth muscle (ASM) to adapt to a wide length range. Increased stability or robustness of myosin filaments may play a role in the pathophysiology of asthmatic airways. Biochemical techniques for the purification of myosin and associated regulatory proteins could help elucidate potential alterations in myosin filament properties of asthmatic ASM. An effective myosin purification approach was originally developed for chicken gizzard smooth muscle myosin. More recently, we successfully adapted the procedure to bovine tracheal smooth muscle. This method yields purified myosin with or without the endogenous regulatory complex of myosin light chain kinase and myosin light chain phosphatase. The tight association of the regulatory complex with the assembled myosin filaments can be valuable in functional experiments. The purification protocol discussed here allows for enzymatic comparisons of myosin regulatory proteins. Furthermore, we detail the methodology for quantification and removal of the co-purified regulatory enzymes as a tool for exploring potentially altered phenotypes of the contractile apparatus in diseases such as asthma. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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17 pages, 1325 KiB

Open AccessReview

Current Understanding of Asthma Pathogenesis and Biomarkers

by Nazia Habib, Muhammad Asghar Pasha and Dale D. Tang

Cells 2022, 11(17), 2764; https://doi.org/10.3390/cells11172764 - 05 Sep 2022

Cited by 51 | Viewed by 11316

Abstract

Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most [...] Read more.

Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most important pathological process for asthma, which is mediated by Th2 cytokines, such as interleukin (IL)-5, IL-4, and IL-13. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2-low asthma can be mediated by non-Th2 cytokines, including IL-17 and tumor necrosis factor-α. There is emerging evidence to demonstrate that inflammation-independent processes also contribute to asthma pathogenesis. Protein kinases, adapter protein, microRNAs, ORMDL3, and gasdermin B are newly identified molecules that drive asthma progression, independent of inflammation. Eosinophils, IgE, fractional exhaled nitric oxide, and periostin are practical biomarkers for Th2-high asthma. Sputum neutrophils are easily used to diagnose Th2-low asthma. Despite progress, more studies are needed to delineate complex endotypes of asthma and to identify new and practical biomarkers for better diagnosis, classification, and treatment. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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23 pages, 1952 KiB

Open AccessReview

Sex Steroids Effects on Asthma: A Network Perspective of Immune and Airway Cells

by Niyati A. Borkar, Colin Kelly Combs and Venkatachalem Sathish

Cells 2022, 11(14), 2238; https://doi.org/10.3390/cells11142238 - 19 Jul 2022

Cited by 8 | Viewed by 3126

Abstract

A multitude of evidence has suggested the differential incidence, prevalence and severity of asthma between males and females. A compilation of recent literature recognized sex differences as a significant non-modifiable risk factor in asthma pathogenesis. Understanding the cellular and mechanistic basis of sex [...] Read more.

A multitude of evidence has suggested the differential incidence, prevalence and severity of asthma between males and females. A compilation of recent literature recognized sex differences as a significant non-modifiable risk factor in asthma pathogenesis. Understanding the cellular and mechanistic basis of sex differences remains complex and the pivotal point of this ever elusive quest, which remains to be clarified in the current scenario. Sex steroids are an integral part of human development and evolution while also playing a critical role in the conditioning of the immune system and thereby influencing the function of peripheral organs. Classical perspectives suggest a pre-defined effect of sex steroids, generalizing estrogens popularly under the “estrogen paradox” due to conflicting reports associating estrogen with a pro- and anti-inflammatory role. On the other hand, androgens are classified as “anti-inflammatory,” serving a protective role in mitigating inflammation. Although considered mainstream and simplistic, this observation remains valid for numerous reasons, as elaborated in the current review. Women appear immune-favored with stronger and more responsive immune elements than men. However, the remarkable female predominance of diverse autoimmune and allergic diseases contradicts this observation suggesting that hormonal differences between the sexes might modulate the normal and dysfunctional regulation of the immune system. This review illustrates the potential relationship between key elements of the immune cell system and their interplay with sex steroids, relevant to structural cells in the pathophysiology of asthma and many other lung diseases. Here, we discuss established and emerging paradigms in the clarification of observed sex differences in asthma in the context of the immune system, which will deepen our understanding of asthma etiopathology. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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