International Journal of Molecular Sciences

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15 pages, 2512 KiB

Open AccessArticle

Extracellular Heat Shock Protein 70 Increases the Glucocorticoid Receptor and Dual-Specificity Phosphatase 1 via Toll-like Receptor 4 and Attenuates Inflammation in Airway Epithelial Cells

by Liang Zhou, Lei Fang, Michael Tamm, Daiana Stolz and Michael Roth

Int. J. Mol. Sci. 2023, 24(14), 11700; https://doi.org/10.3390/ijms241411700 - 20 Jul 2023

Cited by 3 | Viewed by 1118

Abstract

Heat shock protein 70 (HSP70) regulates the ligand binding of the glucocorticoid receptor (GR). In asthma patients, heat treatment increased both the GR expression and secretion of extracellular HSP70 (eHSP70) by bronchial epithelial cells (EC). The objective of this study was to assess [...] Read more.

Heat shock protein 70 (HSP70) regulates the ligand binding of the glucocorticoid receptor (GR). In asthma patients, heat treatment increased both the GR expression and secretion of extracellular HSP70 (eHSP70) by bronchial epithelial cells (EC). The objective of this study was to assess the effects of eHSP70 on GR expression and the GR-dependent regulation of immune response in human bronchial ECs. Cells were treated with either eHSP70 or transfected with an expression vector for intracellular HSP70 (iHSP70). Ribonucleic acid (RNA) and protein levels were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. Interleukin (IL-6 and IL-8) secretion was determined by enzyme linked immunosorbent assay (ELISA). The overexpression of iHSP70 decreased, while eHSP70 increased GR expression. In addition, eHSP70 increased the expression of the GR target dual-specificity phosphatase 1 (DUSP-1). In doing so, eHSP70 reduced the tumor growth factor (TGF)-β1-dependent activation of extracellular signal-regulated kinase (Erk)-1/2 and cyclic AMP response element binding protein (CREB) and the secretion of IL-6 and IL-8. Blocking the GR or Toll-like receptor 4 (TLR4) counteracted all eHSP70-induced effects. This study demonstrates a novel anti-inflammatory effect of eHSP70 by the signaling cascade of TLR4-GR-DUSP1, which inhibits TGF-β1-activated pro-inflammatory ERK1/2-CREB signaling and cytokine secretion. The findings suggest that eHSP70 might present a novel non-steroidal therapeutic strategy to control airway inflammation in asthma. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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14 pages, 4372 KiB

Open AccessArticle

Metformin Counteracts the Deleterious Effects of Methylglyoxal on Ovalbumin-Induced Airway Eosinophilic Inflammation and Remodeling

by Matheus L. Medeiros, Akila L. Oliveira, Glaucia C. Mello and Edson Antunes

Int. J. Mol. Sci. 2023, 24(11), 9549; https://doi.org/10.3390/ijms24119549 - 31 May 2023

Cited by 1 | Viewed by 1420

Abstract

Exposure to methylglyoxal (MGO) increases the levels of receptor for advanced glycation end products (RAGE) and reactive-oxygen species (ROS) in mouse airways, exacerbating the inflammatory responses. Metformin scavenges MGO in plasma of diabetic individuals. We investigated if amelioration by metformin of eosinophilic inflammation [...] Read more.

Exposure to methylglyoxal (MGO) increases the levels of receptor for advanced glycation end products (RAGE) and reactive-oxygen species (ROS) in mouse airways, exacerbating the inflammatory responses. Metformin scavenges MGO in plasma of diabetic individuals. We investigated if amelioration by metformin of eosinophilic inflammation reflects its ability to inactivate MGO. Male mice received 0.5% MGO for 12 weeks together or not with 2-week treatment with metformin. Inflammatory and remodeling markers were evaluated in bronchoalveolar lavage fluid (BALF) and/or lung tissues of ovalbumin (OVA)-challenged mice. MGO intake elevated serum MGO levels and MGO immunostaining in airways, which were reduced by metformin. The infiltration of inflammatory cells and eosinophils and levels of IL-4, IL-5 and eotaxin significantly increased in BALF and/or lung sections of MGO-exposed mice, which were reversed by metformin. The increased mucus production and collagen deposition by MGO exposure were also significantly decreased by metformin. In MGO group, the increases of RAGE and ROS levels were fully counteracted by metformin. Superoxide anion (SOD) expression was enhanced by metformin. In conclusion, metformin counteracts OVA-induced airway eosinophilic inflammation and remodeling, and suppresses the RAGE-ROS activation. Metformin may be an option of adjuvant therapy to improve asthma in individuals with high levels of MGO. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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11 pages, 8533 KiB

Open AccessArticle

Whole Blood Expression Levels of Long Noncoding RNAs: HOTAIRM1, GAS5, MZF1-AS1, and OIP5-AS1 as Biomarkers in Adolescents with Obesity-Related Asthma

by José J. Leija-Martínez, Carlos A. Guzmán-Martín, Javier González-Ramírez, Abraham Giacoman-Martínez, Blanca E. Del-Río-Navarro, Rodrigo Romero-Nava, Santiago Villafaña, José Luis Flores-Saenz, Fausto Sánchez-Muñoz and Fengyang Huang

Int. J. Mol. Sci. 2023, 24(7), 6481; https://doi.org/10.3390/ijms24076481 - 30 Mar 2023

Cited by 1 | Viewed by 1375

Abstract

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low [...] Read more.

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low endotype (obesity-related asthma). Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length, currently involved in many diverse biological functions, such as chromatin remodeling, gene transcription, protein transport, and microRNA processing. Despite the efforts to accurately classify and discriminate all the asthma endotypes and phenotypes, if long noncoding RNAs could play a role as biomarkers in allergic asthmatic and adolescent obesity-related asthma, adolescents remain unknown. To compare expression levels of lncRNAs: HOTAIRM1, OIP5-AS1, MZF1-AS1, and GAS5 from whole blood of Healthy Adolescents (HA), Obese adolescents (O), allergic asthmatic adolescents (AA) and Obesity-related asthma adolescents (OA). We measured and compared expression levels from the whole blood of the groups mentioned above through RT-q-PCR. We found differentially expressed levels of these lncRNAs between the groups of interest. In addition, we found a discriminative value of previously mentioned lncRNAs between studied groups. Finally, we generated an interaction network through bioinformatics. Expression levels of OIP5-AS1, MZF1-AS1, HOTAIRM1, and GAS5 in whole blood from the healthy adolescent population, obese adolescents, allergic asthma adolescents, and obesity-related asthma adolescents are differently expressed. Moreover, these lncRNAs could act as molecular biomarkers that help to discriminate between all studied groups, probably through molecular mechanisms with several genes and miRNAs implicated. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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21 pages, 3787 KiB

Open AccessArticle

Theophylline-Induced Relaxation Is Enhanced after Testosterone Treatment via Increased K_V1.2 and K_V1.5 Protein Expression in Guinea Pig Tracheal Smooth Muscle

by Jorge Reyes-García, Verónica Díaz-Hernández, Abril Carbajal-García, María F. Casas-Hernández, Bettina Sommer and Luis M. Montaño

Int. J. Mol. Sci. 2023, 24(6), 5884; https://doi.org/10.3390/ijms24065884 - 20 Mar 2023

Cited by 1 | Viewed by 1867

Abstract

Theophylline is a drug commonly used to treat asthma due to its anti-inflammatory and bronchodilatory properties. Testosterone (TES) has been suggested to reduce the severity of asthma symptoms. This condition affects boys more than girls in childhood, and this ratio reverses at puberty. [...] Read more.

Theophylline is a drug commonly used to treat asthma due to its anti-inflammatory and bronchodilatory properties. Testosterone (TES) has been suggested to reduce the severity of asthma symptoms. This condition affects boys more than girls in childhood, and this ratio reverses at puberty. We reported that guinea pig tracheal tissue chronic exposure to TES increases the expression of β₂-adrenoreceptors and enhances salbutamol-induced K⁺ currents (IK⁺). Herein, we investigated whether the upregulation of K⁺ channels can enhance the relaxation response to methylxanthines, including theophylline. Chronic incubation of guinea pig tracheas with TES (40 nM, 48 h) enhanced the relaxation induced by caffeine, isobutylmethylxanthine, and theophylline, an effect that was abolished by tetraethylammonium. In tracheal myocytes, chronic incubation with TES increased theophylline-induced IK⁺; flutamide reversed this effect. The increase in IK⁺ was blocked by 4-aminopyridine by ~82%, whereas iberiotoxin reduced IK⁺ by ~17%. Immunofluorescence studies showed that chronic TES exposure increased the expression of K_V1.2 and K_V1.5 in airway smooth muscle (ASM). In conclusion, chronic exposure to TES in guinea pig ASM promotes upregulation of K_V1.2 and K_V1.5 and enhances theophylline relaxation response. Therefore, gender should be considered when prescribing methylxanthines, as teenage boys and males are likely to respond better than females. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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11 pages, 1598 KiB

Open AccessArticle

Severe Asthma Remissions Induced by Biologics Targeting IL5/IL5r: Results from a Multicenter Real-Life Study

by Angelantonio Maglio, Carolina Vitale, Corrado Pelaia, Maria D’Amato, Luigi Ciampo, Eliana Sferra, Antonio Molino, Giulia Pelaia and Alessandro Vatrella

Int. J. Mol. Sci. 2023, 24(3), 2455; https://doi.org/10.3390/ijms24032455 - 27 Jan 2023

Cited by 19 | Viewed by 3193

Abstract

Add-on biological therapy has proven to be effective in many patients with severe eosinophilic asthma. In this observational multicenter retrospective study, we report the results obtained with mepolizumab and benralizumab in severe asthmatics treated for 12 months in a real-life setting. In these [...] Read more.

Add-on biological therapy has proven to be effective in many patients with severe eosinophilic asthma. In this observational multicenter retrospective study, we report the results obtained with mepolizumab and benralizumab in severe asthmatics treated for 12 months in a real-life setting. In these patients, peripheral eosinophil levels, pulmonary function trends, exacerbation rates, systemic corticosteroid use, and symptom control were evaluated during the observation period, to understand which patients met all the criteria in order to be considered in disease remission. The percentage of remittent patients was 30.12% in the mepolizumab-treated subgroup, while in the benralizumab-treated subgroup, patients in complete disease remission were 40%, after 12 months. The results of this study confirm the efficacy of anti-IL-5 biologic drugs in the treatment of severe eosinophilic asthma in a real-life setting. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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Review

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18 pages, 1840 KiB

Open AccessReview

Efferocytosis and Respiratory Disease

by Wenxue Zheng, Zhengjie Zhou, Xiaoping Guo, Xu Zuo, Jiaqi Zhang, Yiming An, Haoyu Zheng, Yuan Yue, Guoqiang Wang and Fang Wang

Int. J. Mol. Sci. 2023, 24(19), 14871; https://doi.org/10.3390/ijms241914871 - 3 Oct 2023

Cited by 1 | Viewed by 1533

Abstract

Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is [...] Read more.

Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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38 pages, 893 KiB

Open AccessReview

Molecular Accounting and Profiling of Human Respiratory Microbial Communities: Toward Precision Medicine by Targeting the Respiratory Microbiome for Disease Diagnosis and Treatment

by Ahmad R. Alsayed, Anas Abed, Heba A. Khader, Laith M. H. Al-Shdifat, Luai Hasoun, Mamoon M. D. Al-Rshaidat, Mohammad Alkhatib and Malek Zihlif

Int. J. Mol. Sci. 2023, 24(4), 4086; https://doi.org/10.3390/ijms24044086 - 17 Feb 2023

Cited by 14 | Viewed by 2635

Abstract

The wide diversity of microbiota at the genera and species levels across sites and individuals is related to various causes and the observed differences between individuals. Efforts are underway to further understand and characterize the human-associated microbiota and its microbiome. Using 16S rDNA [...] Read more.

The wide diversity of microbiota at the genera and species levels across sites and individuals is related to various causes and the observed differences between individuals. Efforts are underway to further understand and characterize the human-associated microbiota and its microbiome. Using 16S rDNA as a genetic marker for bacterial identification improved the detection and profiling of qualitative and quantitative changes within a bacterial population. In this light, this review provides a comprehensive overview of the basic concepts and clinical applications of the respiratory microbiome, alongside an in-depth explanation of the molecular targets and the potential relationship between the respiratory microbiome and respiratory disease pathogenesis. The paucity of robust evidence supporting the correlation between the respiratory microbiome and disease pathogenesis is currently the main challenge for not considering the microbiome as a novel druggable target for therapeutic intervention. Therefore, further studies are needed, especially prospective studies, to identify other drivers of microbiome diversity and to better understand the changes in the lung microbiome along with the potential association with disease and medications. Thus, finding a therapeutic target and unfolding its clinical significance would be crucial. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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26 pages, 6831 KiB

Open AccessReview

Human Lung Mast Cells: Therapeutic Implications in Asthma

by Remo Poto, Gjada Criscuolo, Gianni Marone, Chris E. Brightling and Gilda Varricchi

Int. J. Mol. Sci. 2022, 23(22), 14466; https://doi.org/10.3390/ijms232214466 - 21 Nov 2022

Cited by 9 | Viewed by 4320

Abstract

Mast cells are strategically located in different compartments of the lung in asthmatic patients. These cells are widely recognized as central effectors and immunomodulators in different asthma phenotypes. Mast cell mediators activate a wide spectrum of cells of the innate and adaptive immune [...] Read more.

Mast cells are strategically located in different compartments of the lung in asthmatic patients. These cells are widely recognized as central effectors and immunomodulators in different asthma phenotypes. Mast cell mediators activate a wide spectrum of cells of the innate and adaptive immune system during airway inflammation. Moreover, these cells modulate the activities of several structural cells (i.e., fibroblasts, airway smooth muscle cells, bronchial epithelial and goblet cells, and endothelial cells) in the human lung. These findings indicate that lung mast cells and their mediators significantly contribute to the immune induction of airway remodeling in severe asthma. Therapies targeting mast cell mediators and/or their receptors, including monoclonal antibodies targeting IgE, IL-4/IL-13, IL-5/IL-5Rα, IL-4Rα, TSLP, and IL-33, have been found safe and effective in the treatment of different phenotypes of asthma. Moreover, agonists of inhibitory receptors expressed by human mast cells (Siglec-8, Siglec-6) are under investigation for asthma treatment. Increasing evidence suggests that different approaches to depleting mast cells show promising results in severe asthma treatment. Novel treatments targeting mast cells can presumably change the course of the disease and induce drug-free remission in bronchial asthma. Here, we provide an overview of current and promising treatments for asthma that directly or indirectly target lung mast cells. Full article

(This article belongs to the Special Issue Molecular Research and Therapy of Asthma)

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