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Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma
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Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 22320

Special Issue Editor

Prof. Dr. Michael Roth

E-Mail Website
Collection Editor
Pulmonary Cell Research/Pneumology, Department of Biomedicine/Internal Medicine, University & University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland
Interests: tissue remodeling in chronic lung diseases; asthma; COPD; lung fibrosis; epi-genetics; cell signaling; cell differentiation; epithelial cells; fibroblasts; airway smooth muscle cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Airway wall remodeling is a frequent pathology in asthma which, currently, can only be treated by bronchial thermoplasty. Remodeling narrows the airway lumen, limiting airflow, and reduces the tissue’s flexibility, thereby slowing muscle relaxation. Neither anti-inflammatory drugs nor bronchodilators have any effect on tissue remodeling structural changes. Thus, it seems unlikely that inflammation is the only cause of remodeling. The origin of airway wall remodeling is not well understood, and it is unclear whether remodeling occurs in the same way in all asthma patients. The classic meaning of remodeling involves hyperplasia and hypertrophy of the airway smooth muscle bundle, but these may not be the only factors involved. It is therefore necessary to determine the mechanisms that increase the thickness of the sub-epithelial basal membrane. In addition, the following questions are of interest: What changes the composition of the airway’s extracellular matrix? Why do myo-fibroblasts increase? Recent studies suggest that epigenetic events are the key to understanding asthma and airway wall remodeling. These epigenetic modifications can be handed down over 2–3 generations and pre-dispose the next generation to chronic inflammatory lung diseases.

This collection aims to provide studies to improve the understand of (i) how different asthma triggers (allergic and non-allergic) may activate the same mechanism(s) leading to remodeling and (ii) if there are data that suggest different types of airway wall remodeling.

Prof. Dr. Michael Roth
Collection Editor

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Keywords

  • Asthma associated airway wall remodeling
  • Disease or triggers of specific types of airway wall remodeling
  • Allergic and non-allergic triggers of remodeling
  • Epigenetic mechanisms of remodeling

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Published Papers (5 papers)

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Research

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20 pages, 15591 KiB  
Article
Regulation of Airway Smooth Muscle Cell Proliferation by Diacylglycerol Kinase: Relevance to Airway Remodeling in Asthma
by Miguel Angel Hernandez-Lara, Santosh K. Yadav, Sushrut D. Shah, Mariko Okumura, Yuichi Yokoyama, Raymond B. Penn, Taku Kambayashi and Deepak A. Deshpande
Int. J. Mol. Sci. 2022, 23(19), 11868; https://doi.org/10.3390/ijms231911868 - 6 Oct 2022
Cited by 7 | Viewed by 2319
Abstract
Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, [...] Read more.
Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic second messenger in ASM, and DGK inhibition reduces the conversion of DAG into PA resulting in inhibition of ASM cell proliferation. We assessed the effect of pharmacological inhibition of DGK on pro-mitogenic signaling and proliferation in primary human ASM cells. Pretreatment with DGK inhibitor I (DGKI) significantly inhibited platelet-derived growth factor-stimulated ASM cell proliferation. Anti-mitogenic effect of DGKI was associated with decreased mTOR signaling and expression of cyclin D1. Exogenous PA promoted pro-mitogenic signaling and rescued DGKI-induced attenuation of ASM cell proliferation. Finally, house dust mite (HDM) challenge in wild type mice promoted airway remodeling features, which were attenuated in DGKζ-/- mice. We propose that DGK serves as a potential drug target for mitigating airway remodeling in asthma. Full article
(This article belongs to the Special Issue Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma)
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16 pages, 26198 KiB  
Article
Der f 38 Is a Novel TLR4-Binding Allergen Related to Allergy Pathogenesis from Dermatophagoides farinae
by Geunyeong Kim, Minhwa Hong, Ayesha Kashif, Yujin Hong, Beom-Seok Park, Ji-Young Mun, Hyosun Choi, Ji-Sook Lee, Eun-Ju Yang, Ran-Sook Woo, Soo-Jin Lee, Minseo Yang and In-Sik Kim
Int. J. Mol. Sci. 2021, 22(16), 8440; https://doi.org/10.3390/ijms22168440 - 5 Aug 2021
Cited by 13 | Viewed by 2923
Abstract
It is difficult to treat allergic diseases including asthma completely because its pathogenesis remains unclear. House dust mite (HDM) is a critical allergen and Toll-like receptor (TLR) 4 is a member of the toll-like receptor family, which plays an important role in allergic [...] Read more.
It is difficult to treat allergic diseases including asthma completely because its pathogenesis remains unclear. House dust mite (HDM) is a critical allergen and Toll-like receptor (TLR) 4 is a member of the toll-like receptor family, which plays an important role in allergic diseases. The purpose of this study was to characterize a novel allergen, Der f 38 binding to TLR4, and unveil its role as an inducer of allergy. Der f 38 expression was detected in the body and feces of Dermatophagoides farinae (DF). Electron microscopy revealed that it was located in the granule layer, the epithelium layer, and microvilli of the posterior midgut. The skin prick test showed that 60% of allergic subjects were Der f 38-positive. Der f 38 enhanced surface 203c expression in basophils of Der f 38-positive allergic subjects. By analysis of the model structure of Der p 38, the expected epitope sites are exposed on the exterior side. In animal experiments, Der f 38 triggered an infiltration of inflammatory cells. Intranasal (IN) administration of Der f 38 increased neutrophils in the lung. Intraperitoneal (IP) and IN injections of Der f 38 induced both eosinophils and neutrophils. Increased total IgE level and histopathological features were found in BALB/c mice treated with Der f 38 by IP and IN injections. TLR4 knockout (KO) BALB/c mice exhibited less inflammation and IgE level in the sera compared to wild type (WT) mice. Der f 38 directly binds to TLR4 using biolayer interferometry. Der f 38 suppressed the apoptosis of neutrophils and eosinophils by downregulating proteins in the proapoptotic pathway including caspase 9, caspase 3, and BAX and upregulating proteins in the anti-apoptotic pathway including BCL-2 and MCL-1. These findings might shed light on the pathogenic mechanisms of allergy to HDM. Full article
(This article belongs to the Special Issue Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma)
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Review

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22 pages, 1256 KiB  
Review
Eosinophilic Airway Diseases: From Pathophysiological Mechanisms to Clinical Practice
by Mauro Mormile, Ilaria Mormile, Salvatore Fuschillo, Francesca Wanda Rossi, Laura Lamagna, Pasquale Ambrosino, Amato de Paulis and Mauro Maniscalco
Int. J. Mol. Sci. 2023, 24(8), 7254; https://doi.org/10.3390/ijms24087254 - 14 Apr 2023
Cited by 12 | Viewed by 3211
Abstract
Eosinophils play a key role in airway inflammation in many diseases, such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease. In these chronic disabling conditions, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through [...] Read more.
Eosinophils play a key role in airway inflammation in many diseases, such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease. In these chronic disabling conditions, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through the production a variety of mediators. With the introduction of biological drugs for the treatment of these respiratory diseases, the classification of patients based on clinical characteristics (phenotype) and pathobiological mechanisms (endotype) has become mandatory. This need is particularly evident in severe asthma, where, despite the great scientific efforts to understand the immunological pathways underlying clinical phenotypes, the identification of specific biomarkers defining endotypes or predicting pharmacological response remains unsatisfied. In addition, a significant heterogeneity also exists among patients with other airway diseases. In this review, we describe some of the immunological differences in eosinophilic airway inflammation associated with severe asthma and other airway diseases and how these factors might influence the clinical presentation, with the aim of clarifying when eosinophils play a key pathogenic role and, therefore, represent the preferred therapeutic target. Full article
(This article belongs to the Special Issue Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma)
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16 pages, 1258 KiB  
Review
Advances in the Knowledge of the Underlying Airway Remodeling Mechanisms in Chronic Rhinosinusitis Based on the Endotypes: A Review
by Kijeong Lee, Junhu Tai, Sang Hag Lee and Tae Hoon Kim
Int. J. Mol. Sci. 2021, 22(2), 910; https://doi.org/10.3390/ijms22020910 - 18 Jan 2021
Cited by 40 | Viewed by 6424
Abstract
Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the nasal and paranasal sinus mucosa that affects up to 10% of the population worldwide. CRS is the most representative disease of the upper respiratory tract where airway remodeling occurs, including epithelial damage, thickening [...] Read more.
Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the nasal and paranasal sinus mucosa that affects up to 10% of the population worldwide. CRS is the most representative disease of the upper respiratory tract where airway remodeling occurs, including epithelial damage, thickening of the basement membrane, fibrosis, goblet cell hyperplasia, subepithelial edema, and osteitis. CRS is divided into two phenotypes according to the presence or absence of nasal polyps: CRS with nasal polyp (CRSwNP) and CRS without nasal polyps (CRSsNP). Based on the underlying pathophysiologic mechanism, CRS is also classified as eosinophilic CRS and non-eosinophilic CRS, owing to Type 2 T helper (Th2)-based inflammation and Type 1 T helper (Th1)/Type 17 T helper (Th17) skewed immune response, respectively. Differences in tissue remodeling in CRS are suggested to be based on the clinical phenotype and endotypes; this is because fibrosis is prominent in CRSsNP, whereas edematous changes occur in CRSwNP, especially in the eosinophilic type. This review aims to summarize the latest information on the different mechanisms of airway remodeling in CRS according to distinct endotypes. Full article
(This article belongs to the Special Issue Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma)
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19 pages, 1435 KiB  
Review
Immunologic and Non-Immunologic Mechanisms Leading to Airway Remodeling in Asthma
by Lei Fang, Qinzhu Sun and Michael Roth
Int. J. Mol. Sci. 2020, 21(3), 757; https://doi.org/10.3390/ijms21030757 - 23 Jan 2020
Cited by 50 | Viewed by 6416
Abstract
Asthma increases worldwide without any definite reason and patient numbers double every 10 years. Drugs used for asthma therapy relax the muscles and reduce inflammation, but none of them inhibited airway wall remodeling in clinical studies. Airway wall remodeling can either be induced [...] Read more.
Asthma increases worldwide without any definite reason and patient numbers double every 10 years. Drugs used for asthma therapy relax the muscles and reduce inflammation, but none of them inhibited airway wall remodeling in clinical studies. Airway wall remodeling can either be induced through pro-inflammatory cytokines released by immune cells, or direct binding of IgE to smooth muscle cells, or non-immunological stimuli. Increasing evidence suggests that airway wall remodeling is initiated early in life by epigenetic events that lead to cell type specific pathologies, and modulate the interaction between epithelial and sub-epithelial cells. Animal models are only available for remodeling in allergic asthma, but none for non-allergic asthma. In human asthma, the mechanisms leading to airway wall remodeling are not well understood. In order to improve the understanding of this asthma pathology, the definition of “remodeling” needs to be better specified as it summarizes a wide range of tissue structural changes. Second, it needs to be assessed if specific remodeling patterns occur in specific asthma pheno- or endo-types. Third, the interaction of the immune cells with tissue forming cells needs to be assessed in both directions; e.g., do immune cells always stimulate tissue cells or are inflamed tissue cells calling immune cells to the rescue? This review aims to provide an overview on immunologic and non-immunologic mechanisms controlling airway wall remodeling in asthma. Full article
(This article belongs to the Special Issue Immunologic and Non-immunologic Mechanisms Leading to Airway Remodeling in Asthma)
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