In Vivo Allergen-Activated Eosinophils Promote Collagen I and Fibronectin Gene Expression in Airway Smooth Muscle Cells via TGF-β1 Signaling Pathway in Asthma (original) (raw)
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International Journal of Molecular Sciences
The impaired production of extracellular matrix (ECM) proteins by airway smooth muscle cells (ASMC) and pulmonary fibroblasts (PF) is a part of airway remodeling in asthma. This process might be influenced by eosinophils that migrate to the airway and abundantly secrete various cytokines, including TGF-β. We aimed to investigate the effect of asthmatic eosinophils on the gene expression of ECM proteins in ASMC and PF. A total of 34 study subjects were recruited: 14 with allergic asthma (AA), 9 with severe non-allergic eosinophilic asthma (SNEA), and 11 healthy subjects (HS). All AA patients underwent bronchial allergen challenge with D. pteronyssinus. The peripheral blood eosinophils were isolated using high-density centrifugation and magnetic separation. The individual cell cultures were made using hTERT ASMC and MRC-5 cell lines and the subjects’ eosinophils. The gene expression of ECM and the TGF-β signaling pathway was analyzed using qRT-PCR. We found that asthmatic eosinophils ...
Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy, 2006
Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins a 4 b 1 and a 4 b 7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen-binding integrins (a 1 b 1 and a 2 b 1) may also play a role in eosinophil lung infiltration. Objective To evaluate the possible presence of a 1 b 1 and a 2 b 1 integrins on peripheral blood eosinophils from asthmatic subjects. Methods Collagen receptors were studied on eosinophils separated by immunomagnetic CD16-negative method from healthy donors (n = 13) and patients with moderate persistent atopic bronchial asthma (n = 15). Surface receptor identification was performed by flow cytometry and cell adhesion assay. Results Eosinophils isolated from the patients showed increased expression of both a 1 b 1 and a 2 b 1 integrins as compared with healthy controls. Moreover, adhesive function of eosinophils to collagen type IV was inhibited by snake venom disintegrins: viperistatin and obtustatin. These disintegrins contain KTS active motif and are specific inhibitors of a 1 b 1 integrin. Conclusion We demonstrated for the first time that collagen receptors: a 1 b 1 and a 2 b 1 integrins are overexpressed on the surface of peripheral blood eosinophils of asthmatic subjects. Further studies may reveal potential application of KTS-disintegrins or their structural analogs for therapy of bronchial asthma.
Cells
Enhanced contractility and migration of airway smooth muscle cells (ASMC) and pulmonary fibroblasts (PF) are part of airway remodeling in asthma. Eosinophils are the central inflammatory cells that participate in airway inflammation. However, the role of asthmatic eosinophils in ASMC and PF contractility, migration, and differentiation to contractile phenotype has not yet been precisely described. A total of 38 individuals were included in this study: 13 steroid-free non-severe allergic asthma (AA) patients, 11 severe non-allergic eosinophilic asthma (SNEA) patients, and 14 healthy subjects (HS). For AA patients and HS groups, a bronchial allergen challenge with D. pteronyssinus was performed. Individual combined cell cultures were prepared from isolated peripheral blood eosinophils and immortalized ASMC or commercial PF cell lines separately. The migration of ASMC and PF was evaluated using wound healing assay and contractility using collagen gel assay. Gene expression of contracti...
Role of eosinophilic airway inflammation in models of asthma
Memórias do Instituto Oswaldo Cruz, 1997
Eosinophils play a central role in the establishment and outcome of bronchial inflammation in asthma. Animal models of allergy are useful to answer questions related to mechanisms of allergic inflammation. We have used models of sensitized and boosted guinea pigs to investigate the nature of bronchial inflammation in allergic conditions. These animals develop marked bronchial infiltration composed mainly of CD4+ T-lymphocytes and eosinophils. Further provocation with antigen leads to degranulation of eosinophils and ulceration of the bronchial mucosa. Eosinophils are the first cells to increase in numbers in the mucosa after antigen challenge and depend on the expression of α4 integrin to adhere to the vascular endothelium and transmigrate to the mucosa. Blockage of α4 integrin expression with specific antibody prevents not only the transmigration of eosinophils but also the development of bronchial hyperresponsiveness (BHR) to agonists in sensitized and challenged animals, clearly suggesting a role for this cell type in this altered functional state. Moreover, introduction of antibody against Major Basic Protein into the airways also prevents the development of BHR in similar model. BHR can also be suppressed by the use of FK506, an immunosuppressor that reduces in almost 100% the infiltration of eosinophils into the bronchi of allergic animals. These data support the concept that eosinophil is the most important pro-inflammatory factor in bronchial inflammation associated with allergy.
Eosinophils Induce Airway Smooth Muscle Cell Proliferation
Journal of Clinical Immunology, 2012
Asthma is characterized by eosinophilic airway inflammation and remodeling of the airway wall. Features of airway remodeling include increased airway smooth muscle (ASM) mass. However, little is known about the interaction between inflammatory eosinophils and ASM cells. In this study, we investigated the effect of eosinophils on ASM cell proliferation. Eosinophils were isolated from peripheral blood of mild asthmatics and non-asthmatic subjects and co-cultured with human primary ASM cells. ASM proliferation was estimated using Ki-67 expression assay. The expression of extracellular matrix (ECM) mRNA in ASM cells was measured using quantitative real-time PCR. The role of eosinophil derived Cysteinyl Leukotrienes (CysLTs) in enhancing ASM proliferation was estimated by measuring the release of leukotrienes from eosinophils upon their direct contact with ASM cells using ELISA. This role was confirmed either by blocking eosinophil-ASM contact or co-culturing them in the presence of leukotrienes antagonist. ASM cells co-cultured with eosinophils, isolated from asthmatics, but not non-asthmatics, had a significantly higher rate of proliferation compared to controls. This increase in ASM proliferation was independent of their release of ECM proteins but dependent upon eosinophils release of CysLTs. Eosinophil-ASM cell to cell contact was required for CysLTs release. Preventing eosinophil contact with ASM cells using anti-adhesion molecules antibodies, or blocking the activity of eosinophil derived CysLTs using montelukast inhibited ASM proliferation. Our results indicated that eosinophils contribute to airway remodeling during asthma by enhancing ASM cell proliferation and hence increasing ASM mass. Direct contact of eosinophils with ASM cells triggers their release of CysLTs which enhance ASM proliferation. Eosinophils, and their binding to ASM cells, constitute a potential therapeutic target to interfere with the series of biological events leading to airway remodeling and Asthma.
Journal of Clinical Medicine, 2019
Before eosinophils migrate into the bronchial lumen, they promote airway structural changes after contact with pulmonary cells and extracellular matrix components. We aimed to investigate the impact of eosinophil adhesion to their viability and pro-proliferative effect on airway smooth muscle (ASM) cells and pulmonary fibroblasts during different asthma phenotypes. A total of 39 individuals were included: 14 steroid-free non-severe allergic asthma (AA) patients, 10 severe non-allergic eosinophilic asthma (SNEA) patients, and 15 healthy control subjects (HS). For AA patients and HS groups, a bronchial allergen challenge with Dermatophagoides pteronysinnus was performed. Individual combined cells cultures were prepared between isolated peripheral blood eosinophils and ASM cells or pulmonary fibroblasts. Eosinophil adhesion was measured by evaluating their peroxidase activity, cell viability was performed by annexin V and propidium iodide staining, and proliferation by Alamar blue assa...
The eosinophil and airway remodelling in asthma
The Clinical Respiratory Journal, 2010
Objectives: Eosinophils are common findings cells in allergic asthma as is sub-base membrane thickening of the airways. The objective of this review was to summarise some recent findings linking the activities of eosinophils to airways remodelling. Data Source and Study Selection: The study used a review of current literature with emphasis on our own recent findings. Results: Eosinophils are found at increased numbers in asthma and more so in allergic as compared with non-allergic asthma. A link has been found in several clinical studies on allergic asthmatics, but not in studies on non-allergic asthma, between the presence of eosinophils and signs of airways remodelling. The eosinophil contains and secretes several pro-fibrogenic molecules such as eosinophil cationic protein (ECP) and transforming growth factor b (TGF-b). Genetic studies on subjects developing liver fibrosis as a consequence of Schistosoma mansoni infection show close relationships to ECP genotypes. Conclusion: Several clinical and experimental studies indicate that eosinophils contribute to airways remodelling not only through their secretion of cationic proteins such as ECP and cytokines such as TGF-b1, but also through interactions with mast cells and epithelial cells. Please cite this paper as: Venge P. The eosinophil and airway remodelling in asthma.
The role of eosinophils in asthma
Health, 2013
Asthma is a chronic inflammatory disorder of the airways characterized by recurring episodes of reversible airway obstruction, hyper-responsiveness, wheezing, breathlessness and coughing. Clinical diagnosis of asthma is based on the pattern of clinical symptoms and pulmonary fuction tests. Asthma affectes 5% -10% of the population and the number of worldwide cases is approximately 300 milliones. The incidence of this disease is increasing particulry in western countries [1]. It is the cause of a huge economic burden to national healthcare services. In a minority of cases, asthma is potentially fatal. After a period when fatalities appeared to be increasing [2], in recent years asthma-related mortality has progressively declined due to the development of specific asthma disease management programs, as well as the extensive use of inhaled corticosteroids [3]. Inflammation of the airways is a central component in asthma. Inflammation is associated with infliltration of the airway wall with eosinophiles and or neutronphiles mast cell degranulation and T cell activetion. Other pathological features include, subbasement membrane thickening, loss of epithetlial cell integrity, goblet cells hyperplasia Increase in airway smooth muscle mass. Eosinophils are thought to be vital in the development of airway hyperreactivity, with the eosinophil cationic protein playing a crucial role [4]. The fact that treatment of asthma with corticosteroids reduces eosinophils numbers and decreases airway reactivity further supports this hypothesis.