The Role of IgE-Receptors in IgE-Dependent Airway Smooth Muscle Cell Remodelling

Abstract

BackgroundIn allergic asthma, IgE increases airway remodelling but the mechanism is incompletely understood. Airway remodelling consists of two independent events increased cell numbers and enhanced extracellular matrix deposition, and the mechanism by which IgE up-regulates cell proliferation and extracellular matrix deposition by human airway smooth muscle cells in asthma is unclear.ObjectiveCharacterise the role of the two IgE receptors and associated signalling cascades in airway smooth muscle cell remodelling.MethodsPrimary human airway smooth muscle cells (8 asthmatics, 8 non-asthmatics) were stimulated with human purified antibody-activated IgE. Proliferation was determined by direct cell counts. Total collagen deposition was determined by Sircol; collagen species deposition by ELISA. IgE receptors were silenced by siRNA and mitogen activated protein kinase (MAPK) signalling was blocked by chemical inhibitors.ResultsIgE dose-dependently increased extracellular matrix and collagen deposition by airway smooth muscle cells as well as their proliferation. Specifically in cells of asthma patients IgE increased the deposition of collagen-type-I, -III, –VII and fibronectin, but did not affect the deposition of collagens type-IV. IgE stimulated collagen type-I and type-VII deposition through IgE receptor-I and Erk1/2 MAPK. Proliferation and deposition of collagens type-III and fibronectin involved both IgE receptors as well as Erk1/2 and p38 MAPK. Pre-incubation (30 minutes) with Omalizumab prevented all remodelling effects completely. We observed no changes in gelatinase activity or their inhibitors.Conclusion & Clincal RelevanceOur study provides the molecular biological mechanism by which IgE increases airway remodelling in asthma through increased airway smooth muscle cell proliferation and deposition of pro-inflammatory collagens and fibronectin. Blocking IgE action prevents several aspects of airway smooth muscle cell remodelling. Our findings may explain the recently described reduction of airway wall thickness in severe asthma patients treated with humanised anti-IgE antibodies.

The Prevalence of Increased Serum IgE and Aspergillus Sensitization in Patients With COPD and Their Association With Symptoms and Lung Function

“…One earlier study showed that the median time to recovery was 6 d (1-14) for peak expiratory flow rate (PEFR) and 7d (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) for symptoms, but recovery of PEFR to baseline values was complete in only 75.2% of exacerbations at 35d [34]. In our study, 18% (51/273) of the COPD patients were enrolled within 2~4 weeks after an exacerbation, when the lung functions were still recovering at least in some of the patients.…”

“…In this case, the serum total IgE (T-IgE) may be a more sensitive marker for hypersensitive condition of the host. Meanwhile, it is possible that serum IgE, which was shown to be related to airway inflammation and remodeling in asthma [6][7][8][9], may have effects on symptoms and lung function of COPD. Until now, data on the allergic status of COPD patients and its association with clinical symptoms and lung function are scarce.…”

The Effect of Omalizumab on Eosinophilic Inflammation of the Respiratory Tract in Patients with Allergic Asthma

“…Roth et al [32] observed that IgE increases airway remodelling in asthma by activation of proliferation of smooth muscle cells as well as by increased extracellular deposition of pro-inflammatory collagen (Types: I, III, VII) and fibronectin. Such findings imply a potential role of omalizumab in airway remodelling.…”

An insight into pharmacological and clinical basis of anti-IgE for add-on therapy of severe asthma

“…Furthermore, it has been recently reported that omalizumab can significantly decrease the concentration of endothelin-1 (ET-1) -a peptide involved in the pathogenesis of airway structural changes such as subepithelial fibrosis and proliferation of bronchial smooth muscle cells -in the exhaled © C I C E d i z i o n i I n t e r n a z i o n a l i breath condensate of patients with severe persistent allergic asthma (44). On the other hand, pre-treatment with omalizumab of airway smooth muscle cells obtained from allergic asthmatic patients significantly decreased IgE-dependent production of extracellular matrix proteins such as collagen type I, collagen type III and fibronectin (45). Recent preliminary findings, obtained in a limited number of asthmatic patients by means of computed tomography (CT) imaging, have shown that omalizumab reduced airway wall thickness and increased the bronchial luminal area (46).…”