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.
Highlights
Increased IgE is a major pathology of allergic asthma which stimulates chronic inflammation and airway wall thickening leading to narrowing of the airway lumen [1,2]
Conclusion & Clincal Relevance: Our 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
We confirmed that the airway smooth muscle cells (ASMC) which we isolated from asthma and non-asthma patient airways express Ige-RI and Ige-RII as well as filamentous a-SMA
Summary
Increased IgE is a major pathology of allergic asthma which stimulates chronic inflammation and airway wall thickening leading to narrowing of the airway lumen [1,2] Regarding the mechanism it is unclear if the stimulating effect of IgE on airway wall remodelling is direct through the corresponding receptors or occurs indirect by increasing inflammatory mediator release from immune reactive cells or tissue forming cells [1,2]. It was suggested that in humans IgE may have a direct effect on airway wall remodelling, while earlier animal studies implicated indirect effects of IgE on airway remodelling, through stimulating the release of cytokines and growth factors from immune-reactive cells [8,9,10] None of these studies dissected the role of the two IgE receptors, Ige2RI and Ige2RII (CD23) in airway remodelling. 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
