Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25

Abstract

Rationale: Airway hyperreactivity and remodeling are characteristic features of asthma. Interactions between the airway epithelium and environmental allergens are believed to be important in driving development of pathology, particularly because altered epithelial gene expression is common in individuals with asthma. Objectives: To investigate the interactions between a modified airway epithelium and a common aeroallergen in vivo. Methods: We used an adenoviral vector to generate mice overexpressing the transforming growth factor-b signaling molecule, Smad2, in the airway epithelium and exposed them to house dust mite (HDM) extract intranasally. Measurements and Main Results: Smad2 overexpression resulted in enhanced airway hyperreactivity after allergen challenge concomitant with changes in airway remodeling. Subepithelial collagen deposition was increased and smooth muscle hyperplasia was evident resulting in thickening of the airway smooth muscle layer. However, there was no increase in airway inflammation in mice given the Smad2 vector compared with the control vector. Enhanced airway hyperreactivity and remodeling did not correlate with elevated levels of Th2 cytokines, such as IL-13 or IL-4. However, mice overexpressing Smad2 in the airway epithelium showed significantly enhanced levels of IL-25 and activin A after HDM exposure. Blocking activin A with a neutralizing antibody prevented the increase in lung IL-25 and inhibited subsequent collagen deposition and also the enhanced airway hyperreactivity observed in the Smad2 overexpressing HDM-exposed mice. Conclusions: Epithelial overexpression of Smad2 can specifically alter airway hyperreactivity and remodeling in response to an aeroallergen. Moreover, we have identified novel roles for IL-25 and activin A in driving airway hyperreactivity and remodeling.

Role of activin-A in cigarette smoke-induced inflammation and COPD

“…In vitro results indicate that activin-A can stimulate proliferation of human lung fibroblasts and smooth muscle cells [41,42]. Moreover, blocking activin-A inhibited collagen deposition and thickening of the subepithelial smooth muscle layer in two different murine models of allergic asthma [43,44]. Similarly, it would be helpful to study the relationship between activin-A and peribronchial fibrosis in patients with COPD.…”

Transforming Growth Factor-β: Master Regulator of the Respiratory System in Health and Disease

“…Interestingly, in the airways of humans with asthma, TGF-b1 levels are elevated compared with normal control subjects, perhaps suggesting a role in the repair of injured asthmatic airways or the existence of a negative feedback loop controlling airway inflammation (40). TGFb signaling can also promote ECM deposition, airway smooth muscle cell proliferation, and mucus production in animal models of allergic asthma, with overexpression of Smad2 resulting in airway smooth muscle cell proliferation and collagen deposition after an allergen challenge (79,80). In asthma pathogenesis, activation of TGF-b can occur via epithelial cell, mast cell, or fibroblast activity (6).…”

Novel concepts in airway inflammation and remodelling in asthma

“…Strikingly, however, methacholine challenge induced only bronchoconstriction and remodelling without inflammation [43]. Data from experimental models also suggest a much tighter relationship between airway contraction, lung function and remodelling than any association between inflammation and remodelling [44]. In late-onset (adult) murine models it is becoming increasingly apparent that remodelling can develop despite minimal or absent airway inflammation [45].…”

“…Both of the studies have highlighted a therapeutic role for IL-33, but have used complex murine models combined with data from patients. There is evidence from experimental models that molecules such as IL-25, activin A and transforming growth factor (TGF)-β are involved in the induction of airway remodelling [44,45], and that blocking their action improves both airway remodelling and lung function. However, these are also complex models that involve altered tissue-specific (epithelial) gene expression, not simple knockout mice.…”