Protein tyrosine phosphatase SHP2 regulates TGF‐β1 production in airway epithelia and asthmatic airway remodeling in mice

Abstract

Background Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling. Objectives To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling. Methods The airways of Shp2flox/flox mice were infected with recombinant adenovirus vectors expressing a Cre recombinase–green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1. Results Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression. Conclusions SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation. Clinical Implications Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP2 represents a potentially novel therapeutic target for the treatment of asthmatics.

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

“…Therefore, it can be speculated that the SHP2-induced deactivation of Smad2/3 could be the consequence of direct SHP2 phosphatase-dependent dephosphorylation of c-Abl. Our results are consistent with observations that SHP2 loss from AECs promotes epithelial-mesenchymal transition and fibrotic growth (19) but differ from those showing that SHP2 overexpression positively regulates TGFb 1 -induced airway remodeling in bronchial epithelial cells (39). Although the reasons for this discrepancy are unclear, it is possible that SHP2 will have different effects on different cells as has been previously proposed (33).…”

Th17 cells and tissue remodeling in atopic and contact dermatitis

“…As inflammation and, in particular, Th17 cell differentiation and activation are regulated by cytokines released by resident and/or inflammatory cells , the expression of TGF‐β, TNF‐α, IL‐1, IL‐6, IL‐23, and IL‐33 was assessed in the different eczema types over time (Fig. A–F).…”

Asthma research in China: A five‐year review

“…A large number of cytokines and chemokines, such as IL‐25, IL‐33, TSLP, TGF‐β, eotaxins, monocyte chemotactic proteins (MCP) and mucins, are released from airway epithelium upon allergen challenges that initiate and/or promote the asthmatic inflammation. Our recent study demonstrated that the protein tyrosine phosphatase SHP2 regulated TGF‐β1 production in airway epithelium, thereby regulating airway remodelling. Conditional shp2 gene knockdown in airway epithelia resulted in significantly attenuated airway remodelling and lung dysfunction, for example decreased inflammatory scores, collagen deposition, smooth muscle hyperplasia and AHR.…”