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Protein tyrosine phosphatase SHP 2 regulates TGF ‐β1 production in airway epithelia and asthmatic airway remodeling in mice
Author(s) -
Qin X.J.,
Zhang G.S.,
Zhang X.,
Qiu Z.W.,
Wang P.L.,
Li Y.W.,
Li W.,
Xie Q.M.,
Ke Y.H.,
Lee J. J,
Shen H.H.
Publication year - 2012
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12048
Subject(s) - ovalbumin , protein tyrosine phosphatase , immunology , gene knockdown , respiratory epithelium , fibrosis , lung , medicine , biology , microbiology and biotechnology , pathology , signal transduction , immune system , cell culture , genetics
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 SHP 2 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 Shp2 flox/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 SHP 2 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 SHP 2 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 SHP 2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP 2 represents a potentially novel therapeutic target for the treatment of asthmatics. Capsule summary Airway epithelial protein tyrosine phosphatase SHP 2 appears to modulate TGF ‐β1 activities as part of one or more cellular pathways leading to regulating the airway remodeling and lung dysfunction occurring in mouse models of allergic respiratory inflammation.