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shRNA for Thymic Stromal Lymphopoietin: A Novel Therapeutic Approach for Pulmonary Fibrosis

Tsung-Jen Hung, Shu-Fen Liu, Guo-Zheng Liu, Pei-fang Hsieh, Lea-Yea Chuang, Jinn-Yuh Guh, Chang-Chi Hsieh, Yu-Ju Hung, Yow-Ling Shiue and Yang Yu- Lin

Thymic stromal lymphopoietin (TSLP) was recently identified as a master switch for Th2 responses. This study discusses the role of TSLP in pulmonary fibrosis. We show that TGF-β1 (a Fibrogenic Growth Factor) up regulates TSLP proteins in human lung fibroblasts (HFL-1) on a dose- and time-course-dependent basis. Additionally, TSLP increases fibronectin expression on a dose- (1 ng/ml to 100 ng/ml) and time-course-dependent basis concomitantly with the upregulation of pSmad2/3 and Smad4, which is the essential downstream signal regulator for TGF-β. Silencing TSLP by TSLP shRNA dramatically reverses TGF-β1-induced cellular fibrosis concomitantly with the suppression of type I TGF-β receptors and pSmad2/3. Parallel results are observed in vivo. Bleomycin-treated C57BL/6 mice show intense staining for TSLP in fibrotic lung tissue by immunohistochemistry. More importantly, Sirius red and H&E staining from bleomycin-treated mice demonstrate that transfection with TSLP shRNA (by intranasal instillation) dramatically decreases both infiltration of inflammatory cells and deposition of collagen compared to the control. Moreover, a whole-body plethysmography test showed that TSLP shRNA transgenic mice significantly attenuate the increase in airway respiratory resistance induced by bleomycin. Thus, it may be possible to use TSLP shRNA as a novel therapeutic approach for treating pulmonary fibrosis by down-regulating TGF-β signal proteins.