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Modifiers of TGF-b1 effector function as novel therapeutic targets of pulmonary fibrosis

The Korean Journal of Internal Medicine 2014년 29권 3호 p.281 ~ p.290

이창민(Lee Chang-Min) - Yale University School of Medicine Section of Pulmonary and Critical Care Medicine
박진욱(Park Jin-Wook) - Yale University School of Medicine Section of Pulmonary and Critical Care Medicine
조원경(Cho Won-Kyung) - Yale University School of Medicine Section of Pulmonary and Critical Care Medicine
(Zhou Yang) - Yale University School of Medicine Section of Pulmonary and Critical Care Medicine
한보람(Han Bo-Ram) - Bioneer Corporation
(Yoon Pyoung-Oh) - Bioneer Corporation
(Chae Jei-Wook) - Bioneer Corporation
(Elias Jack A) - Brown University Warren Alpert School of Medicine Dean of Medicine and Biological Science
이춘근(Lee Chun-Geun) - Yale University School of Medicine Section of Pulmonary and Critical Care Medicine

Abstract

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-b1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-b1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-b1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-b1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-b1 could be an alternative approach that selectively inhibits TGF-b1-stimulated fibrotic tissue response while preserving major physiological function of TGF-b1. Recent studies from our laboratory revealed that TGF-b1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-b1 signaling as a new biomarker and therapeutic target of scleroderma- associated pulmonary fibrosis. These newly identified modifiers of TGF-b1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-b1 plays a significant role.