Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis.
Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-β1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-β1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-β1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-β1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-β1 could be an alternative approach that selectively inhibits TGF-β1-stimulated fibrotic tissue response while preserving major physiological function of TGF-β1. Recent studies from our laboratory revealed that TGF-β1 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-β1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-β1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-β1 plays a significant role.
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
Chang-Min
CM
Lee
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
Jin Wook
JW
Park
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
Won-Kyung
WK
Cho
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
Yang
Y
Zhou
Bioneer Corporation, Daejeon, Korea.
Boram
B
Han
Bioneer Corporation, Daejeon, Korea.
Pyoung Oh
PO
Yoon
Bioneer Corporation, Daejeon, Korea.
Jeiwook
J
Chae
Dean of Medicine and Biological Science, Brown University, Warren Alpert School of Medicine, Providence, RI, USA.
Jack A
JA
Elias
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA.
Chun Geun
CG
Lee
D000818:Animals; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006596:Hexosaminidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020239:Receptor Cross-Talk; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C512478:EGFR protein, human; D066246:ErbB Receptors; D006596:Hexosaminidases; C086400:chitotriosidase
Amphiregulin; Chitotriosidase; Pulmonary fibrosis; Response modifiers; Transforming growth factor beta1