Modifiers of TGF-beta1 effector function as novel therapeutic targets of pulmonary fibrosis.
10.3904/kjim.2014.29.3.281
- Author:
Chang Min LEE
1
;
Jin Wook PARK
;
Won Kyung CHO
;
Yang ZHOU
;
Boram HAN
;
Pyoung Oh YOON
;
Jeiwook CHAE
;
Jack A ELIAS
;
Chun Geun LEE
Author Information
1. Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA. chungeun.lee@yale.edu
- Publication Type:Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
- Keywords:
Transforming growth factor beta1;
Pulmonary fibrosis;
Response modifiers;
Amphiregulin;
Chitotriosidase
- MeSH:
Animals;
Drug Design;
Hexosaminidases/antagonists & inhibitors/metabolism;
Humans;
Lung/*drug effects/metabolism/pathology;
Molecular Targeted Therapy;
Pulmonary Fibrosis/*drug therapy/metabolism/pathology;
Receptor Cross-Talk;
Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism;
Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism;
Signal Transduction;
Transforming Growth Factor beta1/*antagonists & inhibitors/metabolism
- From:The Korean Journal of Internal Medicine
2014;29(3):281-290
- CountryRepublic of Korea
- Language:English
-
Abstract:
Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-beta1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-beta1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-beta1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-beta1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-beta1 could be an alternative approach that selectively inhibits TGF-beta1-stimulated fibrotic tissue response while preserving major physiological function of TGF-beta1. Recent studies from our laboratory revealed that TGF-beta1 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-beta1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-beta1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-beta1 plays a significant role.
