Korean J Intern Med.  2014 May;29(3):281-290. 10.3904/kjim.2014.29.3.281.

Modifiers of TGF-beta1 effector function as novel therapeutic targets of pulmonary fibrosis

• Lee CM
• Park JW
• Cho WK
• Zhou Y
• Han B
• Yoon PO
• Chae J
• Elias JA
• Lee CG

• KMID: 1792051
• DOI: http://doi.org/10.3904/kjim.2014.29.3.281

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.

Keyword

Transforming growth factor beta1; Pulmonary fibrosis; Response modifiers; Amphiregulin; Chitotriosidase

MeSH Terms

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
Hexosaminidases
Receptor, Epidermal Growth Factor
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta1