Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts.
OBJECTIVE
Fibrosis is excessive scarring caused by the accumulation and contraction of extracellular matrix proteins and is a common end pathway in many chronic diseases, including scleroderma (systemic sclerosis [SSc]). Indeed, pulmonary fibrosis is a major cause of death in SSc. Transforming growth factor beta (TGFbeta) induces endothelin 1 (ET-1) in human lung fibroblasts by a Smad-independent, JNK-dependent mechanism. The goal of this study was to assess whether ET-1 is a downstream mediator of the profibrotic effects of TGFbeta in lung fibroblasts.


METHODS
We used a specific endothelin receptor antagonist to determine whether ET-1 is a downstream mediator of TGFbeta responses in lung fibroblasts, using microarray technology, real-time polymerase chain reaction, and Western blot analyses.


RESULTS
The ability of TGFbeta to induce the expression of a cohort of profibrotic genes, including type I collagen, fibronectin, and CCN2, and to contract a collagen gel matrix, depends on ET-1.


CONCLUSIONS
ET-1 contributes to the ability of TGFbeta to promote a profibrotic phenotype in human lung fibroblasts, consistent with the notion that endothelin receptor antagonism may be beneficial in controlling fibrogenic responses in lung fibroblasts.
Shi-wen
Xu
X
Royal Free Hospital, University College London, London, UK.
Kennedy
Laura
L
Renzoni
Elisabetta A
EA
Bou-Gharios
George
G
du Bois
Roland M
RM
Black
Carol M
CM
Denton
Christopher P
CP
Abraham
David J
DJ
Leask
Andrew
A
D000077300:Bosentan; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C526317:CCN2 protein, human; D024042:Collagen Type I; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D000077300:Bosentan