Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts

Arthritis Rheum. 2007 Dec;56(12):4189-94. doi: 10.1002/art.23134.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bosentan
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Connective Tissue Growth Factor
  • Endothelin Receptor Antagonists
  • Endothelin-1 / metabolism*
  • Extracellular Matrix / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibronectins / metabolism
  • Gene Expression Profiling
  • Humans
  • Immediate-Early Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Phenotype
  • Pulmonary Fibrosis / metabolism*
  • Sulfonamides / pharmacology
  • Transforming Growth Factor beta / metabolism*


  • CCN2 protein, human
  • Collagen Type I
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Fibronectins
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Sulfonamides
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor
  • Bosentan