Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression

Fei Liu, Justin D. Mih, Barry S. Shea, Alvin T. Kho, Asma S. Sharif, Andrew M. Tager, Daniel J. Tschumperlin

Research output: Contribution to journalArticlepeer-review

389 Scopus citations

Abstract

Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E2 (PGE2), an autocrine inhibitor of fibrogenesis. Exogenous PGE2 or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE2, in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis.

Original languageEnglish (US)
Pages (from-to)693-706
Number of pages14
JournalJournal of Cell Biology
Volume190
Issue number4
DOIs
StatePublished - Aug 23 2010

ASJC Scopus subject areas

  • Cell Biology

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