Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia

Steven K. Huang, Scott H. Wettlaufer, Cory M. Hogaboam, Kevin R. Flaherty, Fernando J. Martinez, Jeffrey L. Myers, Thomas V. Colby, William D. Travis, Galen B. Toews, Marc Peters-Golden

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Rationale: Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator. Objectives: To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts. Methods: Fibroblasts were grown in vitro from well characterized control (n = 7), UIP (n = 17), or other DPLD (n = 13) lung tissue. The effects of PGE2 on fibroblast proliferation and collagen expression were determined. Measurements and Main Results: Only 3 of 12 UIP fibroblast lines exhibited PGE 2-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE2 resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE2, whereas other DPLD fibroblasts manifested a degree of resistance intermediate to control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A. Conclusions: The recognition that UIP fibroblasts manifest variable refractoriness to PGE2 suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.

Original languageEnglish (US)
Pages (from-to)66-74
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume177
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • Collagen
  • Idiopathic pulmonary fibrosis
  • Nonspecific interstitial pneumonia
  • Proliferation
  • cAMP

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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