Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2

Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L342-9. doi: 10.1152/ajplung.00168.2002. Epub 2002 Oct 4.


CC chemokine receptor 2 (CCR2) -/- mice are protected from experimental pulmonary fibrosis, a disease increasingly recognized as being mediated by dysfunctional interactions between epithelial cells and fibroblasts. We have sought to investigate the interactions between alveolar epithelial cells (AECs) and fibroblasts in these fibrosis-resistant (CCR2 -/-) and fibrosis-sensitive (CCR2 +/+) mice. AECs from CCR2 -/- mice suppress fibroblast proliferation more than AECs from CCR2 +/+ mice (77 vs. 43%). Exogenous administration of the CCR2 ligand monocyte chemoattractant protein-1 (MCP-1) to the fibroblast-AEC cocultures reverses the suppression mediated by CCR2 +/+ AECs but has no effect with CCR2 -/- AECs. MCP-1 regulates AEC function but not fibroblast function. AEC inhibition of fibroblast proliferation was mediated by a soluble, aspirin-sensitive factor. Accordingly, AECs from CCR2 -/- mice produce greater quantities of PGE(2) than do AECs from CCR2 +/+ mice, and MCP-1 inhibits AEC-derived PGE(2) synthesis. Diminished PGE(2) production by AECs results in enhanced fibroproliferation. Thus an important profibrotic mechanism of MCP-1/CCR2 interactions is to limit PGE(2) production in AECs after injury, thus promoting fibrogenesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Division / physiology
  • Chemokine CCL2 / pharmacology
  • Chemokine CCL2 / physiology*
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / physiology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology
  • Fibroblasts / cytology*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout / genetics
  • Prostaglandins / biosynthesis
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / physiology*
  • Receptors, CCR2
  • Receptors, Chemokine / physiology*


  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Prostaglandins
  • Receptors, CCR2
  • Receptors, Chemokine
  • Dinoprostone