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

1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109; 2 Pulmonary Section of the Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48108; and 3 College of Natural Sciences, University of Texas, Austin, Texas 78712 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. lipid mediators; lung; chemokines; monocyte chemoattractant protein-1; CC chemokine receptor 2