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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 PGE2 than do AECs from
CCR2 +/+ mice, and MCP-1 inhibits AEC-derived PGE2
synthesis. Diminished PGE2 production by AECs results in enhanced fibroproliferation. Thus an important profibrotic mechanism of
MCP-1/CCR2 interactions is to limit PGE2 production in AECs after injury, thus promoting fibrogenesis.
lipid mediators; lung; chemokines; monocyte chemoattractant protein-1; CC chemokine receptor 2
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