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Published ahead of print on July 3, 2003, doi:10.1165/rcmb.2003-0005OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 1, January 2004, 91-100

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Submitted on January 8, 2003
Revised on July 2, 2003

Role of cytosolic phospholipase A2 in prostaglandin E2 production by lung fibroblasts

Moumita Ghosh1, Allison Stewart2, Dawn E Tucker1, Joseph V Bonventre3, Robert C Murphy1, and Christina C Leslie1*

1 Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA, 2 Safety Assessment, AstraZeneca R and D Charnwood, Loughborough, England, United Kingdom, 3 Department of Medicine, Massachusetts General Hospital East, Charlestown, MA, USA

* To whom correspondence should be addressed. E-mail: lesliec{at}njc.org.

PGE2 acts in an autocrine fashion to suppress proliferation of lung fibroblasts and production of collagen, and may negatively regulate pulmonary fibrosis. The role of Group IVA cytosolic phospholipase A2 alpha (cPLA2{alpha}) in PGE2production was investigated by comparing lung fibroblasts from wild type and cPLA2{alpha}-deficient mice. Arachidonic acid release from wild-type mouse lung fibroblasts (MLF+/+) was stimulated by serum, A23187 plus PMA, and lysophosphatidic acid (LPA) plus PDGF but was >=80% lower from cPLA2{alpha}-deficient MLF (MLF-/-). TGF{beta} increased cyclooxygenase-2 (COX2) expression to similar levels in MLF+/+ and MLF-/-, but MLF+/+ produced an order of magnitude more PGE2 than MLF-/- in response to A23187/PMA or PDGF/LPA. MLF+/+ synthesized less collagen than MLF-/- supporting a role for PGE2 in suppressing collagen production. An SV40 immortalized line developed from MLF+/+ released arachidonic acid and expressed COX2 to similar levels as primary fibroblasts but produced 30-fold lower amounts of PGE2. Unlike primary fibroblasts, immortalized cells were deficient in microsomal prostaglandin E synthase (mPGES) but expressed slightly higher levels of cytosolic PGES. The results demonstrate a primary role for cPLA2{alpha} in providing arachidonic acid for PGE2 production in mouse lung fibroblasts and support a role for this pathway in regulating collagen production.




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