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This Article Full Text Full Text (PDF) All Versions of this Article: 290/6/L1260    most recent 00182.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Meyer, A. M. Articles by Malkinson, A. M. Search for Related Content PubMed PubMed Citation Articles by Meyer, A. M. Articles by Malkinson, A. M.

Attenuation of the pulmonary inflammatory response following butylated hydroxytoluene treatment of cytosolic phospholipase A₂ null mice

Departments of ¹Pharmacology, ²Pharmaceutical Sciences, and ³Medicine, University of Colorado Health Sciences Center, Denver; ⁴Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado; and ⁵Division of Nephrology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School and Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Charlestown, Massachusetts

Submitted 22 April 2005 ; accepted in final form 20 January 2006

Administration of butylated hydroxytoluene (BHT) to mice causes lung damage characterized by the death of alveolar type I pneumocytes and the proliferation and subsequent differentiation of type II cells to replace them. Herein, we demonstrate this injury elicits an inflammatory response marked by chemokine secretion, alveolar macrophage recruitment, and elevated expression of enzymes in the eicosanoid pathway. Cytosolic phospholipase A₂ (cPLA₂) catalyzes release of arachidonic acid from membrane phospholipids to initiate the synthesis of prostaglandins and other inflammatory mediators. A role for cPLA₂ in this response was examined by determining cPLA₂ expression and enzymatic activity in distal respiratory epithelia and macrophages and by assessing the consequences of cPLA₂ genetic ablation. BHT-induced lung inflammation, particularly monocyte infiltration, was depressed in cPLA₂ null mice. Monocyte chemotactic protein-1 (MCP-1) content in bronchoalveolar lavage fluid increases after BHT treatment but before monocyte influx, suggesting a causative role. Bronchiolar Clara cells isolated from cPLA₂ null mice secrete less MCP-1 than Clara cells from wild-type mice, consistent with the hypothesis that cPLA₂ is required to secrete sufficient MCP-1 to induce an inflammatory monocytic response.

eicosanoids; Clara cells; macrophages