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Am J Physiol Lung Cell Mol Physiol (January 27, 2006). doi:10.1152/ajplung.00182.2005
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Submitted on April 22, 2005
Accepted on January 20, 2006

Attenuation of the pulmonary inflammatory response following butylated hydroxytoluene (BHT) treatment of cytosolic phospholipase A2 (cPLA2) null mice

Amy M Meyer1, Lori D Dwyer-Nield2, Gregory Hurteau3, Robert L Keith4, Yanli Ouyang3, Brian M Freed3, Lori R Kisley2, Mark W Geraci3, Joseph V Bonventre5, Raphael A Nemenoff3, and Alvin M Malkinson2*

1 Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO, USA
2 Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO, USA
3 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
4 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Denver VA Medical Center, Denver, CO, USA
5 Division of Nephrology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Charlestown, MA, USA

* To whom correspondence should be addressed. E-mail: al.malkinson{at}uchsc.edu.

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 following BHT treatment but prior to 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 a hypothesis that cPLA2 is required to secrete sufficient MCP-1 to induce an inflammatory monocytic response.




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