Attenuation of the pulmonary inflammatory response following butylated hydroxytoluene treatment of cytosolic phospholipase A2 null mice.
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 A(2) (cPLA(2)) catalyzes release of arachidonic acid from membrane phospholipids to initiate the synthesis of prostaglandins and other inflammatory mediators. A role for cPLA(2) in this response was examined by determining cPLA(2) expression and enzymatic activity in distal respiratory epithelia and macrophages and by assessing the consequences of cPLA(2) genetic ablation. BHT-induced lung inflammation, particularly monocyte infiltration, was depressed in cPLA(2) 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 cPLA(2) null mice secrete less MCP-1 than Clara cells from wild-type mice, consistent with the hypothesis that cPLA(2) is required to secrete sufficient MCP-1 to induce an inflammatory monocytic response.
Meyer
Amy M
AM
University of Colorado Health Sciences Center, School of Pharmacy, Box C238, 4200 E. 9th Avenue, Denver, CO 80262, USA.
Dwyer-Nield
Lori D
LD
Hurteau
Gregory
G
Keith
Robert L
RL
Ouyang
Yanli
Y
Freed
Brian M
BM
Kisley
Lori R
LR
Geraci
Mark W
MW
Bonventre
Joseph V
JV
Nemenoff
Raphael A
RA
Malkinson
Alvin M
AM
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002084:Butylated Hydroxytoluene / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000032:analysis; D054412:Chemokine CCL8; D003600:Cytosol / Q000201:enzymology; D007249:Inflammation / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D008171:Lung Diseases / Q000201:enzymology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000032:analysis; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics*; D054467:Phospholipases A2
D000975:Antioxidants; C515454:Ccl8 protein, mouse; D018932:Chemokine CCL2; D054412:Chemokine CCL8; D018945:Monocyte Chemoattractant Proteins; D002084:Butylated Hydroxytoluene; D010741:Phospholipases A; D054467:Phospholipases A2