title: Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient cyclooxygenase-2.
abstract: Previous studies have shown that injury initiated by toxicants progresses even after most of the toxicant is eliminated from the body. One mechanism of progression of injury is the extracellular appearance of hydrolytic enzymes following leakage or upon cell lyses. Under normal conditions, after exposure to low to moderate doses of toxicants, secretory phospholipase A(2) (sPLA(2)) and other hydrolytic enzymes are known to appear in the extracellular spaces in order to cleanup the post-necrotic debris in tissues. We tested the hypothesis that sPLA(2) contributes to progression of toxicant-initiated liver injury because of hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas in the absence of sufficient cyclooxygenase-2 (COX-2). Male Sprague-Dawley rats were administered either a moderately hepatotoxic dose (MD, 2 ml CCl(4)/kg, ip) or a highly hepatotoxic dose (HD, 3 ml CCl(4)/kg, ip) of CCl(4). After MD, liver sPLA(2) and COX-2 were co-localized in the necrotic and perinecrotic areas and their activities in plasma and liver increased before decreasing in tandem with liver injury (ALT and histopathology) leading to 100% survival. In contrast, after the HD, high extracellular and hepatic sPLA(2) activities were accompanied by minimal COX-2 activity and localization in the liver throughout the time course. This led to progression of liver injury and 70% mortality. These data suggested a destructive role of sPLA(2) in the absence of sufficient COX-2. Time- and dose-dependent destruction of hepatocytes by sPLA(2) in isolated hepatocyte incubations confirmed the destructive ability of sPLA(2) when present extracellularly, suggesting its ability to spread injury in vivo. These findings suggest that sPLA(2), secreted for cleanup of necrotic debris upon initiation of hepatic necrosis, requires the co-presence of sufficiently induced COX-2 activity to prevent the run-away destructive action of sPLA(2) in the absence of the tissue protective mechanisms afforded by COX-2 induction.
authors.affiliation: Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209, USA.
authors.forename: Vishakha S
authors.initials: VS
authors.lastname: Bhave
authors.forename: Shashikiran
authors.initials: S
authors.lastname: Donthamsetty
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000208:Acute Disease; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000401:mortality; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D054497:Phospholipases A2, Secretory / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013997:Time Factors
chemical_list: D002251:Carbon Tetrachloride; D007770:L-Lactate Dehydrogenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000410:Alanine Transaminase; D054497:Phospholipases A2, Secretory; D015232:Dinoprostone