Amelioration of TNBS-induced colon inflammation in rats by phospholipase A2 inhibitor.
The pathophysiology of inflammatory bowel disease (IBD) involves the production of diverse lipid mediators, namely eicosanoids, lysophospholipids, and platelet-activating factor, in which phospholipase A2 (PLA2) is the key enzyme. Accordingly, it has been postulated that control of lipid mediator production by inhibition of PLA2 would be useful for the treatment of IBD. This hypothesis was tested in the present study by examining the therapeutic effect of a novel extracellular PLA2 inhibitor (ExPLI), composed of carboxymethylcellulose-linked phosphatidylethanolamine (CMPE), on trinitrobenzenesulfonic acid-induced colitis. Intraperitoneal administration of CMPE suppressed the colitis as measured by mortality rate, intestinal permeability, plasma PLA2 activity, intestinal myeloperoxidase activity, and histological morphometry. Current therapeutic approaches for inflammatory conditions focus on the selective control of a lipid mediator(s) (e.g., prostaglandins or leukotrienes). The present study supports the concept that inclusive control of lipid mediator production by PLA2 inhibition is a plausible approach to the treatment of colitis and introduces the ExPLIs as a prototype of a novel NSAID for the treatment of intestinal inflammation.
Department of Biochemistry, Hadassah Medical School, Hebrew University Faculty of Medicine, Jerusalem, Israel 91120.
M
M
Krimsky
S
S
Yedgar
L
L
Aptekar
O
O
Schwob
G
G
Goshen
A
A
Gruzman
S
S
Sasson
M
M
Ligumsky
D000818:Animals; D002480:Cellulase; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D003106:Colon / Q000473:pathology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000097:blood; D054467:Phospholipases A2; D051381:Rats; D011919:Rats, Inbred Strains; D014302:Trinitrobenzenesulfonic Acid
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D010714:Phosphatidylethanolamines; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D010741:Phospholipases A; D054467:Phospholipases A2; D006026:Glycoside Hydrolases; D002480:Cellulase; C019826:carboxymethylcellulase