Role of cyclooxygenase enzymes in a murine model of experimental cholera.
Nonsteroidal anti-inflammatory drugs (e.g., indomethacin) inhibit and reduce the fluid secretion responses elicited by cholera toxin (CT), but it has not been conclusively determined which cyclooxygenase (COX) isoform is involved in CT's action. This study evaluated the role of the COX enzymes and their arachidonic acid metabolites in experimental cholera. Swiss-Webster mice were dosed with celecoxib and rofecoxib and challenged with CT in ligated small intestinal loops, and intestinal segments from mice deficient in COX-1 and COX-2 were challenged with CT. The effects of CT on fluid accumulation, prostaglandin E(2) production, mucosal tissue injury, and markers of oxidative stress were measured. Celecoxib and rofecoxib given at 160 micro g per mouse inhibited CT-induced fluid accumulation by 48% and 31%, respectively, but there was no significant difference among cox-1(-/-) and cox-2(-/-) mice in response to CT compared to wild-type controls. CT elevated tissue levels of oxidized glutathione and lipid peroxides and elicited small intestinal tissue injury in two of five cox-1(-/-) and four of five cox-2(-/-) mice. A role for COX-2 in CT's mechanism of action has previously been suggested by the effectiveness of COX-2 inhibitors in reducing CT-induced fluid secretion, but CT challenge of COX-1 and COX-2 knockout mice did not corroborate the pharmacological data. The results of this study show that CT induced oxidative stress in COX-deficient mice and suggest a tissue-protective role for arachidonic acid metabolites in the small intestine against oxidative stress.
Gessell-Lee
Deborah L
DL
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-0609, USA. dlgessel@utmb.edu
Popov
Vsevolod L
VL
Boldogh
Istvan
I
Olano
Juan P
JP
Peterson
Johnny W
JW
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000068579:Celecoxib; D002771:Cholera / Q000378:metabolism*; D002772:Cholera Toxin / Q000633:toxicity; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology*; D007783:Lactones / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011720:Pyrazoles; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000447:Aldehydes; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C116926:rofecoxib; D007975:Leukotriene B4; D008315:Malondialdehyde; D002772:Cholera Toxin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D005978:Glutathione; D000068579:Celecoxib; C027576:4-hydroxy-2-nonenal