SOD prevents damage and attenuates eicosanoid release in a rabbit model of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) was produced in anesthetized rabbits by transmural injection of intestinal loops with an acidified solution of casein and calcium gluconate, mimicking the luminal milieu of afflicted neonates. Intravenous infusion of superoxide dismutase (SOD) 15 min after NEC induction prevented intestinal damage. In ex vivo perfused intestinal loops, we determined the sites of eicosanoid release and their contribution to the vascular effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in damaged and SOD-salvaged intestine. The vascular effluent was the primary site of stimulated eicosanoid release. The vascular responses to fMLP (vasoconstriction) and PAF (vasodilation) were not altered by SOD, although vascular resistance was higher in the SOD group. SOD treatment attenuated 1) transmural fluid shifts in ex vivo perfused intestinal preparations, an index of vascular permeability, 2) fMLP-induced prostaglandin E2, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) release, and 3) PAF-induced release of 6-keto-PGF1 alpha and LTB4. Stimulated thromboxane B2 release was not altered by SOD. Thus NEC can be established by a luminal insult that causes local generation of free radicals and exaggerated release of prostaglandins and leukotrienes.
Miller
M J
MJ
Department of Pharmacology, New York Medical College, Valhalla 10595.
McNeill
H
H
Mullane
K M
KM
Caravella
S J
SJ
Clark
D A
DA
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D003864:Depression, Chemical; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy*; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D011817:Rabbits; D013482:Superoxide Dismutase / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000378:metabolism
D015289:Leukotrienes; D010972:Platelet Activating Factor; D011453:Prostaglandins; D007975:Leukotriene B4; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013482:Superoxide Dismutase; D015232:Dinoprostone