Clark D A, Fornabaio D M, McNeill H, Mullane K M, Caravella S J, Miller M J
Department of Pharmacology, New York Medical College, Valhalla 10595.
Am J Pathol. 1988 Mar;130(3):537-42.
Oxygen-derived free radicals, particularly superoxide anion, are considered important mediators of intestinal injury induced by ischemia/reperfusion based on the protective effects of superoxide dismutase and allopurinol. A role for free radicals was investigated in a model of necrotizing enterocolitis (NEC) which was initiated by a luminal, as opposed to a vascular, insult. Intestinal loops of weanling rabbits received either saline (control loops) or a solution of 10 mg/ml casein and 50 mg/ml calcium gluconate acidified to pH 4 with proprionic acid (treated loops). When the animals were sacrificed 3 hours later, severe damage was noted in the treated loops, which included blunting of villi and edema, with all animals surviving. At 16 hours only 5 of 8 rabbits survived, and 3 had hemorrhagic necrosis. Control loops were normal in each case. Intravenous infusion of superoxide dismutase (4 mg/kg/hr), commencing 15 minutes after NEC induction, totally prevented intestinal injury. On the other hand, pretreatment with allopurinol, an inhibitor of xanthine oxidase, for 2 days (30 and 60 mg/kg by mouth) was not protective against intestinal damage. A cellular infiltration in treated loops was not histologically evident in the majority of animals at 3 hours after treatment, a finding confirmed by the minimal accumulation of 111In-labeled leukocytes in damaged and intact intestinal tissue. These results suggest that superoxide generated locally from sources other than xanthine oxidase play a critical and early role in experimental NEC and that superoxide dismutase may prove to be an effective therapy in this devastating neonatal disease.
基于超氧化物歧化酶和别嘌呤醇的保护作用，氧衍生的自由基，尤其是超氧阴离子，被认为是缺血/再灌注诱导的肠道损伤的重要介质。在坏死性小肠结肠炎（NEC）模型中研究了自由基的作用，该模型由腔内而非血管损伤引发。断奶兔的肠袢接受生理盐水（对照肠袢）或用丙酸酸化至pH 4的10 mg/ml酪蛋白和50 mg/ml葡萄糖酸钙溶液（处理过的肠袢）。3小时后处死动物时，发现处理过的肠袢有严重损伤，包括绒毛变钝和水肿，所有动物均存活。16小时时，8只兔子中只有5只存活，3只出现出血性坏死。对照肠袢在每种情况下均正常。在NEC诱导后15分钟开始静脉输注超氧化物歧化酶（4 mg/kg/小时），可完全预防肠道损伤。另一方面，用黄嘌呤氧化酶抑制剂别嘌呤醇预处理2天（口服30和60 mg/kg）对肠道损伤没有保护作用。在处理后3小时，大多数动物的处理过的肠袢中细胞浸润在组织学上不明显，这一发现通过受损和完整肠道组织中111In标记的白细胞的最小积累得到证实。这些结果表明，黄嘌呤氧化酶以外的来源局部产生的超氧阴离子在实验性NEC中起关键的早期作用，并且超氧化物歧化酶可能被证明是治疗这种毁灭性新生儿疾病的有效疗法。
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