Wallace J L, MacNaughton W K, Morris G P, Beck P L
Department of Physiology, Queen's University, Kingston, Ontario, Canada.
Gastroenterology. 1989 Jan;96(1):29-36. doi: 10.1016/0016-5085(89)90760-9.
The role of leukotrienes in the pathogenesis of chronic colitis was investigated using a rat model. Ulceration and inflammation of the distal colon was initiated by the intracolonic administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. Leukotriene B4 synthesis increased significantly within 4 h after induction of damage, with the greatest increase observed 24-72 h after administration of the hapten. The increase in leukotriene B4 synthesis correlated well (r = 0.88) with an increase in colonic myeloperoxidase activity, a biochemical marker of neutrophil infiltration. Daily intracolonic treatment with a specific 5-lipoxygenase inhibitor, L651,392, during the first 4 days after initiation of colitis, resulted in significant reductions of colonic leukotriene B4 synthesis, colonic damage score, and colon wet weight. When examined 2 wk after initiation of colitis, the group treated with L651,392 (for the first 4 days) showed significantly less colonic damage (assessed macroscopically and histologically) and colonic inflammation (assessed histologically and by measurement of myeloperoxidase activity). The healing produced by treatment with L651,392 was comparable to that observed after treatment with 5-aminosalicylic acid in a similar manner. Although a reduction of colonic damage could be produced in this model by intracolonic pretreatment with a prostaglandin E1 analogue (rioprostil), the mechanism of action of L651,392 did not appear to be through prevention of the initial injury induced by the hapten and ethanol solution. These results demonstrate that inhibition of leukotriene synthesis results in a marked acceleration of the healing of colonic ulcers and resolution of colonic inflammation in this animal model of chronic colitis. The results are therefore consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal inflammation.
使用大鼠模型研究了白三烯在慢性结肠炎发病机制中的作用。通过在50%乙醇中结肠内给予半抗原三硝基苯磺酸引发远端结肠溃疡和炎症。损伤诱导后4小时内白三烯B4合成显著增加，给予半抗原后24 - 72小时观察到最大增幅。白三烯B4合成的增加与结肠髓过氧化物酶活性的增加密切相关（r = 0.88），髓过氧化物酶活性是中性粒细胞浸润的生化标志物。在结肠炎发病后的前4天，每天结肠内给予特异性5 - 脂氧合酶抑制剂L651,392，导致结肠白三烯B4合成、结肠损伤评分和结肠湿重显著降低。在结肠炎发病2周后检查时，用L651,392治疗（前4天）的组显示结肠损伤（通过宏观和组织学评估）和结肠炎症（通过组织学和髓过氧化物酶活性测量评估）明显减轻。L651,392治疗产生的愈合效果与以类似方式用5 - 氨基水杨酸治疗后观察到的效果相当。尽管通过结肠内用前列腺素E1类似物（利奥前列素）预处理可在该模型中减少结肠损伤，但L651,392的作用机制似乎不是通过预防半抗原和乙醇溶液诱导的初始损伤。这些结果表明，在这种慢性结肠炎动物模型中，抑制白三烯合成可显著加速结肠溃疡的愈合和结肠炎症的消退。因此，这些结果与白三烯在肠道炎症发病机制中起重要作用的假设一致。
