Sandoval M, Liu X, Mannick E E, Clark D A, Miller M J
Department of Pediatrics, Louisiana State University School of Medicine, New Orleans 70112, USA.
Gastroenterology. 1997 Nov;113(5):1480-8. doi: 10.1053/gast.1997.v113.pm9352850.
BACKGROUND & AIMS: Peroxynitrite (PN), a potent oxidant, has been implicated in the pathogenesis of gut inflammation and epithelial cell apoptosis. The aim of this study was to investigate mesalamine, a standard therapy for inflammatory bowel disease, to see if it attenuates PN-induced cytotoxicity in human intestinal epithelial cells and if mesalamine directly interacts with PN or its precursor, nitric oxide.
T84 and HT29 cells were divided in several protocols: mesalamine was administered 2 hours before, simultaneously, or 30 minutes after PN. T84 cells, grown in filter chamber inserts, were used to determine if basolateral or apical administration of PN initiated apoptosis and epithelial barrier function. The effects of mesalamine on PN decomposition and NO half-life were determined.
Mesalamine resulted in a dose-dependent decrease in PN-induced apoptosis, whether mesalamine was administered before (>10 micromol/L; IC50, 16 micromol/L), simultaneously (25-200 micromol/L; IC50, 24 micromol/L), or 30 minutes (200 micromol/L) after PN exposure. Mesalamine protected the epithelial barrier function of T84 cells against PN. Mesalamine rapidly degraded PN, whereas the half-life of NO was not affected.
The beneficial effects of mesalamine in the treatment of inflammatory bowel disease may involve an attenuation of PN-induced cell injury and apoptosis through direct and indirect mechanisms without affecting NO levels.
过氧亚硝酸根（PN）是一种强效氧化剂，与肠道炎症和上皮细胞凋亡的发病机制有关。本研究旨在探究用于治疗炎症性肠病的标准疗法美沙拉嗪，观察其是否能减轻PN诱导的人肠上皮细胞毒性，以及美沙拉嗪是否直接与PN或其前体一氧化氮相互作用。
将T84和HT29细胞分为几个方案：在PN处理前2小时、同时或处理后30分钟给予美沙拉嗪。将生长在滤膜小室插入物中的T84细胞用于确定PN从基底外侧或顶端给药是否会引发细胞凋亡和上皮屏障功能。测定美沙拉嗪对PN分解和NO半衰期的影响。
无论美沙拉嗪是在PN处理前（>10 μmol/L；半数抑制浓度[IC50]，16 μmol/L）、同时（25 - 200 μmol/L；IC50，24 μmol/L）还是PN暴露后30分钟（200 μmol/L）给予，美沙拉嗪都会导致PN诱导的细胞凋亡呈剂量依赖性降低。美沙拉嗪保护T84细胞的上皮屏障功能免受PN影响。美沙拉嗪能迅速降解PN，而NO的半衰期不受影响。
美沙拉嗪在炎症性肠病治疗中的有益作用可能涉及通过直接和间接机制减轻PN诱导的细胞损伤和凋亡，而不影响NO水平。
