Carneiro-Filho B A, Lima I P F, Araujo D H, Cavalcante M C, Carvalho G H P, Brito G A C, Lima V, Monteiro S M N, Santos F N, Ribeiro R A, Lima A A M
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, Ceara, Brasil.
Dig Dis Sci. 2004 Jan;49(1):65-72. doi: 10.1023/b:ddas.0000011604.45531.2c.
Chemotherapy-induced mucositis is an important dose-limiting and costly side effect for which there is no definitive prophylaxis or treatment. This is due in part to the lack of understanding of its pathophysiology and impact on intestinal function. The objectives of this study were to investigate the small intestine barrier function and electrolyte and water transport in an experimental model of methotrexate-induced mucositis, and to correlate these alterations with histological damage. Wistar rats were treated with methotrexate (1.5-3.5 mg/kg) for 3 days to induce mucositis. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following administration by gavage. Intestinal perfusion was performed in vivo for evaluation of water and electrolyte transports. Methotrexate-treated rats lost a significant amount of weight and presented a marked reduction in food intake. Methotrexate induced significant and dose-dependent villous atrophy and elongation of crypts in duodenum, jejunum, and ileum. Methotrexate also induced an increase in sodium and potassium secretion and an important reduction of the mucosa absorptive surface area, shown by the decrease in the mannitol excretion ratio. In conclusion, methotrexate caused major changes in small bowel function by disrupting intestinal permeability and inducing electrolyte secretion in parallel with substantial histological damage.
化疗引起的粘膜炎是一种重要的剂量限制性且代价高昂的副作用，对此尚无确切的预防或治疗方法。部分原因在于对其病理生理学以及对肠道功能的影响缺乏了解。本研究的目的是在甲氨蝶呤诱导的粘膜炎实验模型中研究小肠屏障功能以及电解质和水的转运，并将这些改变与组织学损伤相关联。用甲氨蝶呤（1.5 - 3.5毫克/千克）对Wistar大鼠进行为期3天的治疗以诱导粘膜炎。通过灌胃给药后，通过乳果糖和甘露醇的尿排泄率来测量肠道通透性。在体内进行肠道灌注以评估水和电解质的转运。经甲氨蝶呤治疗的大鼠体重显著减轻，食物摄入量明显减少。甲氨蝶呤在十二指肠、空肠和回肠中诱导了显著的、剂量依赖性的绒毛萎缩和隐窝延长。甲氨蝶呤还导致钠和钾分泌增加，并且粘膜吸收表面积显著减少，这通过甘露醇排泄率的降低得以体现。总之，甲氨蝶呤通过破坏肠道通透性并诱导电解质分泌，同时伴有实质性的组织学损伤，从而引起小肠功能的重大改变。
