Yang Bingchang, Gao Min, Wang Kangkai, Jiang Yu, Peng Yue, Zhang Huali, Yang Mingshi, Xiao Xianzhong
Translational Medicine Center of Sepsis, Department of Pathophysiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
Translational Medicine Center of Sepsis, Department of Pathophysiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
J Surg Res. 2017 May 1;211:70-78. doi: 10.1016/j.jss.2016.11.061. Epub 2016 Dec 14.
Intravenous administration of ulinastatin (UTI), a broad spectral protease inhibitor, has been used on an experimental basis with severe sepsis patients in Asia. However, the effects of intraintestinal administration of UTI on intestinal and multiple organ damage in sepsis have not been reported.
In this study, we established a sepsis model in rats using cecal ligation and puncture and compared the effects of intraintestinal administration of UTI through an artificial fistula of duodenum and intraperitoneal administration of UTI on the pathophysiological changes of sepsis.
It was found that intraintestinal administration of UTI (1) significantly improved the survival of septic rats, (2) significantly reduced the serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 as well as intestinal injury biomarkers diamine oxidase, D-lactic acid, and fluorescein isothiocyanate-dextran 4, and (3) significantly reduced intestinal microscopic and ultrastructural damage of septic rats. In addition, the protective effects of intraintestinal administration of UTI were significantly better than those of intraperitoneal administration of UTI.
Overall, the present study for the first time revealed that intraintestinal administration of protease inhibitor UTI could reduce systemic inflammatory responses and multiple organ dysfunction in rats with sepsis by inhibiting autodigestion of intestinal wall due to proteases and provided new research ideas and experimental evidences for treatment of sepsis by intraintestinal administration of UTI.
广谱蛋白酶抑制剂乌司他丁（UTI）的静脉给药已在亚洲用于重症脓毒症患者的实验性治疗。然而，UTI肠内给药对脓毒症肠道及多器官损伤的影响尚未见报道。
在本研究中，我们采用盲肠结扎穿刺法建立大鼠脓毒症模型，比较经十二指肠人工瘘管肠内给药UTI和腹腔内给药UTI对脓毒症病理生理变化的影响。
发现肠内给药UTI（1）显著提高脓毒症大鼠的存活率，（2）显著降低血清肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-6水平以及肠损伤生物标志物二胺氧化酶、D-乳酸和异硫氰酸荧光素-葡聚糖4的水平，（3）显著减轻脓毒症大鼠肠道的微观和超微结构损伤。此外，肠内给药UTI的保护作用显著优于腹腔内给药UTI。
总体而言，本研究首次揭示蛋白酶抑制剂UTI肠内给药可通过抑制蛋白酶对肠壁的自身消化，减轻脓毒症大鼠的全身炎症反应和多器官功能障碍，为UTI肠内给药治疗脓毒症提供了新的研究思路和实验依据。
