Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis
Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis
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DOI：
10.1164/rccm.200109-014oc
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发表时间：
2002-07-01
影响因子：
24.7
通讯作者：
Hollenberg, SM
中科院分区：
文献类型：
--
作者：
Cohen, ES;Law, WR;Hollenberg, SM
研究了内源性腺苷增加对脓毒症微血管紊乱的缓解作用。在盲肠结扎穿刺诱导脓毒症小鼠后立即给予戊他汀（2′-脱氧仿甲霉素），一种腺苷脱氨酶抑制剂。活体视频显微镜检查毛细血管后小静脉增厚。与对照组小鼠相比，脓毒症小鼠白细胞滚动和粘附明显增加。用喷他汀治疗脓毒症小鼠可显著降低白细胞滚动和粘附（6.02 +/- 0.09对1.72 +/- 0.12滚动细胞/分钟，2.07 +/- 0.04对0.62 +/- 0.05粘附细胞/分钟，p < 0.001）。经戊他汀治疗的脓毒症动物白蛋白漏出率显著降低（0.42 +/- 0.05 vs 0.21 +/- 0.04; p < 0.01）。经戊他汀治疗的脓毒症小鼠血液中白细胞介素-6、肿瘤坏死因子α和可溶性肿瘤坏死因子II型受体水平降低。喷他汀治疗小鼠48小时存活率显著提高。这些结果表明腺苷在脓毒症中调节白细胞依赖性和非依赖性内皮损伤机制中的重要作用。利用内源性腺苷的有利作用为脓毒症的治疗提供了一种潜在的有用的新治疗方法。
The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied. Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture. Intravital video microscopy of cremasteric postcapillary venules was performed. Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice. Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 mum per minute; p < 0.001). Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01). Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin. Survival was significantly improved at 48 hours in mice treated with pentostatin. These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis. Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.