Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis
Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis
复制标题
DOI：
10.1164/rccm.200702-291oc
复制
发表时间：
2007-10-01
影响因子：
24.7
通讯作者：
Catravas, John D.
中科院分区：
文献类型：
--
作者：
Chatterjee, Anuran;Dimitropoulou, Christiana;Catravas, John D.
理由-严重脓毒症是重症监护病房患者死亡的主要原因。严重脓毒症患者会因炎症反应失控而出现多器官衰竭，包括急性肺损伤（ALI）。普遍存在的分子伴侣热休克蛋白 90 (Hsp90) 的抑制剂可在体外阻断某些促炎介质的活性。我们假设 Hsp90 抑制剂可以改善与严重脓毒症相关的炎症和 ALI。目的：检验 Hsp90 抑制剂在脓毒症小鼠模型中延长生存、减轻炎症和减少肺损伤的假设。方法：雄性 C57BL/6 小鼠在接受致死剂量的内毒素（6.75 X 10(4) 内毒素单位/克体重）前 24、12、6 和 0 小时接受两种 Hsp90 抑制剂（根赤霉素或 17-烯丙氨基脱甲氧基格尔德霉素 (17AAG)）中的一种。结果包括存活率和全身炎症参数（血浆中性粒细胞、细胞因子、趋化因子和亚硝酸盐/硝酸盐水平）、肺部炎症（肺核因子-κB和髓过氧化物酶活性、诱导型一氧化氮合酶表达、诱导型一氧化氮合酶-Hsp90复合物形成和白细胞浸润），以及 肺损伤（肺毛细血管渗漏和肺功能）。测量和主要结果：用媒介物预处理并接受内毒素的小鼠表现出 100% 24 小时致死率，全身和肺部炎症的所有参数显着增加，毛细血管渗漏增加，肺功能下降。与它们相比，在接受内毒素之前接受根基酚或17-AAG的小鼠表现出更长的生存期，减少或消除了全身和肺部炎症参数的增加，减少了毛细血管渗漏，并恢复了正常的肺功能。结论：Hsp90 抑制剂可能为治疗严重脓毒症和严重脓毒症引起的 ALI 提供新的药理学工具。
Rationale- Severe sepsis is the leading cause of death for patients in intensive care units. Patients with severe sepsis develop multiple organ failure, including acute lung injury (ALI), resulting from a deregulated inflammatory response. Inhibitors of the ubiquitous chaperone, heat shock protein 90 (Hsp90), block the activity of certain proinflammatory mediators in vitro. We hypothesized that Hsp90 inhibitors may ameliorate the inflammation and ALI associated with severe sepsis. Objectives: To test the hypothesis that Hsp90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in a murine model of sepsis. Methods: Male C57BL/6 mice received either one of two Hsp90 inhibitors, radicicol or 17-allylaminodemethoxygeldanamycin (17AAG), 24, 12, 6, and 0 hours before receiving a lethal dose of endotoxin (6.75 X 10(4) endotoxin units/g body weight). Outcomes included survival and parameters of systemic inflammation (plasma neutrophil, cytokine, chemokine, and nitrite/nitrate levels), pulmonary inflammation (lung nuclear factor-kappa B and myeloperoxidase activities, inducible nitric oxide synthase expression, inducible nitric oxide synthase-Hsp90 complex formation, and leukocyte infiltration), and lung injury (pulmonary capillary leak and lung function). Measurements and Main Results: Mice pretreated with vehicle and receiving endotoxin exhibited 100% 24-hour lethality, a dramatic increase in all parameters of systemic and pulmonary inflammation, increased capillary leak, and reduced lung function. Compared with them, mice receiving either radicicol or 17-AAG before endotoxin exhibited prolonged survival, reduced or abolished increases in systemic and pulmonary inflammatory parameters, attenuated capillary leak, and restored, normal lung function. Conclusions: Hsp90 inhibitors may offer a new pharmacological tool in the management of severe sepsis and severe sepsis-induced ALI.