热休克蛋白抑制剂格尔德霉素衍生物在机械通气肺损伤中的作用研究

目的探讨热休克蛋白（heat shock protein，HSP）90抑制剂格尔德霉素衍生物（17-dimethvlaminoethvlamino-17-demethoxygeldanamycin，17-DMAG）对机械通气肺损伤的保护作用及其作用机制。方法28只7周-9周的清洁级ICR雄性小鼠，按完全随机分组方法随机分为4组（每组7只）：对照组（CON组）、机械通气组（VEN组）、17-DMAG组和17-DMAG＋机械通气组（17-DMAG＋VEN组）。机械通气4h后或CON组与17-DMAG组麻醉插管后检测支气管肺泡灌洗液（bronchoalveolar lavage fluid，BALF）中蛋白浓度、细胞数量变化以及肺组织湿／干重比（wet-to-dry weight ratio，W／D），观察肺组织病理改变，并用酶联免疫吸附法（enzyme-linked immunosorbent assay，ELISA）检测肺组织白细胞介素（interleukin,IL）-1β、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）以及高迁移率族蛋白1（high mobility groupbox1，HMGB1）的含量。结果BALF中蛋白浓度和细胞数量：VEN组分别为（0．29±0．05）g／L和（2．84±0．55）个／ml，与CON组比较明显升高（P〈0．01）；17-DMAG＋VEN组分别为（0．22±0．03）g／L和（1．99±0．44）个／ml，与VEN组比较显著下降（P〈0．01）。VEN组肺组织W／D（5．14±0．19）与CON组（4．65±0．15）比较，差异有统计学意义（P〈0．01），17-DMAG＋VEN组肺组织W／D（4．79±0．14）与VEN组比较，差异有统计学意义（P〈0．01）。17-DMAG预处理能显著减轻通气诱导的肺组织病理损伤。机械通气4h可诱导肺组织中IL-1β、TNF-α、HMGB1蛋白表达显著升高，17-DMAG预处理可显著减轻机械通气诱导的HMGB1表达：17-DMAG＋VEN组（15．4±3．0）ms／g与VEN组（18．9±2．5）mg／s比较，差异有统计学意义（P〈0．05）。结论17-DMAG可能通过抑制炎症因子HMGB1的蛋白表达，减轻肺水肿，而在机械通气肺损伤中发挥保护作用。

Study of the role of heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin in mechanical ventilation-induced lung injury

Objective To investigate the effects and mechanisms of the heat shock protein （HSP） 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin （17-DMAG） on mechanical ventilation-induced lung injury. Methods Twenty-eight Male ICR mice（7-9 weeks old ） were randomly divided into four groups by random number table method（n=7 ）：control group （ CON group ）, mechanical ventilation group （ VEN group ）, 17 -DMAG group and 17 -DMAG ＋ Mechanical ventilation group （ 17 - DMAG＋VEN group）. The protein concentration and cell counts of bronchoalveolar lavage fluid were detected after four hours of ventilation. The wet-to-dry weight ratio （W/D） and pathological changes of lung tissue were examined. Interleukin （IL）-1β, tumor necrosis factor-α （TNF-α） and high mobility group box 1 （HMGB1） levels in lung tissue homogenates were measured by enzymelinked immunosorbent assay （ELISA）. Results Protein concentration and cell count from bronehoalveolar lavage fluid in VEN group were （0.29±0.05） g/L and （2.84±0.55）/ml, significantly higher（P〈0.01 ） than those in both CON groups and 17-DMAG＋VEN group （P〈0.01）. Lung tissue W/D in VEN group was （5.14±0.19） much higher than that in both control group （4.65±0.15 ） and 17- DMAG＋VEN group （4.79±0.14） （P〈0.01）. Pre-treatment with 17-DMAG could significantly reduce the ventilation-induced lung tissue damage. Four hours of mechanical ventilation could induce IL-1β, TNF-α and HMGB1 protein expression in lung tissue. Pretreatment with 17-DMAG could significantly reduce the mechanical ventilation -induced HMGB1 expression： there was statistical difference between 17-DMAG＋VEN group （15.4±3.0） mg/g and VEN group （ 18.9±2.5 ） mg/g in HMGB 1 （P〈0.05）. Conclusions Our results indicate that 17-DMAG can reduce pulmonary edema and exert protective effects in mechanical ventilation-induced lung injury by inhibiting the protein expression of HMGB1.