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

Abstract

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)-1 β,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 bronchoalveolar 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 HMGB1 (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. Key words: Mechanical ventilation; Lung injury; Inflammatory cytokines; High mobility group box 1; Heat shock protein; 17-dimethylaminoethylamino-17-demethoxygeldanamycin