Abstract 200: Hsp90 Binding Inhibitors Improve Survival and Attenuate the Inflammatory Insult in a Murine Model of Sepsis-Induced Acute Lung Injury.
Sepsis-induced acute lung injury (ALI) is associated with the activation of numerous pro-inflammatory pathways, key components of which (e.g., NFkB iNOS, Src kinase, STAT3, etc.) are hsp90-dependent. Hsp90 binding inhibitors reduce the function and promote the breakdown of client proteins. Therefore, we tested the hypothesis that hsp90 binding inhibitors would ameliorate sepsis-induced ALI. C57Bl/6 male mice received vehicle (DMSO) or one of two hsp90 binding inhibitors, radicicol (RA: 3mg/kg, ip) or 17-AAG (5mg/kg, ip) at 24, 12, 6 and 0h before E.coli endotoxin (LPS; 6.75x104 EU/g, ip). Vehicle-treated mice receiving LPS exhibited 100% mortality by 23h post LPS; both RA and 17-AAG significantly increased survival to more than five days. Vehicle-pretreated and LPS-treated mice also exhibited a significant increase in lung iNOS expression, hsp90-iNOS complex formation, plasma nitrite/nitrate levels, pulmonary neutrophil sequestration (reflected in lung myeloperoxidase activity), lung edema (measured both as wet/dry lung weight and from the leak of iv-administered Evan’s Blue dye into the lungs), lung NFκB activity and plasma levels of IL6, MCP1, IL12, IFNγ and TNFα. Pretreatment of mice with RA or 17-AAG dramatically prevented the increase in all aforementioned indices of inflammation and significantly reduced edema formation. Histologic evaluation of lung tissue revealed characteristic hypercellularity, septal thickness and exudates in vehicle-pretreated and LPS-treated animals, which was significantly ameliorated by either RA or 17-AAG. We conclude that hsp90 binding inhibitors exert significant protection against a common cause of ALI; these anti-inflammatory effects of hsp90 binding inhibitors may warrant their development as potential pharmacological candidates for the management of sepsis- induced ALI
(supported by HL66993 and HL70214).