Abstract
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 (17-AAG), 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-kappaB 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.