Published ahead of print on July 5, 2007, doi:10.1164/rccm.200702-291OC Am. J. Respir. Crit. Care Med., Volume 176, Number 7, October 2007, 667-675 A more recent version of this article appeared on October 1, 2007
Submitted on February 20, 2007 Hsp90 Inhibitors Prolong Survival, Attenuate Inflammation and Reduce Lung Injury in Murine SepsisAnuran Chatterjee1,1 Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA, 2 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA, 3 Inflammation Core Laboratory, School of Allied Health Sciences, Medical College of Georgia, Augusta, GA, USA, 4 Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA, 5 Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA * To whom correspondence should be addressed. E-mail: jcatrava{at}mcg.edu.
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, resulting from a deregulated inflammatory response. Inhibitors of the ubiquitous chaperone, heat shock protein 90(hsp90), block the activity of certain pro-inflammatory mediators, in vitro. We hypothesized that hsp90 inhibitors may ameliorate the inflammation and acute lung injury associated with severe sepsis.
Objective: 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), at 24,12,6 and 0 hr before receiving a lethal dose of endotoxin (6.75 x 104 EU / g body weight). Outcomes included survival and parameters of systemic inflammation (plasma neutrophil, cytokine, chemokine and nitrite/nitrate levels), pulmonary inflammation (lung NF Key words: hsp90 inhibitors, sepsis, acute lung injury
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B and myeloperoxidase activities, iNOS expression, iNOS-hsp90 complex formation, leukocyte infiltration), and lung injury (pulmonary capillary leak, lung function).
Measurements and main results: Mice pre-treated with vehicle and receiving endotoxin exhibited 100% 24-hr lethality, dramatic increase in all parameters of systemic and pulmonary inflammation, increased capillary leak and reduced lung function. Compared to them, mice receiving either radicicol or 17-AAG prior to endotoxin, exhibited prolonged survival, reduced or abolished increases in systemic and pulmonary inflammatory parameters, attenuated capillary leak and restored, normal lung function.
Conclusion: Hsp90 inhibitors may offer a new pharmacological tool in the management of severe sepsis and severe sepsis-induced ALI.
