Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis

Anuran Chatterjee, Christiana Dimitropoulou, Fotios Drakopanayiotakis, Galina Antonova, Connie Snead, Joseph Gerard Cannon, Richard C Venema, John D. Catravas

Research output: Contribution to journalArticle

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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 × 104 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-κB 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.

Original languageEnglish (US)
Pages (from-to)667-675
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume176
Issue number7
DOIs
StatePublished - Oct 1 2007

Fingerprint

HSP90 Heat-Shock Proteins
Lung Injury
Sepsis
Inflammation
Endotoxins
Lung
Survival
Acute Lung Injury
Nitric Oxide Synthase Type II
Pneumonia
Multiple Organ Failure
Nitrites
Inbred C57BL Mouse
Chemokines
Nitrates
Peroxidase
Intensive Care Units
Cause of Death
Neutrophils
Leukocytes

Keywords

  • Acute lung injury
  • Hsp90 inhibitors
  • Sepsis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Chatterjee, A., Dimitropoulou, C., Drakopanayiotakis, F., Antonova, G., Snead, C., Cannon, J. G., ... Catravas, J. D. (2007). Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis. American Journal of Respiratory and Critical Care Medicine, 176(7), 667-675. https://doi.org/10.1164/rccm.200702-291OC

Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis. / Chatterjee, Anuran; Dimitropoulou, Christiana; Drakopanayiotakis, Fotios; Antonova, Galina; Snead, Connie; Cannon, Joseph Gerard; Venema, Richard C; Catravas, John D.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 176, No. 7, 01.10.2007, p. 667-675.

Research output: Contribution to journalArticle

Chatterjee, A, Dimitropoulou, C, Drakopanayiotakis, F, Antonova, G, Snead, C, Cannon, JG, Venema, RC & Catravas, JD 2007, 'Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis', American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 7, pp. 667-675. https://doi.org/10.1164/rccm.200702-291OC
Chatterjee, Anuran ; Dimitropoulou, Christiana ; Drakopanayiotakis, Fotios ; Antonova, Galina ; Snead, Connie ; Cannon, Joseph Gerard ; Venema, Richard C ; Catravas, John D. / Heat shock protein 90 inhibitors prolong survival, attenuate inflammation, and reduce lung injury in murine sepsis. In: American Journal of Respiratory and Critical Care Medicine. 2007 ; Vol. 176, No. 7. pp. 667-675.
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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 × 104 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-κB 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.",
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AB - 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 × 104 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-κB 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.

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