HSP90 Inhibitors in Sepsis and Sepsis-induced Acute Lung Injury

Hdl Handle:
http://hdl.handle.net/10675.2/316953
Title:
HSP90 Inhibitors in Sepsis and Sepsis-induced Acute Lung Injury
Authors:
Chatterjee, Anuran
Abstract:
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 dysregulated 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. 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 cytokine, chemokine and nitrite/nitrate levels), pulmonary inflammation (lung NF-κB and myeloperoxidase activities, inducible nitric oxide or iNOS expression, iNOS-hsp90 complex formation, leukocyte infiltration), and lung injury (pulmonary capillary leak, expression of endothelial specific cell-adhesion or adherens junction proteins, lung function). Mice pre-treated with vehicle and receiving endotoxin exhibited 100% 24-hr lethality, dramatic increase in all parameters of systemic and pulmonary inflammation, reduced lung function and increased capillary leak associated with reduced expression of functional adherens junction proteins. In comparison, mice receiving either radicicol or 17-AAG prior to endotoxin, exhibited prolonged survival, reduced or abolished increases in systemic and pulmonary inflammatory parameters, normal lung function and attenuated capillary leak with restored expression of adherens junction proteins. Additionally, in an in vitro model of endotoxin and activated neutrophil-induced endothelial barrier dysfunction, we show that pre-incubation of neutrophils or endothelial cells or both with hsp90 inhibitors impart a profound barrier protective effect, which is mediated, at-least in part, through reduced activation of pp60Src kinase (an hsp90 client protein) and phosphorylation of the focal adhesion protein paxillin, a pp60Src kinase substrate. Hsp90 inhibitors are drugs already in use clinically as adjunct cancer treatment. Therefore, these findings point to a potential clinical use of these drugs in sepsis and sepsis induced ALI.
Affiliation:
Vascular Biology Center
Issue Date:
Jun-2007
URI:
http://hdl.handle.net/10675.2/316953
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304789731?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorChatterjee, Anuranen
dc.date.accessioned2014-05-14T19:23:20Z-
dc.date.available2014-05-14T19:23:20Z-
dc.date.issued2007-06-
dc.identifier.urihttp://hdl.handle.net/10675.2/316953-
dc.description.abstractSevere 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 dysregulated 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. 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 cytokine, chemokine and nitrite/nitrate levels), pulmonary inflammation (lung NF-κB and myeloperoxidase activities, inducible nitric oxide or iNOS expression, iNOS-hsp90 complex formation, leukocyte infiltration), and lung injury (pulmonary capillary leak, expression of endothelial specific cell-adhesion or adherens junction proteins, lung function). Mice pre-treated with vehicle and receiving endotoxin exhibited 100% 24-hr lethality, dramatic increase in all parameters of systemic and pulmonary inflammation, reduced lung function and increased capillary leak associated with reduced expression of functional adherens junction proteins. In comparison, mice receiving either radicicol or 17-AAG prior to endotoxin, exhibited prolonged survival, reduced or abolished increases in systemic and pulmonary inflammatory parameters, normal lung function and attenuated capillary leak with restored expression of adherens junction proteins. Additionally, in an in vitro model of endotoxin and activated neutrophil-induced endothelial barrier dysfunction, we show that pre-incubation of neutrophils or endothelial cells or both with hsp90 inhibitors impart a profound barrier protective effect, which is mediated, at-least in part, through reduced activation of pp60Src kinase (an hsp90 client protein) and phosphorylation of the focal adhesion protein paxillin, a pp60Src kinase substrate. Hsp90 inhibitors are drugs already in use clinically as adjunct cancer treatment. Therefore, these findings point to a potential clinical use of these drugs in sepsis and sepsis induced ALI.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/304789731?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.rights.uriAn error occurred getting the license - uri.*
dc.subjectSepsisen
dc.subjectAcute Lung Injuryen
dc.subjectInflammationen
dc.subjectSurvivalen
dc.subjectRadicicolen
dc.subject17- AAGen
dc.subjectInducible Nitric Oxideen
dc.subjectNF-κBen
dc.subjectHeat Shock Protein 90en
dc.subjectEndothelial Barrier Dysfunctionen
dc.titleHSP90 Inhibitors in Sepsis and Sepsis-induced Acute Lung Injuryen
dc.typeDissertationen
dc.contributor.departmentVascular Biology Centeren
dc.description.advisorCatravas, Johnen
dc.description.committeeVenema, Richard; Pollock, David; Ergul, Adviye; Verin, Alexander.en
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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