The goal of this new grant cycle is to determine how the activation of the stress protein response (SPR) protects the integrity of the alveolar capillary barrier in acute lung injury (All). We therefore developed a model of ischemia-reperfusion (l/R)-mediated lung injury in rats and mice as a clinically relevant model of All. In preliminary experiments, SPR activation inhibited the vascular endothelial growth factor (VEGF) mediated lung endothelial leak and prevented the iNOS/NO-mediated inhibition of alveolar edema removal by the lung epithelium after onset of I/R injury. We will test the central hypothesis that SPR activation inhibits these two cell signaling pathways (VEGF, JAK/Stat1-induced iNOS/NO) by: (a) first by an immediate dissociation of Hsp90 from its clients proteins that are critical part of these two signaling pathways, thus rendering them nonfunctional, then (b) by a de novo synthesis of heat shock proteins, such as Hsp70, that binds to Hsp90 client proteins and prevents their aggregation and proteasomal degradation until the Hsp90 can re-complex with the proteins.
In aim 1, we will provide new insights into the molecular mechanisms explaining how SPR activation inhibits VEGF-dependent cell signaling that causes the leakage in the lung endothelial barrier.
In aim 2 , we will examine how SPR activation restores normal alveolar fluid transport by inhibiting the effect of JAK/Stat1-induced iNOS-dependent NO release in the airspaces on the basal and cAMP-regulated ion and fluid transport across the lung epithelium.
In aim 3, we will determine the in vivo relevance of the SPR-mediated inhibition of the VEGF-induced increase in lung vascular permeability and NO-mediated impairment of alveolar epithelial fluid transport and protein permeability in a rat/mouse model of I/R injury.The information that will be obtained from these experiments has an important therapeutic significance. Indeed, the stress response could be activated using pharmacological agents that are safe in humans as an early prophylactic therapy and protect patients from I/R lung injury in lung transplants, severe shock from trauma or intraoperative ischemia. The present application will provide new information to explain how the cellular response to stress may protect the lungs against injury caused by the lack of blood flow. The results of studies may help to identify new cellular targets for the development of treatments that will protect trauma and lung transplant patients from acute lung injury. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Dunsmore, Sarah
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Carles, Michel; Wagener, Brant M; Lafargue, Mathieu et al. (2014) Heat-shock response increases lung injury caused by Pseudomonas aeruginosa via an interleukin-10-dependent mechanism in mice. Anesthesiology 120:1450-62
Miller, David W; Pittet, Jean-Francois (2013) Targeting aspiration pneumonitis. Anesthesiology 119:752-4
Howard, Marybeth; Roux, Jérémie; Iles, Karen E et al. (2013) Activation of the heat shock response attenuates the interleukin 1?-mediated inhibition of the amiloride-sensitive alveolar epithelial ion transport. Shock 39:189-96
Roux, Jérémie; McNicholas, Carmel M; Carles, Michel et al. (2013) IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism. FASEB J 27:1095-106
Lafargue, Mathieu; Xu, Lijun; Carles, Michel et al. (2012) Stroke-induced activation of the ýý7 nicotinic receptor increases Pseudomonas aeruginosa lung injury. FASEB J 26:2919-29
Bir, Nastasha; Lafargue, Mathieu; Howard, Marybeth et al. (2011) Cytoprotective-selective activated protein C attenuates Pseudomonas aeruginosa-induced lung injury in mice. Am J Respir Cell Mol Biol 45:632-41
Cohen, Mitchell J; Carles, Michel; Brohi, Karim et al. (2010) Early release of soluble receptor for advanced glycation endproducts after severe trauma in humans. J Trauma 68:1273-8
Carles, Michel; Lafargue, Mathieu; Goolaerts, Arnaud et al. (2010) Critical role of the small GTPase RhoA in the development of pulmonary edema induced by Pseudomonas aeruginosa in mice. Anesthesiology 113:1134-43
Howard, Marybeth; Roux, Jeremie; Lee, Hyon et al. (2010) Activation of the stress protein response inhibits the STAT1 signalling pathway and iNOS function in alveolar macrophages: role of Hsp90 and Hsp70. Thorax 65:346-53
Cohen, Mitchell J; Brohi, Karim; Calfee, Carolyn S et al. (2009) Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit Care 13:R174

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