Microtubule control of septic inflammation

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 DESCRIPTION (provided by applicant): Severe sepsis is a common, expensive, and frequently fatal condition which is the leading cause of death in the ICU in the United States. It s especially common in the elderly and is likely to increase substantially as the U.S. population ages. Sepsis develops as a result of the host response to infection, and often presents as systemic inflammatory response syndrome (SIRS), but may also develop into multiple organ failure (MOF) with vascular endothelial inflammation and lung dysfunction among major fatal complications in critically ill patients. Typically, 50% of all sepsis cases start as an infection n the lungs. In the last decade, gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Activated vascular endothelium plays a key role in propagation of inflammation by increasing the extravasation of inflammatory cells, cytokines and chemokines. Endothelial inflammation and barrier compromise in septic conditions may lead to multiple organ dysfunction and disseminated intravascular coagulation. Although the essential role of endothelium in these events is well recognized, precise mechanisms modulating inflammatory activation of vascular endothelium in septic conditions are poorly understood. Our previous studies defined the role of microtubule dynamics in the disruption of lung endothelial barrier and vascular leak caused by vasoactive growth factors and agonists. However, the involvement of microtubule-dependent mechanisms in endothelial inflammatory processes awaits further investigation. The central hypothesis supported by our novel preliminary data which will be tested in this application is that activation of microtubule-specific histone deacetylase HDAC6 in endothelial cells challenged with Staphylococcus aureus causes microtubule destabilization and reduction in anti-inflammatory activity of microtubule-associated Suppressor Of Cytokine Signaling, SOCS3. As a result of SOCS3 inactivation, augmented Jak2/STAT3 signaling will unleash cytokine release and exacerbate ongoing inflammatory reaction to bacterial pathogen causing collateral damage of the host organism. We speculate that stabilization of the microtubules via inhibition of HDAC6 leading to preservation of SOCS3 activity may protect against excessive septic inflammation. Aim-1 will characterize the changes in endothelial microtubule dynamics and their regulation by HDAC6 in the models of lung septic inflammation; AIm-2 will examine how altered microtubule dynamics modulate SOCS3-dependent inflammatory signaling induced by bacterial pathogens; and Aim-3 will study the role of microtubule-associated signaling in the modulation of inflammatory response in vivo. We believe that this study will identify new targets for therapies designed to blunt sepsis-activated pathologic signaling circuits and may result in a breakthrough in current practices of sepsis treatment.