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Endothelial injury during sepsis: do NET-attached proteases participate in this process? (NET-INJURY-IN-SEPSIS)
Date du début: 9 janv. 2012, Date de fin: 8 janv. 2015 PROJET  TERMINÉ 

"Every year over 400.000 EU citizens suffer from sepsis and every third of them dies due to the severity of this systemic inflammation. The mortality results from excessive neutrophil activation leading to vasculature malfunctioning and subsequent multiorgan failure.Recently, we (outgoing host) revealed that during bacterial sepsis neutrophils activated by platelets release NETs (neutrophil extracellular traps) that trap and kill bacteria but this occurs at the expense of injury to endothelium (Nature Medicine, 2007, 13: 463-9).NETs are web-like structures composed of DNA and proteins released from neutrophil granules, including proteases such as MMP-9 (matrix metalloproteinase 9) and NE (neutrophil elastase). We (researcher) showed that the proteases co-facilitate migration of neutrophils (J Leukocyt Biol, 2009, 85: 374-81) and we (return host) pointed out MMP-9 inhibitors as therapy for acute inflammatory diseases (Nature Rev Drug Discovery, 2007, 6: 480-98).We propose a novel concept that the damage to blood vessels occurring during sepsis is a consequence of NET formation and results from protease activity. This is strengthened by observation that damage to endothelia is detected in sepsis and when NET formation is blocked no injury is noticed.Therefore we will address the hypothesis that proteases (MMP-9, NE) attached to NETs cause injury to endothelial cells through the following specific aims:-evaluation of endothelial damage in transgenic mice deficient in either MMP-9 or NE-determination of intercellular and inter-protease events leading to the injury-identification of endothelial substrates of MMP-9 and NE.The experiments will implement state of the art methodologies including intravital microscopy and multidimensional degradomics.Overall, the studies will elucidate NET-linked protease-dependent mechanisms leading to the damage of endothelium and will point out targets for new therapies in sepsis."