Novel pharmacological strategies for modulation of capillary leakage during sepsis – SEPSIS-Perm

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, i.e. a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs (doi:10.1001/jama.2016.0287). Sepsis is thus a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection and is a major public health concern, accounting for more than $20 billion (5.2%) of total US hospital costs in 2011, see (http://www.ncbi.nlm.nih.gov/books /NBK169005). It is well appreciated that microvascular leak plays a critical role in the outcome of sepsis. Indeed, fluid balance (difference between fluid input and output) is regulated by an impaired capillary permeability which allows fluid to leave the circulation and redistribute into the extravascular space, thereby affecting microvascular perfusion and tissue oxygenation, independently correlates with mortality during septic shock (doi: 10.1186/cc13072). Though, despite intensive research, current therapeutic approaches are focused on antibiotics, fluid resuscitation, vasopressors and oxygen/ventilatory support (doi: 10.1097/CCM.0000000000005337) but therapeutic targets and translation studies aimed at counteracting vascular permeability are crucially lacking.
Based on our strong preliminary results both in humans and in relevant animal models, we have identified a candidate that modulates vascular permeability during sepsis. The final goal of our project is to identify a therapeutic target to control SIRS-induced capillary leakage. This proposal is in accordance with ANR2025 Axis C.09 Translational health research. There is indeed an unmet medical need to identify potential new targets as there is no specific therapy available to date.