Determinants of capillary leakage during severe cardiogenic shock

Introduction Although capillary leakage is a major feature of systemic inflammatory response syndrome (SIRS) associated with shocks, molecular mechanisms remain uncharacterized in humans. Patients with severe cardiogenic shock were recruited from La Pitie-Salpetriere intensive care unit (ICU) and RNAseq analysis of circulating monocytes was performed. Thirty-eight genes associated with capillary leakage were thus identified. Beyond them, amphiregulin is a ligand of EGF receptor involved in angiogenesis, and its expression is triggered by lipopolysaccharides in monocytes. We first confirmed association between AMPHIREGULIN plasma level and vascular leakage in a validation cohort of 77 cardiogenic shock patients. Objectif We here hypothesize that AMPHIREGULIN may play a role in SIRS-induced capillary leakage. The aim of the project is to characterize its mechanisms of action. Methods Vascular permeability was compared in amphiregulin-KO or WT-mice using a model of LPS-induced capillary leakage. Total/dry weight ratio (W/D ratio) of lungs, heart, liver and kidney as well as quantification of Evans blue leakage were used to quantify vascular permeability. Results In two preliminary experiments (n= 15 KO and 9 WT), lung W/D ratio of amphiregulin-KO mice was significantly reduced compared to WT-mice after LPS injection (median 4.27 [IQR 4.16-4.42] vs. 4.53 [4.41-4.61], P  Conclusion These preliminary results indicate that AMPHIREGULIN may be an important regulator of vascular permeability in SIRS induced by cardiogenic shock. Further experiments are presently ongoing to confirm these results.