Determinants of capillary leakage during severe cardiogenic shock.

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 Pitié-Salpêtrière 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. 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. 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. 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 < 0.01). A similar trend was quantified in the liver (3.38 [3.3-3.49] vs. 3.52 [3.38-3.56], P = 0.096). In contrast, W/D ratio in other organs were not affected. 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. [ABSTRACT FROM AUTHOR]