Liver sinusoidal endothelial cells undergo apoptosis during sepsis, leading to organ dysfunction. (54.13)

Abstract

Sepsis is the leading cause of death in critically ill patients, and treatment options are limited. Our laboratory studies polymicrobial sepsis in murine models, and uses the liver as a model organ to investigate the disease’s pathophysiology. The liver, characterized as an immune tolerant organ, is susceptible to septic induced inflammation. We have previously reported that there is a twofold increase in the number of liver CD8+ T cells, 24 hours following cecal ligation and puncture (CLP—a surgical procedure that generates sepsis in mice). Since activated T lymphocytes must transverse the endothelium to reach the site of infection, it is possible that they directly interact with LSECs, and mediate liver injury through Fas-mediated apoptosis. This led us to hypothesize that as CD8+ T cells directly interact with LSECs, endothelial cell dysfunction occurs. Our preliminary results indicate that septic liver CD8+ T cells have cytotoxic effects on endothelial monolayer integrity, and release pro-inflammatory cytokines when directly co-cultured with CRL-2167, a murine endothelial cell line. We have also observed through flow cytometry that LSECs (CD146+/CD45- and CD31+/CD45- populations) have an increased expression of CD54 (ICAM-1), Fas, and Annexin V staining in vivo. These data suggest that CD8+ T cells directly interact with LSECs, alter the tolerance capacity of LSECs, and potentially kill LSECs through the Fas-FasL system, ultimately leading to liver organ injury in sepsis.