Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis

Background. Fas/Fas ligand (FasL) system is one of the major pathways trigg ering apoptosis that has been shown to play an important role in developmen t and pathogenesis of various diseases including liver and gastrointestinal diseases. Studies indicate that FasL deficiency provides a survival advant age in mice subjected to polymicrobial sepsis. However, the extent to which Fas/FasL contributes to organ injury during sepsis is unclear. Thus, the a im of this study was to determine whether in vivo administration of a Fas-s ignaling inhibitor during sepsis preserves organ Junction. Methods. Male adult C3H/HeN mice were subjected to cecal ligation and punct ure (CLP) or sham CLP (sham). Twelve hours after CLP, mice received either Fas-receptor fusion protein (FasFP) (200 mug/kg body weight) or the saline vehicle. Twenty-four hours after the onset of sepsis, cardiac output and or gan blood flow were measured with radioactive microspheres. Plasma levels o f alanine aminotransferase, aspartate aminotransferase, and lactate dehydro genase were assessed as indexes of litter damage. Changes in systemic cytok ines were measured by enzyme-linked immunosorbent assay. Results. The data indicate that although cardiac output and organ blood flo w in the liver, intestine, kidneys, spleen, and heart decreased markedly at 24 hours after CLP, treatment with FasFP maintained the measured hemodynam ic parameters and improved hepatic, intestinal, and heart bloodflow (P < .0 5) and partially restored spleen and renal bloodflow. Moreover, FasFP treat ment markedly attenuated the systemic rise in alanine aminotransferase, asp artate aminotransferase, lactate dehydrogenase, and interleukin 10 (P < .05 ). Conclusions. These results not only indicate that there is a role for Fas/F asL-mediated processes in the induction of organ injury but suggest that in hibition of Fas/FasL pathway may represent a novel therapeutic modality for maintaining organ perfusion and preventing liver injury during sepsis.