BACKGROUND: Fas/Fas ligand (FasL) system is one of the major pathways triggering apoptosis that has been shown to play an important role in development and pathogenesis of various diseases including liver and gastrointestinal diseases. Studies indicate that FasL deficiency provides a survival advantage in mice subjected to polymicrobial sepsis. However, the extent to which Fas/FasL contributes to organ injury during sepsis is unclear. Thus, the aim of this study was to determine whether in vivo administration of a Fas-signaling inhibitor during sepsis preserves organ function. METHODS: Male adult C3H/HeN mice were subjected to cecal ligation and puncture (CLP) or sham CLP (sham). Twelve hours after CLP, mice received either Fas-receptor fusion protein (FasFP) (200 microg/kg body weight) or the saline vehicle. Twenty-four hours after the onset of sepsis, cardiac output and organ blood flow were measured with radioactive microspheres. Plasma levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were assessed as indexes of liver damage. Changes in systemic cytokines were measured by enzyme-linked immunosorbent assay. RESULTS. The data indicate that although cardiac output and organ blood flow in the liver, intestine, kidneys, spleen, and heart decreased markedly at 24 hours after CLP, treatment with FasFP maintained the measured hemodynamic parameters and improved hepatic, intestinal, and heart blood flow (P <.05) and partially restored spleen and renal blood flow. Moreover, FasFP treatment markedly attenuated the systemic rise in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and interleukin 10 (P <.05). CONCLUSIONS: These results not only indicate that there is a role for Fas/FasL-mediated processes in the induction of organ injury but suggest that inhibition of Fas/FasL pathway may represent a novel therapeutic modality for maintaining organ perfusion and preventing liver injury during sepsis.
BACKGROUND: Fas/Fas ligand (FasL) system is one of the major pathways triggering apoptosis that has been shown to play an important role in development and pathogenesis of various diseases including liver and gastrointestinal diseases. Studies indicate that FasL deficiency provides a survival advantage in mice subjected to polymicrobial sepsis. However, the extent to which Fas/FasL contributes to organ injury during sepsis is unclear. Thus, the aim of this study was to determine whether in vivo administration of a Fas-signaling inhibitor during sepsis preserves organ function. METHODS: Male adult C3H/HeN mice were subjected to cecal ligation and puncture (CLP) or sham CLP (sham). Twelve hours after CLP, mice received either Fas-receptor fusion protein (FasFP) (200 microg/kg body weight) or the saline vehicle. Twenty-four hours after the onset of sepsis, cardiac output and organ blood flow were measured with radioactive microspheres. Plasma levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were assessed as indexes of liver damage. Changes in systemic cytokines were measured by enzyme-linked immunosorbent assay. RESULTS. The data indicate that although cardiac output and organ blood flow in the liver, intestine, kidneys, spleen, and heart decreased markedly at 24 hours after CLP, treatment with FasFP maintained the measured hemodynamic parameters and improved hepatic, intestinal, and heart blood flow (P <.05) and partially restored spleen and renal blood flow. Moreover, FasFP treatment markedly attenuated the systemic rise in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and interleukin 10 (P <.05). CONCLUSIONS: These results not only indicate that there is a role for Fas/FasL-mediated processes in the induction of organ injury but suggest that inhibition of Fas/FasL pathway may represent a novel therapeutic modality for maintaining organ perfusion and preventing liver injury during sepsis.
Authors: Alfred Ayala; Chun-Shiang Chung; Joanne L Lomas; Grace Y Song; Lesley A Doughty; Stephen H Gregory; William G Cioffi; Brian W LeBlanc; Jonathan Reichner; H Hank Simms; Patricia S Grutkoski Journal: Am J Pathol Date: 2002-12 Impact factor: 4.307
Authors: Chun-Shiang Chung; Fabienne Venet; Yaping Chen; Leslie N Jones; Douglas C Wilson; Carol A Ayala; Alfred Ayala Journal: Shock Date: 2010-08 Impact factor: 3.454
Authors: Hendrik Freise; Fritz Daudel; Christina Grosserichter; Stefan Lauer; Juergen Hinkelmann; Hugo K Van Aken; Andreas W Sielenkaemper; Martin Westphal; Lars G Fischer Journal: Crit Care Date: 2009-07-13 Impact factor: 9.097
Authors: Doreen E Wesche-Soldato; Chun-Shiang Chung; Stephen H Gregory; Thais P Salazar-Mather; Carol A Ayala; Alfred Ayala Journal: Am J Pathol Date: 2007-07 Impact factor: 4.307
Authors: Pavan Brahmamdam; Eizo Watanabe; Jacqueline Unsinger; Katherine C Chang; William Schierding; Andrew S Hoekzema; Tony T Zhou; Jacquelyn S McDonough; Heather Holemon; Jeremy D Heidel; Craig M Coopersmith; Jonathan E McDunn; Richard S Hotchkiss Journal: Shock Date: 2009-08 Impact factor: 3.454