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Septic Immune/Organ Injury: Did They Commit Suicide or Were They Murdered?

Studies have shown that critically ill patients and septic rodents show a decrease in various T‐cell populations, which may contribute to multiple organ failure (MOF) and eventual death. The Fas pathway has been reported to contribute to the loss of CD4+ and CD8+ T cells and B cells of the spleen and intestine of septic/cecal ligation and puncture (CLP) mice. However, reports suggest that CD8+ T cells may also play a hyper‐inflammatory role in sepsis leading to MOF after CLP. Since studies blocking the Fas pathway, using FasL −/− mice, as well as the in vivo delivery of Fas siRNA have shown decreased liver damage (↓ALT & ↓AST), decreased apoptosis, and improvement in septic survival, we hypothesize that these treatments prevent immune cell apoptosis and/or hepatic damage by lymphocyte‐mediated extrinsic killing. Western blot and flow cytometry, revealed an increase in FasL expression and a 2‐fold increase in the number of CD8+ T cells present in CLP mouse livers. FasL expression in the spleen did not change with CLP, however, there was an increase in Fas receptor and a loss of T and B cells. In vivo hydrodynamic administration of Fas siRNA in mice decreased the levels of Fas expression on hepatocytes, decreased the number of CD8+ T cells that migrated to the liver, and reduced levels of ALT and AST. Adoptive transfer of CD8+ liver T cells from FasL +/+ but not FasL −/− CLP mice induced liver damage in SCID recipient mice. In the spleen, Fas siRNA reduced the loss of T and B cells after CLP. Together this suggests that FasL‐Fas therapies, like Fas siRNA, work to protect immune/non‐immune cell targets from CD8+ T cell mediated extrinsic death in the spleen and liver (NIH GM53209, GAANN P200A030100).