Kupffer cells protect liver sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130.

Endothelial cell (EC) dysfunction is a key feature of multiple organ injury, the primary cause of fatality seen in critically ill patients. Although the development of EC dysfunction in the heart and lung is well studied in sepsis, it remains unclear in the liver. Herein, we report that liver sinusoidal ECs (LSECs; defined as CD146(+)CD45(-)) exhibit increased intercellular adhesion molecule-1 (CD54) and Fas in response to sepsis induced by cecal ligation and puncture (CLP).

Structural Correlates of PPAR Agonist Rescue of Experimental Chronic Alcohol-Induced Steatohepatitis.

Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that have anti-inflammatory/anti-oxidant effects. We previously showed that PPAR agonists can restore hepatic insulin responsiveness in chronic ethanol-fed rats with steatohepatitis.

Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival.

Increased apoptotic cell death is believed to play a pathological role in patients with sepsis and experimental animals. Apoptosis can be induced by either a cell death receptor (extrinsic) or a mitochondrial (intrinsic) pathway. Bid, a proapoptotic member of the Bcl-2 family, is thought to mediate the cross talk between the extrinsic and intrinsic pathways of apoptosis; however, little is known about the action of Bid in the development of apoptosis and organ-specific tissue damage/cell death as seen in polymicrobial sepsis.

CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL.

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8(+) T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8(+) and CD4(+) T cells) versus the liver (increased FasL expression on CD8(+) T cells and increase in percentage/number). Adoptive transfer of CLP FasL(+/+) versus FasL(-/-) mouse liver CD8(+) T cells to severe combined immunodeficient or RAG1(-/-) recipient mice indicated that these cells could induce inflammation.