While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation. IntroductionThe adaptive and the innate immune systems are both capable of initiating inflammation. The two are interconnected at several levels, including the synthesis and action of cytokines, molecules regulating cell-cell interactions, and the activation of transcription factors (1-9). While the molecular events leading to activation of the immune response are well understood, less is known about factors that perpetuate inflammation. One mechanism considered central in the cross-talk between the innate and adaptive immune systems is the redox-dependent activation of the transcription factor NF-κB (1, 4, 9-13). Members of the NF-κB family control the initiation of inflammation by regulating expression of leukocyte adhesion molecules, cytokines, and other factors (10-13), but are also central in terminating inflammation (14)(15)(16)(17)(18). This leaves unanswered the question of the perpetuation of inflammation of the adaptive and innate immune responses.Recently, studies of the receptor for advanced glycation end products (RAGE) (19-23), a member of the immunoglobulin superfamily (23) whose gene is located in the vicinity of the MHC

While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation. IntroductionThe adaptive and the innate immune systems are both capable of initiating inflammation. The two are interconnected at several levels, including the synthesis and action of cytokines, molecules regulating cell-cell interactions, and the activation of transcription factors (1-9). While the molecular events leading to activation of the immune response are well understood, less is known about factors that perpetuate inflammation. One mechanism considered central in the cross-talk between the innate and adaptive immune systems is the redox-dependent activation of the transcription factor NF-κB (1, 4, 9-13). Members of the NF-κB family control the initiation of inflammation by regulating expression of leukocyte adhesion molecules, cytokines, and other factors (10-13), but are also central in terminating inflammation (14)(15)(16)(17)(18). This leaves unanswered the question of the perpetuation of inflammation of the adaptive and innate immune responses.Recently, studies of the receptor for advanced glycation end products (RAGE) (19-23), a member of the immunoglobulin superfamily (23) whose gene is located in the vicinity of the MHC

NAC attenuated the increase in alpha-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion of the donor liver, indicating possible cytoprotective effects of NAC.

Neurological complications contribute significantly to morbidity and mortality of patients after orthotopic liver transplantation (OLT). One possible cause of postoperative neurological complications is cerebral ischemia during the surgical procedure. In this study, we investigated the relationship between intraoperative changes in regional cerebral oxygen saturation (rSo(2)) and postoperative values of neuron-specific enolase (NSE) and S-100, which are specific variables that indicate cerebral disturbances due to hypoxia/ischemia. The rSo(2) was monitored continuously by near-infrared spectroscopy in 16 patients undergoing OLT. In addition, NSE and S-100 were determined in arterial blood before surgery and 24 h after reperfusion of the donor liver. Interestingly, clamping of the recipient's liver led to a significant decline in rSo(2) in eight patients, whereas the others tolerated clamping without major changes in rSo(2). The decrease in rSo(2) after clamping correlated significantly with postoperative increases in NSE (r(2) = 0.57) and S-100 (r(2) = 0.52). However, there were no significant differences between patients with and without rSo(2) decline concerning hemodynamic variables. There were no significant correlations between DeltarSo(2) and cardiac output (r(2) = 0.20), NSE and cardiac output (r(2) = 0.37), or S-100 and cardiac output (r(2) = 0.24). Monitoring of rSo(2) may be a useful noninvasive tool to estimate disturbances in rSo(2) during OLT.

In murine skeletal muscle fibers, Ca2+-release from the SR decreases during sepsis, with effects being most pronounced 2-3 days after CLP. In parallel, Ca2+-sensitivity of the contractile apparatus is increased, and all changes are reversible. Thus, these effects might be involved in skeletal muscle dysfunction during sepsis as corresponding changes are less pronounced or absent in control groups.