Despite the progress made in the clinical management of sepsis, sepsis morbidity and mortality rates remain high. The inflammatory pathogenesis and organ injury leading to death from sepsis are not fully understood for vital organs, especially the liver. Only recently has the role of the liver in sepsis begun to be revealed. Pre-existing liver dysfunction is a risk factor for the progression of infection to sepsis. Liver dysfunction after sepsis is an independent risk factor for multiple organ dysfunction and sepsis-induced death. The liver works as a lymphoid organ in response to sepsis. Acting as a double-edged sword in sepsis, the liver-mediated immune response is responsible for clearing bacteria and toxins but also causes inflammation, immunosuppression, and organ damage. Attenuating liver injury and restoring liver function lowers morbidity and mortality rates in patients with sepsis. This review summarizes the central role of liver in the host immune response to sepsis and in clinical outcomes.

The NTD birth prevalence rate in the study area is among the highest worldwide. Folic acid deficiency may be one important risk factor.

The transcription factor NF-κB is an important regulator of homeostatic growth and inflammation. Although gene-targeting studies have revealed important roles for NF-κB, they have been complicated by component redundancy and lethal phenotypes. To examine the role of NF-κB in endothelial tissues, Tie2 promoter/enhancer-IκBα S32A/S36A transgenic mice were generated. These mice grew normally but exhibited enhanced sensitivity to LPS-induced toxemia, notable for an increase in vascular permeability and apoptosis. Moreover, B16-BL6 tumors grew significantly more aggressively in transgenic mice, underscoring a new role for NF-κB in the homeostatic response to cancer. Tumor vasculature in transgenic mice was extensive and disorganized. This correlated with a marked loss in tight junction formation and suggests that NF-κB plays an important role in the maintenance of vascular integrity and response to stress.

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These results support the notion that vascular FXR may serve as a novel molecular target for manipulating the expression of eNOS for the treatment of vascular diseases.

In this study, we show that both mouse and rat lung EC display constitutive expression of TLR9 mRNA. Exposure to CpG DNA induced a potent proinflammatory response as manifested by an increased expression of IL-8 and ICAM-1 in mouse pulmonary EC. The proinflammatary response was sensitive to chloroquine, consistent with a role of endosomal contribution. A role for p38 MAPK and NF-B pathway was apparent as the response was sensitive to inhibitors of p38 MAPK and NF-B but was not affected by inhibitors of ERK1/2. A synergistic effect of CpG DNA and LPS on the inflammatory response is consistent with multiple TLR interaction in EC. This study suggests a possible role for CpG DNA-mediated EC immune response in the host defense system. It also has important implications in plasmid DNA-mediated pulmonary endothelium gene transfer. CpG motif; lung THE VASCULAR ENDOTHELIUM SERVES as the key barrier between the intravascular compartment and extravascular tissues and plays a critical role in a large number of physiological and pathological processes (8,19). As a critical part of inflammation, endothelial cells (EC) can recognize the molecular patterns commonly associated with many microbial agents and subsequently initiate the transcription of inflammatory genes (23,29). Specific conserved components of microbes include lipopolysaccharides (LPS) from gram-negative bacteria, CpG DNA, and flagellin (11,21,22). A large body of evidence has shown that LPS is highly proinflammatory and elicits a wide array of immune responses in EC (1, 10). Little information is available on the direct biological effect of bacterial CpG DNA on the vascular EC.Unlike LPS, which is recognized by Toll-like receptor (TLR) 4, CpG DNA is recognized by TLR9 (14). The signaling of these two receptors, however, shares similar downstream pathways, including activation of kinases like the stress kinases c-Jun NH 2 -terminal kinase, p38, and the IB kinase (IKK) complex (25). A number of studies have shown that CpG DNA has strong stimulatory effects on murine and human lymphocytes in vitro and murine lymphocytes in vivo (5, 13, 18). These stimulatory effects include triggering B cell proliferation, resistance to apoptosis, and release of IL-6 and IL-12; natural killer cell secretion of IFN-␥ and increased lytic activity; and monocyte/macrophage secretion of IFN-␣/␤, IL-6, IL-12, granulocyte-monocyte colony-stimulating factor, chemokines, and TNF-␣. A recent study has shown that human colonic epithelial cells can also respond to CpG DNA via upregulation of IL-8, suggesting a new mechanism for the epithelial defense system against microbial agents (2). The purpose of the current study was to determine the CpGmediated inflammatory responses in pulmonary EC.In the present study, we provide evidence to demonstrate for the first time that mouse and rat EC constitutively express TLR9 mRNA. Exposure to CpG DNA induced a potent proinflammatory response as manifested by an increased expression of IL-8 and ICAM-1 in EC. We further show that LPS and CpG DNA have a syne...

Sorting nexins (SNXs) are phosphoinositide-binding proteins implicated in the sorting of various membrane proteins in vitro, but the in vivo functions of them remain largely unknown. We reported previously that SNX10 is a unique member of the SNX family genes in that it has vacuolation activity in cells. We investigate the biological function of SNX10 by loss-of-function assay in this study and demonstrate that SNX10 is required for the formation of primary cilia in cultured cells. In zebrafish, SNX10 is involved in ciliogenesis in the Kupffer's vesicle and essential for left-right patterning of visceral organs. Mechanistically, SNX10 interacts with V-ATPase complex and targets it to the centrosome where ciliogenesis is initiated. Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo and does so synergistically with SNX10. We further discover that SNX10 and V-ATPase regulate the ciliary trafficking of Rab8a, which is a critical regulator of ciliary membrane extension. These results identify an SNX10/V-ATPaseregulated vesicular trafficking pathway that is crucial for ciliogenesis, and reveal that SNX10/V-ATPase, through the regulation of cilia formation in various organs, play an essential role during early embryonic development.

Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R). Toll-like receptor 4 (TLR4) is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105) is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI). Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham). After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.