However,

Paneth cell-depleted mice still had a significant degree of hepatocyte necrosis (and elevated plasma ALT) due to prolonged liver http://www.selleckchem.com/products/gsk126.html ischemia (Figs. 7D, 8D). These findings suggest that both Paneth cell independent (hepatocyte necrosis) and Paneth cell-dependent extrahepatic injury contribute to hepatic IR injury in vivo. With pharmacological or genetic Paneth cell granule depletion, we observed a striking reduction in IL-17A up-regulation in isolated crypts with profound hepatic, intestinal, and renal protection after liver IR. Although significantly attenuated, plasma and tissue IL-17A levels in Paneth cell-depleted mice (Figs. 7, 8) subjected to liver IR were still elevated compared to sham-operated mice. It is likely that several cell types including leukocytes and epithelial cells can generate IL-17A in response to liver IR and oxidant stress during reperfusion.3, 6 The mechanisms leading to Paneth cell degranulation and increased Paneth cell-derived IL-17A after hepatic IR remain to be determined. Our model of hepatic IR with partial portal vein and

artery occlusion avoids total intestinal outflow obstruction. However, intestinal venous congestion with resultant partial intestinal ischemia may occur, as 100% of intestinal blood flow is diverted to ≈30% of hepatic mass. Partial intestinal IR may have contributed to Paneth cell degranulation and dysregulation. In addition, hepatic IR releases endogenous damage-associated molecular pattern molecules (DAMPs including endotoxin, HMGB-1, PD 332991 see more mitochondrial DNA, urinic acid) that

can activate several Toll-like receptors (TLRs).35 TLR-mediated Paneth cell degranulation has been described.36, 37 In summary, we show that neutralization or genetic deletion of IL-17A provides powerful multiorgan protection after liver IR. In addition, we demonstrated that small intestinal Paneth cells degranulate to play a critical role in hepatic, intestinal, and renal injury after liver IR. In addition, Paneth cells are a major initial source of IL-17A production after hepatic IR. We propose that the small intestinal Paneth cell generation of IL-17A leads to hepatic injury and extrahepatic organ dysfunction. Modulation of Paneth cell dysregulation may have important therapeutic implications in reducing systemic complications arising from hepatic IR injury. We thank Dr. Andre J. Ouellette (Keck School of Medicine of the University of Southern California, Los Angeles, CA) for providing mouse alpha-defensin antibody and Dr. Yuko Mori-Akiyama (Baylor College of Medicine, Houston, TX) for sending breeder pairs of intestine-specific SOX9 null mice. Additional Supporting Information may be found in the online version of this article. “
“To evaluate the feasibility of fusion of conventional imaging modalities to facilitate assessment of ablative margin of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC).