[37] This was associated with elevated levels of TLR4 ligands in the portal blood, supporting a PAMP-driven inflammatory response in NASH. There is therefore very strong evidence for a TLR4/TLR9-initiated and inflammasome/IL-1β-mediated pathway of steatosis, hepatitis, and fibrosis in NASH. PAMPs and DAMPs are likely both contributing to the TLR ligand pool. After acetaminophen toxicity, the release of a number of DAMPs can be detected in the serum in rodents

and humans. These include HMGB1, hyaluronic acid, DNA, keratin, and cyclophilin A, and the neutralization of individual DAMPs has reduced injury.[2, 49-55] Antibody-mediated neutralization of HMGB1 was shown to result in less inflammation after acetaminophen (APAP) toxicity, and liver perfusate from mice treated with high doses of APAP contained HMGB1 and HSP-70,

and was pro-inflammatory to Kupffer cells, resulting in up-regulation of IL-1β and MCP-1.[54, 2] Mice Fer-1 nmr with deficiency in TLR4 or TLR9 signaling have reduced histological injury and serum transaminases after APAP challenge.[7, 56] All of these DAMPs provide signal 1, and cytokines that use MyD88 associated receptors and activate an NFκβ pathway (IL-1α and IL-1β) can further amplify this. Recently, the importance of ATP and its receptor (P2X7) in providing MK-2206 chemical structure signal 2 in APAP hepatotoxicity was demonstrated.[57] There was less injury in P2X7 deficient mice and in wild-type mice after depletion of ATP by apyrase. The requirement for ATP and P2X7 points to a direct involvement of the NLRP3 inflammasome, and this was demonstrated in mice lacking NLRP3, ASC, and caspase-1, but this was not reproduced in a second study.[7, 58] Mice lacking IL-1R, or neutralization NADPH-cytochrome-c2 reductase of IL-1β and IL-1α in wild-type mice, resulted in significantly less APAP toxicity, but this was also not reproduced in a second

study.[59, 60] Collectively, there is a large body of evidence for a role of DAMPs and SI in APAP-induced hepatotoxicity. This has added to the known toxic metabolic pathways of APAP hepatotoxicity, and this has suggested DAMP receptors and signaling pathways as new targets for therapy. Acute pancreatitis is predominantly a sterile inflammatory condition, whether induced by alcohol, pancreatic duct obstruction by biliary stones, hypercalcemia, hypertriglyceridemia, or medication toxicities. Evidence from randomized controlled trials has established that broad-spectrum antibiotic therapy does not alter the natural history of severe acute pancreatitis early in the course of disease, providing strong evidence that infectious etiology is unlikely a significant contributor to the evolving pancreatic inflammation and necrosis. Chronic pancreatitis is similarly thought to be a sterile inflammatory process, induced by chronic alcohol ingestion or recurrent acute pancreatitis, yet conspicuously persistent in the absence of ongoing noxious stimuli.