[8] Specifically, genetic deletion of TLR9 or treatment with a TLR7/9 antagonist, IRS954, before or after the onset of acute pancreatitis, decreased the severity of pancreatic injury, inflammatory cell recruitment, intrapancreatic zymogen activation, and intrapancreatic pro-IL-1β find more production. Moreover, TLR9 was detected on the major resident immune cell of the pancreas, F4/80 positive tissue macrophages. Additionally, genomic DNA, a TLR9 ligand, was detectable in the circulation of mice very early in the course of acute pancreatitis. Extracellular genomic DNA could also serve as a TLR9 ligand in primary murine

macrophages. NLRP3 and ASC were also identified as required for full tissue injury and inflammation in experimental acute pancreatitis

through the use of mice harboring genetic deletion of these respective genes. P2X7 was similarly identified as an innate immune sensor of DAMPs in acute pancreatitiss.[8] Genetic deletion or small molecule pharmacologic antagonism of P2X7 with A438079 before or after the onset of acute pancreatitis also decreased the severity of pancreatic injury and inflammatory cell recruitment. Of note, the contribution of P2X7 to acute pancreatic injury and inflammation was much less significant than its contribution to acute liver injury as discussed earlier, highlighting organ-specific effects.[57] ABT-737 cell line Polymorphisms of ASC, NLRP3, TLR9, and P2X7 have so far not been

investigated in the published literature as determinants of the susceptibility to or the severity of pancreatitis in humans. Recently, Lactated Ringers resuscitation therapy has shown to decrease SIRS complications in a randomized controlled trial in acute pancreatitis in comparison with normal saline.[85] The mechanism of this effect is currently undefined. Curiously, ethylpyruvate and ethyllactate, long-lasting derivatives of pyruvate and lactate, inhibit NF-κB induction by TLR4 ligands through undefined mechanisms.[86] Moreover, ethylpyruvate post-treatment has shown to reduce SIRS and mortality in the taurocholate model of acute pancreatitis in mice. It is clear that antagonism of NF-κB immune pathways is advantageous in acute pancreatitis.[87] Moreover, the ethylpyruvate medroxyprogesterone finding lends further support to the concept that NF-κB-driven immune responses, determined substantially by TLR4 and TLR9 contributions in experimental models, affect not only SIRS but also mortality in severe acute pancreatitis. This opens the door for consideration of lactate and lactate derivates as not only resuscitation fluid but also immune-modifying therapy in acute pancreatitis. Collectively, the data above provide robust evidence for SI having an important role in a variety of liver diseases and in pancreatitis. It is, however, important to note the limitations of disease models and experimental systems.