Sterile inflammatory response in acute pancreatitis.

The initial injury in acute pancreatitis (AP) is characteristically sterile and results in acinar cells necrosis. Intracellular contents released from damaged cells into the extracellular space serve as damage associated molecular patterns (DAMPs) that trigger inflammation. There is increasing evidence that this sterile inflammatory response mediated through DAMPs released from necrotic acinar cells is a key determinant of further pancreatic injury, remote organ injury, and disease resolution in experimental models. A number of DAMPS, including high-mobility group box protein 1 (HMGB1), DNA, ATP, and heat shock protein 70 (hsp70), have been shown to have a role in experimental pancreatitis. Many of these DAMPs are also detectable in the human pancreatitis. Genetic deletion and pharmacologic antagonism demonstrate that specific DAMP receptors, including TOLL-like receptor 4 (TLR4), TOLL-like receptor 9 (TLR9) and P2X7, are also required for inflammation in experimental AP. Down-stream DAMP sensing components include NLRP3, caspase1, interleukin-1β (IL-1), interleukin-18 (IL-18), and IL-1 receptor (IL-1R), and also are required for full experimental pancreatitis. These DAMP-mediated pathways provide novel therapeutic targets using antagonists of TLR’s and other receptors.