Hypothermia slows sequential and parallel steps initiated during caerulein pancreatitis

Background and objectives: Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature range over which inhibition of such deleterious signaling occurs. Methods: Caerulein (100 nM) induced trypsinogen activation (TGA), CXCL1, CXCL2 mRNA levels, cell injury were studied at 37°C, 34°C, 31°C, 29°C and 25°C in acinar cells. Trypsin, cathepsin B activities and cathepsin B mediated TGA were studied at 37°C, 23°C and 4°C. Results: There was >80% reduction in TGA, CXCL1 and CXCL2 mRNA levels at 29°C, and in cell injury at 34°C, compared to those at 37°C. Trypsin activity, cathepsin B activity and cathepsin B mediated TGA at 23°C were respectively, 53%, 64% and 26% of that at 37°C. Acinar cooling to 31°C reduced LDH leakage even when cooling was initiated an hour after caerulein stimulation at 37°C. Conclusions: Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by caerulein, thereby reducing TGA, upregulation of inflammatory mediators and acinar injury.