Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury

Pancreatic proteases are secreted in acute pancreatitis, but their contribu tion to associated lung injury is unclear. Applying models of mild edematou s (intravenous caerulein) and severe necrotizing (intraductal glycodeoxycho lic acid) pancreatitis in rats, we showed that both trypsinogen and trypsin concentrations in peripheral blood, as well as lung injury, correlate with the severity of the disease. To isolate the potential contribution of prot eases to lung injury, trypsin or trypsinogen was injected into healthy rats or trypsinogen secreted in caerulein pancreatitis was activated by intrave nous enterokinase. Pulmonary injury induced by protease infusions was dose dependent and was ameliorated by neutrophil depletion. Trypsinogen activati on worsened lung injury in mild pancreatitis. In vitro incubation of leukoc ytes with trypsinogen showed that stimulated leukocytes can convert trypsin ogen to trypsin. In conclusion, this study demonstrates that the occurrence and severity of pancreatitis-associated lung injury (PALI) corresponds to the levels of circulating trypsinogen and its activation to trypsin. Neutro phils are involved in both protease activation and development of pulmonary injury.