Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury.
Pancreatic proteases are secreted in acute pancreatitis, but their contribution to associated lung injury is unclear. Applying models of mild edematous (intravenous caerulein) and severe necrotizing (intraductal glycodeoxycholic 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 proteases to lung injury, trypsin or trypsinogen was injected into healthy rats or trypsinogen secreted in caerulein pancreatitis was activated by intravenous enterokinase. Pulmonary injury induced by protease infusions was dose dependent and was ameliorated by neutrophil depletion. Trypsinogen activation worsened lung injury in mild pancreatitis. In vitro incubation of leukocytes with trypsinogen showed that stimulated leukocytes can convert trypsinogen 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. Neutrophils are involved in both protease activation and development of pulmonary injury.
Hartwig
W
W
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Werner
J
J
Jimenez
R E
RE
Z'graggen
K
K
Weimann
J
J
Lewandrowski
K B
KB
Warshaw
A L
AL
Fernández-del Castillo
C
C
D000208:Acute Disease; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002108:Ceruletide; D003902:Detergents; D010450:Endopeptidases / Q000378:metabolism; D004765:Enteropeptidase; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006002:Glycodeoxycholic Acid; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009842:Oligopeptides / Q000032:analysis / Q000097:blood; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology*; D014362:Trypsinogen / Q000032:analysis / Q000097:blood* / Q000494:pharmacology
D002273:Carcinogens; D003902:Detergents; D009842:Oligopeptides; C080396:trypsinogen activation peptide; D006002:Glycodeoxycholic Acid; D002108:Ceruletide; D014362:Trypsinogen; D009195:Peroxidase; D010450:Endopeptidases; D014357:Trypsin; D004765:Enteropeptidase; D013755:Tetradecanoylphorbol Acetate