Elastase mimics pancreatitis-induced hepatic injury via inflammatory mediators.
BACKGROUND
Recent evidence suggests that pancreatitis-associated hepatic injury is regulated by inflammatory mediator production. Our laboratory demonstrated in vitro that pancreatic elastase is a pancreatic enzyme that can induce inflammatory cell cytokine production. Therefore we now explore the in vivo effects of elastase on the liver.


METHODS
Elastase (1.5 U) +/- CNI-1493, which attenuates mediator production through p38 MAP kinase inhibition, was administered intraperitoneally to mice while control animals received saline. Acute pancreatitis (AP) was induced with a choline-deficient, ethionine-supplemented (CDE) diet. Serum hepatic enzymes and hepatic neutrophil infiltration by myeloperoxidase (MPO) activity were measured as indicators of hepatic insult. Serum tumor necrosis factor (TNF) protein (ELISA), hepatic TNF mRNA (reverse transcription polymerase chain reaction), and hepatic activation of the transcription factor nuclear factor kappa B (electrophoretic mobility shift assay) were also determined.


RESULTS
A significant increase in hepatic enzymes and MPO activity was induced by AP and mirrored by intraperitoneal elastase. Both types of liver injury resulted in near identical elevations in serum TNF protein and hepatic TNF mRNA. Elastase-treated animals with mediator production inhibited (CNI-1493) had attenuated hepatic enzymes, MPO activity, TNF protein, and TNF mRNA. Activation of nuclear factor kappa B occurred 30 min after elastase administration.


CONCLUSIONS
Exposure of the liver to pancreatic elastase results in hepatic inflammation and injury which appears identical to that seen during severe AP. Prevention of inflammatory mediator production by intrahepatic leukocytes attenuates injury and supports recent adult respiratory distress syndrome and in vitro data suggesting that elastase is the principal factor that propagates pancreatic inflammation into a systemic illness through direct activation of systemic inflammatory cells.
Jaffray
C
C
Department of Surgery, University of South Florida, Tampa, Florida 33601, USA.
Yang
J
J
Norman
J
J
D000276:Adjuvants, Immunologic / Q000032:analysis / Q000235:genetics; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000276:immunology; D006835:Hydrazones / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008107:Liver Diseases / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000032:analysis / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010196:Pancreatic Elastase / Q000009:adverse effects*; D010195:Pancreatitis / Q000139:chemically induced* / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000276:immunology; D000813:Anilides; D006146:Guanidines
D000276:Adjuvants, Immunologic; D001219:Aspartate Aminotransferases; D006835:Hydrazones; D007166:Immunosuppressive Agents; D007770:L-Lactate Dehydrogenase; D016328:NF-kappa B; D010196:Pancreatic Elastase; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines