Elastase mimics pancreatitis-induced hepatic injury via inflammatory mediators

Background. Recent evidence suggests that pancreatitis-associated hepatic i njury is regulated by inflammatory mediator production. Our laboratory demo nstrated 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. Materials and methods. Elastase (1.5 U) +/- CNI-1493, which attenuates medi ator production through p38 MAP kinase inhibition, was administered intrape ritoneally to mice while control animals received saline. Acute pancreatiti s (AP) was induced with a choline-deficient, ethionine-supplemented (CDE) d iet. Serum hepatic enzymes and hepatic neutrophil infiltration by myelopero xidase (MPO) activity were measured as indicators of hepatic insult. Serum tumor necrosis factor (TNF) protein (ELISA), hepatic TNF mRNA (reverse tran scription polymerase chain reaction), and hepatic activation of the transcr iption factor nuclear factor kappa B (electrophoretic mobility shift assay) were also determined. Results. A significant increase in hepatic enzymes and MPO activity was ind uced by AP and mirrored by intraperitoneal elastase. Both types of liver in jury resulted in near identical elevations in serum TNF protein and hepatic TNF mRNA. Elastase-treated animals with mediator production inhibited (CM- 1493) had attenuated hepatic enzymes, MPO activity, TNF protein, and TNF mR NA. Activation of nuclear factor kappa B occurred 30 min after elastase adm inistration. Conclusion. 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 leukocy tes attenuates injury and supports recent adult respiratory distress syndro me and in vitro data suggesting that elastase is the principal factor that propagates pancreatic inflammation into a systemic illness through direct a ctivation of systemic inflammatory cells, (C) 2000 Academic Press.