Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-Kappa B.
Liver injury is a manifestation of the systemic inflammatory response during acute pancreatitis. We have demonstrated that elastase induces macrophage tumor necrosis factor (TNF) production in distant organs, thus mimicking pancreatitis-associated organ injury. The aim of this study was to determine the mechanism by which elastase induces hepatic cytokine production. Rat livers (n = 40) were perfused with elastase +/- gadolinium (Gd) to inhibit Kupffer cells. Liver parenchymal enzymes and TNF were measured in the effluent. In vitro, rat hepatocytes or Kupffer cells were treated with elastase (1 U/ml) +/- Gd (0.5 mg/ml) or pyrrolidine dithiocarbamate (PDTC; 0.5 mg/ml). TNF protein, TNF messenger RNA, and NF-kappa B activation were determined. In vivo, Gd blunted the elastase-induced TNF production and decreased AST, ALT, LDH, and nonviable cells (propidium iodide) (P < or= 0.03 vs. elastase). In vitro, elastase induced TNF production from Kupffer cells (P < 0.001 vs. control) but not from hepatocytes. Gd or PDTC significantly attenuated the elastase-induced TNF production (P < 0.001). Elastase-induced overexpression of TNF messengerRNA and activation of NF-kappa B was attenuated by Gd. Pancreatic elastase induces a pattern of liver injury similar to that seen during acute pancreatitis by activating cytokine production and gene expression within Kupffer cells via NF-kappa B. Gd exhibits a protective effect against elastase-induced liver injury by inhibiting activation of NF-kappa B.
Murr
Michel M
MM
Department of Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, FL, USA. mmurr@usf.edu
Yang
Jun
J
Fier
Adam
A
Kaylor
Pam
P
Mastorides
Stephen
S
Norman
James G
JG
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D024202:Electrophoretic Mobility Shift Assay; D022781:Hepatocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D010196:Pancreatic Elastase / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D010196:Pancreatic Elastase