Abstract
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-kB activation were determined. In vivo, Gd blunted the elastase-induced TNF production and decreased AST, ALT, LDH, and nonviable cells (propidium iodide) (P ≤ 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-kB 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-kB. Gd exhibits a protective effect against elastase-induced liver injury by inhibiting activation of NF-kB.
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References
Norman J. Role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 1998;175:76–83.
Norman J, Fink G, Franz M. Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression. Arch Surg 1995;130:966–970.
Norman J, Franz M, Riker A, Gower W. Rapid elevation of cytokines during acute pancreatitis and their origination within the pancreas. Surg Forum 1994;45:148–150.
Yang J, Jaffray C, Carter G, Norman J. Pancreatic elastase-induced lung injury mimics pancreatitis-associated ARDS. Dig Dis Sci (submitted for publication).
Jaffray C, YangJ, Norman J. Elastase mimics pancreatitis-induced hepatic injury via inflammatory mediators. J Surg Res 2000;90:95–101.
Gloor B, Todd K, Lane J, Lewis M, Reber H. Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice. J Gastrointest Surg 1998;2:430–435.
Zhu X, Zellweger R, Ayala A, Chaudry I. Cytokine gene expression in Kupffer cells following hemorrhage. Cytokine 1996;8:134–140.
Koo D, Chaudry I, Wang P. Kuppfer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis. J Surg Res 1999;83:151–157.
Hems R, Ross BD, Berry MN, Krebs HA. Gluconeogenesis in the perfused rat liver. Biochem J 1966; 101:284–292.
Kamimura S, Tsukamoto H. Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease. Hepatology 1995;21:1304–1309.
Lee SJ, Friedman SL, Whalen R, Boyer TD. Cellular sources of glutathione S-transferase P in primary cultured rat hepatocytes: Localization by in situ hybridization. Biochem J 1994;229:79–83.
Yang J, Denham W, Carter G, Tracey KJ, Norman J. Macrophage pacification reduces pancreatitis-induced hepato-cellular injury through downregulation of hepatic TNF and IL-1. Hepatology 1998;28:1282–1288.
Denham W, YangJ, Fink G, Zervos EE, Carter G, Norman J. Pancreatic ascites as a powerful inducer of inflammatory cytokines: The role of known vs. unknown factors. Arch Surg 1997;132:1231–1236.
Jaffray C, Mendez C, Denham W, Carter G, Norman J. Specific pancreatic enzymes activate macrophages to produce TNF-alpha: Role of Nuclear Factor Kappa B and Inhibitory Kappa B proteins. J Gastrointest Surg 2000;4:370–378.
Pahl HL. Activation and target genes of Rel/NF-kB transcription factors. Oncogene 1999;18:8653–8666.
Husztik E, Lazar G, Parducz A. Electron microscope study of Kupffer cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol 1980;61:624–630.
Roland C, Naziruddin B, Mohanakumar T, Flye W. Gadolinium blocks rat Kupffer cell calcium channels: Relevance to calcium-dependent prostaglandin E2 synthesis and septic mortality. Hepatology 1999, 29:756–765.
Mizgerd J, Molina R, Stearns R, Brain J, Warner A. Gadolinium induces macrophage apoptosis. J Leukocyte Biol 1996;59:189–195.
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Presented in part at the Annual Meeting of the Association of VA Surgeons, Atlanta, Georgia, May 5–7, 2001; the Annual Meeting of the Japan Surgical Society, Sendai, Japan, April 7–14, 2001; and the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (poster presentation); and published as abstracts in Gastroenterology 120:A174 and A348, 2001.
Recipient of the 2001 SSAT Career Development Reward at the Forty-Second Annual Meeting of The Society for the Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001.
Supported by a Veterans Administration Merit Award (J.N.) and a University of South Florida-Surgery Seed Grant (M.M.).
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Murr, M.M., Yang, J., Fier, A. et al. Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-kappa B. J Gastrointest Surg 6, 474–480 (2002). https://doi.org/10.1016/S1091-255X(01)00071-3
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DOI: https://doi.org/10.1016/S1091-255X(01)00071-3