Activation of nuclear factor kappa B and severe hepatic necrosis may mediate systemic inflammation in choline-deficient/ethionine-supplemented diet-induced pancreatitis

Keith Gray, Misho O. Simovic, Timothy S. Blackwell, John W. Christman, Addison K. May, Kelly S. Parman, William C. Chapman, Steven C. Stain

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

OBJECTIVES: We hypothesized that hepatic injury is associated with severe acute pancreatitis (SAP) and may result in lung injury through nuclear factor kappa B (NF-κB)-dependent inflammatory mediators. The study characterizes the timing and determines the involvement of selected cytokines and chemokines in the pathogenesis of hepatocellular injury associated with SAP. METHODS: The SAP was induced in C57BL/6 mice by feeding a choline-deficient/ethionine- supplemented diet. The mice were killed at 12-hour intervals for 96 hours. Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining was used to determine the extent of hepatic apoptosis. The NF-κB activation in nuclear protein extracts from liver tissue was measured using a sensitive RelA enzyme-linked immunoadsorbent assay. Tumor necrosis factor α, interleukin 6, macrophage inflammatory protein (MIP) 2, and keratinocyte-derived chemokine (KC) levels in homogenates of liver and lung tissues were measured by enzyme-linked immunoadsorbent assay. The SAP-associated neutrophil lung inflammation was measured as tissue myeloperoxidase activity. RESULTS: The SAP and subsequent liver injury were confirmed by histological analysis and rises in plasma amylase and transaminase levels. Severe hepatocellular apoptosis was detected at 36 and 48 hours after the diet initiation by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (P < 0.05) and subsequently progressed to hepatic necrosis. Liver NF-κB activation was detected at 36 hours (P < 0.05) and followed by a sharp increase in hepatocellular levels of interleukin 6, MIP-2, and KC at 72 hours and thereafter (P < 0.05). Levels of MIP-2 and KC in lung tissue were also elevated at 72 hours (P < 0.05) and closely correlated with increased myeloperoxidase activity and increased inflammatory cell infiltrate in the lung. CONCLUSIONS: Choline-deficient/ethionine-supplemented diet-induced SAP is accompanied with hepatocellular apoptosis and eventual necrosis. This injury is associated with the hepatic NF-κB activation leading to the production of NF-κB-dependent cytokines and chemokines in the liver, which may mediate the lung injury.

Original languageEnglish (US)
Pages (from-to)260-267
Number of pages8
JournalPancreas
Volume33
Issue number3
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

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Ethionine
NF-kappa B
Choline
Pancreatitis
Necrosis
Diet
Inflammation
Liver
Chemokine CXCL2
Immunosorbents
DNA Nucleotidylexotransferase
Wounds and Injuries
Lung Injury
Apoptosis
Chemokines
Lung
Peroxidase
Interleukin-6
Staining and Labeling
Cytokines

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

Cite this

Activation of nuclear factor kappa B and severe hepatic necrosis may mediate systemic inflammation in choline-deficient/ethionine-supplemented diet-induced pancreatitis. / Gray, Keith; Simovic, Misho O.; Blackwell, Timothy S.; Christman, John W.; May, Addison K.; Parman, Kelly S.; Chapman, William C.; Stain, Steven C.

In: Pancreas, Vol. 33, No. 3, 01.10.2006, p. 260-267.

Research output: Contribution to journalArticle

Gray, Keith ; Simovic, Misho O. ; Blackwell, Timothy S. ; Christman, John W. ; May, Addison K. ; Parman, Kelly S. ; Chapman, William C. ; Stain, Steven C. / Activation of nuclear factor kappa B and severe hepatic necrosis may mediate systemic inflammation in choline-deficient/ethionine-supplemented diet-induced pancreatitis. In: Pancreas. 2006 ; Vol. 33, No. 3. pp. 260-267.
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abstract = "OBJECTIVES: We hypothesized that hepatic injury is associated with severe acute pancreatitis (SAP) and may result in lung injury through nuclear factor kappa B (NF-κB)-dependent inflammatory mediators. The study characterizes the timing and determines the involvement of selected cytokines and chemokines in the pathogenesis of hepatocellular injury associated with SAP. METHODS: The SAP was induced in C57BL/6 mice by feeding a choline-deficient/ethionine- supplemented diet. The mice were killed at 12-hour intervals for 96 hours. Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining was used to determine the extent of hepatic apoptosis. The NF-κB activation in nuclear protein extracts from liver tissue was measured using a sensitive RelA enzyme-linked immunoadsorbent assay. Tumor necrosis factor α, interleukin 6, macrophage inflammatory protein (MIP) 2, and keratinocyte-derived chemokine (KC) levels in homogenates of liver and lung tissues were measured by enzyme-linked immunoadsorbent assay. The SAP-associated neutrophil lung inflammation was measured as tissue myeloperoxidase activity. RESULTS: The SAP and subsequent liver injury were confirmed by histological analysis and rises in plasma amylase and transaminase levels. Severe hepatocellular apoptosis was detected at 36 and 48 hours after the diet initiation by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (P < 0.05) and subsequently progressed to hepatic necrosis. Liver NF-κB activation was detected at 36 hours (P < 0.05) and followed by a sharp increase in hepatocellular levels of interleukin 6, MIP-2, and KC at 72 hours and thereafter (P < 0.05). Levels of MIP-2 and KC in lung tissue were also elevated at 72 hours (P < 0.05) and closely correlated with increased myeloperoxidase activity and increased inflammatory cell infiltrate in the lung. CONCLUSIONS: Choline-deficient/ethionine-supplemented diet-induced SAP is accompanied with hepatocellular apoptosis and eventual necrosis. This injury is associated with the hepatic NF-κB activation leading to the production of NF-κB-dependent cytokines and chemokines in the liver, which may mediate the lung injury.",
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T1 - Activation of nuclear factor kappa B and severe hepatic necrosis may mediate systemic inflammation in choline-deficient/ethionine-supplemented diet-induced pancreatitis

AU - Gray, Keith

AU - Simovic, Misho O.

AU - Blackwell, Timothy S.

AU - Christman, John W.

AU - May, Addison K.

AU - Parman, Kelly S.

AU - Chapman, William C.

AU - Stain, Steven C.

PY - 2006/10/1

Y1 - 2006/10/1

N2 - OBJECTIVES: We hypothesized that hepatic injury is associated with severe acute pancreatitis (SAP) and may result in lung injury through nuclear factor kappa B (NF-κB)-dependent inflammatory mediators. The study characterizes the timing and determines the involvement of selected cytokines and chemokines in the pathogenesis of hepatocellular injury associated with SAP. METHODS: The SAP was induced in C57BL/6 mice by feeding a choline-deficient/ethionine- supplemented diet. The mice were killed at 12-hour intervals for 96 hours. Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining was used to determine the extent of hepatic apoptosis. The NF-κB activation in nuclear protein extracts from liver tissue was measured using a sensitive RelA enzyme-linked immunoadsorbent assay. Tumor necrosis factor α, interleukin 6, macrophage inflammatory protein (MIP) 2, and keratinocyte-derived chemokine (KC) levels in homogenates of liver and lung tissues were measured by enzyme-linked immunoadsorbent assay. The SAP-associated neutrophil lung inflammation was measured as tissue myeloperoxidase activity. RESULTS: The SAP and subsequent liver injury were confirmed by histological analysis and rises in plasma amylase and transaminase levels. Severe hepatocellular apoptosis was detected at 36 and 48 hours after the diet initiation by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (P < 0.05) and subsequently progressed to hepatic necrosis. Liver NF-κB activation was detected at 36 hours (P < 0.05) and followed by a sharp increase in hepatocellular levels of interleukin 6, MIP-2, and KC at 72 hours and thereafter (P < 0.05). Levels of MIP-2 and KC in lung tissue were also elevated at 72 hours (P < 0.05) and closely correlated with increased myeloperoxidase activity and increased inflammatory cell infiltrate in the lung. CONCLUSIONS: Choline-deficient/ethionine-supplemented diet-induced SAP is accompanied with hepatocellular apoptosis and eventual necrosis. This injury is associated with the hepatic NF-κB activation leading to the production of NF-κB-dependent cytokines and chemokines in the liver, which may mediate the lung injury.

AB - OBJECTIVES: We hypothesized that hepatic injury is associated with severe acute pancreatitis (SAP) and may result in lung injury through nuclear factor kappa B (NF-κB)-dependent inflammatory mediators. The study characterizes the timing and determines the involvement of selected cytokines and chemokines in the pathogenesis of hepatocellular injury associated with SAP. METHODS: The SAP was induced in C57BL/6 mice by feeding a choline-deficient/ethionine- supplemented diet. The mice were killed at 12-hour intervals for 96 hours. Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining was used to determine the extent of hepatic apoptosis. The NF-κB activation in nuclear protein extracts from liver tissue was measured using a sensitive RelA enzyme-linked immunoadsorbent assay. Tumor necrosis factor α, interleukin 6, macrophage inflammatory protein (MIP) 2, and keratinocyte-derived chemokine (KC) levels in homogenates of liver and lung tissues were measured by enzyme-linked immunoadsorbent assay. The SAP-associated neutrophil lung inflammation was measured as tissue myeloperoxidase activity. RESULTS: The SAP and subsequent liver injury were confirmed by histological analysis and rises in plasma amylase and transaminase levels. Severe hepatocellular apoptosis was detected at 36 and 48 hours after the diet initiation by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (P < 0.05) and subsequently progressed to hepatic necrosis. Liver NF-κB activation was detected at 36 hours (P < 0.05) and followed by a sharp increase in hepatocellular levels of interleukin 6, MIP-2, and KC at 72 hours and thereafter (P < 0.05). Levels of MIP-2 and KC in lung tissue were also elevated at 72 hours (P < 0.05) and closely correlated with increased myeloperoxidase activity and increased inflammatory cell infiltrate in the lung. CONCLUSIONS: Choline-deficient/ethionine-supplemented diet-induced SAP is accompanied with hepatocellular apoptosis and eventual necrosis. This injury is associated with the hepatic NF-κB activation leading to the production of NF-κB-dependent cytokines and chemokines in the liver, which may mediate the lung injury.

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