Selective inhibition of NF-κB attenuates the severity of cerulein-induced acute pancreatitis

Richard T. Ethridge, Koji Hashimoto, Dai H. Chung, Richard A. Ehlers, Srinivasan Rajaraman, B. Mark Evers

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

BACKGROUND: Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-κB is activated by degradation of its inhibitory factor, IκB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-κB binding activity with a novel peptide that binds to the NF-κB essential modifier binding domain (NBD) could attenuate the severity of AP. STUDY DESIGN: AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 μg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-κB binding activity and steady-state levels of IκB and NF-κB subunits were determined by gel shift and Western blot, respectively. RESULTS: AP resulted in increased NF-κB DNA-binding activity and decreased steady-state levels of IκB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: The marked induction of NF-κB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-κB may prove to be useful treatment of AP and AP-associated lung injury.

Original languageEnglish (US)
Pages (from-to)497-505
Number of pages9
JournalJournal of the American College of Surgeons
Volume195
Issue number4
DOIs
StatePublished - Oct 1 2002
Externally publishedYes

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Ceruletide
Pancreatitis
Pancreas
Peptides
Lung
Peroxidase
Transcription Factors
Cytokines
Inflammation
Injections
Cholecystokinin
Lung Injury
Neutrophils
Therapeutics
Western Blotting
Gels
Hemorrhage
DNA
Wounds and Injuries

ASJC Scopus subject areas

  • Surgery

Cite this

Selective inhibition of NF-κB attenuates the severity of cerulein-induced acute pancreatitis. / Ethridge, Richard T.; Hashimoto, Koji; Chung, Dai H.; Ehlers, Richard A.; Rajaraman, Srinivasan; Evers, B. Mark.

In: Journal of the American College of Surgeons, Vol. 195, No. 4, 01.10.2002, p. 497-505.

Research output: Contribution to journalArticle

Ethridge, Richard T. ; Hashimoto, Koji ; Chung, Dai H. ; Ehlers, Richard A. ; Rajaraman, Srinivasan ; Evers, B. Mark. / Selective inhibition of NF-κB attenuates the severity of cerulein-induced acute pancreatitis. In: Journal of the American College of Surgeons. 2002 ; Vol. 195, No. 4. pp. 497-505.
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abstract = "BACKGROUND: Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-κB is activated by degradation of its inhibitory factor, IκB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-κB binding activity with a novel peptide that binds to the NF-κB essential modifier binding domain (NBD) could attenuate the severity of AP. STUDY DESIGN: AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 μg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-κB binding activity and steady-state levels of IκB and NF-κB subunits were determined by gel shift and Western blot, respectively. RESULTS: AP resulted in increased NF-κB DNA-binding activity and decreased steady-state levels of IκB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: The marked induction of NF-κB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-κB may prove to be useful treatment of AP and AP-associated lung injury.",
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N2 - BACKGROUND: Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-κB is activated by degradation of its inhibitory factor, IκB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-κB binding activity with a novel peptide that binds to the NF-κB essential modifier binding domain (NBD) could attenuate the severity of AP. STUDY DESIGN: AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 μg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-κB binding activity and steady-state levels of IκB and NF-κB subunits were determined by gel shift and Western blot, respectively. RESULTS: AP resulted in increased NF-κB DNA-binding activity and decreased steady-state levels of IκB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: The marked induction of NF-κB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-κB may prove to be useful treatment of AP and AP-associated lung injury.

AB - BACKGROUND: Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-κB is activated by degradation of its inhibitory factor, IκB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-κB binding activity with a novel peptide that binds to the NF-κB essential modifier binding domain (NBD) could attenuate the severity of AP. STUDY DESIGN: AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 μg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-κB binding activity and steady-state levels of IκB and NF-κB subunits were determined by gel shift and Western blot, respectively. RESULTS: AP resulted in increased NF-κB DNA-binding activity and decreased steady-state levels of IκB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: The marked induction of NF-κB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-κB may prove to be useful treatment of AP and AP-associated lung injury.

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