Selective Inhibition of NF-κB Attenuates the Severity of... : Journal of the American College of Surgeons (original) (raw)

Original scientific article

Selective Inhibition of NF-κB Attenuates the Severity of Cerulein-Induced Acute Pancreatitis

Ethridge, Richard T MS*; Hashimoto, Koji MD*; Chung, Dai H MD*; Ehlers, Richard A MD*; Rajaraman, Srinivasan MD†; Evers, Mark B. MD, FACS*, **

* Department of Surgery (Ethridge, Hashimoto, Chung, Ehlers, Evers), The University of Texas Medical Branch, Galveston, Texas, USA

† Department of Pathology (Rajaraman), The University of Texas Medical Branch, Galveston, TX, USA

**Correspondence address: B Mark Evers, MD, FACS, Department of Surgery, The University of Texas Medical Branch, 301 University Blvd, Galveston TX 77555-0533, USA.

Received February 5, 2002; accepted February 5, 2002.

☆No competing interests declared.

This work was supported by grants from the National Institutes of Health (PO1 DK35608, RO1 DK48498, T32 DK07639). Mr Ethridge is a recipient of an Alpha Omega Alpha Student Research Fellowship and a McLaughlin Fellowship Award. Dr Ehlers is a recipient of an Individual Research Service Award (F32 CA79187) and a Jeanne B Kempner Award.

Presented, in part, at the American College of Surgeons 87th Annual Clinical Congress, Surgical Forum, New Orleans, LA, October 2001.

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.