NF-κB in acute pancreatitis: Mechanisms and therapeutic potential.
The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies. Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.
Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India.
Aparna
A
Jakkampudi
Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India.
Ramaiah
R
Jangala
Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India.
B Ratnakar
BR
Reddy
Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India.
Sasikala
S
Mitnala
Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
D
D
Nageshwar Reddy
Wellcome-DBT Laboratory, Asian Healthcare Foundation, Hyderabad, India; Dept. of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India. Electronic address: rup_talukdar@yahoo.com.
Rupjyoti
R
Talukdar
D016207:Cytokines / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D019283:Pancreatitis, Acute Necrotizing / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B
Acute pancreatitis; Clinical implications; Cytokines; IκB; NF-κB; Nuclear factor kappa B