Abstract
BackgroundPoly(ADP-ribose) polymerase (PARP) participates in multi-organ failure in various inflammatory diseases including acute necrotizing pancreatitis (ANP). Since pancreatitis-associated adrenal insufficiency is partly caused by inflammatory damage to the adrenal cortex, we examined whether PARP antagonism could alleviate adrenal insufficiency in a rat model of ANP.MethodsANP was induced by retrograde infusion of sodium taurocholate into the bile-pancreatic duct. At 30 min prior to taurocholate infusion, rats were pretreated with the PARP inhibitor 3-Aminobenzamide (3-AB, 20 mg/kg) or vehicle. Pancreatic pathological injury, adrenal histology, neutrophil infiltration, cell apoptosis, and serum corticosterone level were assessed at various times points. Activities of poly(ADP-ribosyl)ated protein (PAR), nuclear factor-kappaB (NF-kB), tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in the adrenal were also examined.ResultsPARP overactivation in ANP rats is associated with reduced serum corticosterone level and marked cellular alterations in adrenocortical tissue. Inflammatory stress caused by ANP reduced adrenal corticosterone release. 3-AB reduced the activation of PARP and inflammatory markers, decreased myeloperoxidase activity, attenuated adrenal morphologic lesions and cells apoptosis, simultaneously improved the impaired adrenal function.ConclusionsOur data demonstrate the involvement of PARP overactivation in the pathogenesis of adrenal dysfunction after ANP. PARP inhibition may suppress inflammation and promote functional recovery from adrenal injury.
Highlights
Poly(ADP-ribose) polymerase (PARP) participates in multi-organ failure in various inflammatory diseases including acute necrotizing pancreatitis (ANP)
PARP was activated in the adrenal glands after ANP Western blot revealed increased Poly(ADP-ribosyl)ated protein, as early as 3 h after sodium taurocholate (TCA) retrograde infusion (Fig. 2)
The present study demonstrated that PARP inhibition with 3-AB could suppress inflammation and promotes recovery from adrenal injury in a rat model of ANP
Summary
Poly(ADP-ribose) polymerase (PARP) participates in multi-organ failure in various inflammatory diseases including acute necrotizing pancreatitis (ANP). Relative adrenal insufficiency (RAI), defined as inadequate adrenal corticosteroid production, is common in critically ill patients due to a variety of conditions, including severe acute pancreatitis (SAP) [1,2,3,4]. Dysfunction of the hypothalamic-pituitaryadrenal (HPA) axis is a major contributing factor to adrenal insufficiency under such conditions [5] Another key factor is organic damage to the adrenal gland. In animal models of acute necrotizing pancreatitis (ANP), adrenal insufficiency could be largely attributed to pathologically verifiable damage to the adrenal gland [6, 7], caused by a variety of pathological processes, including ischemia, hemorrhage, inflammation, and apoptosis [1, 8, 9]. Poly(ADP-ribosyl)ation performs a multitude of biological functions, including regulation of gene expression and gene amplification, cellular differentiation, cellular division and DNA replication, as well as modulating cell apoptosis [11]
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