Abstract
Because little is known about the role of corticotropin-releasing factor (CRF) agonists in regulating responses in pancreatitis, we evaluated the effects of urocortin 2 (UCN2) and stressin1 in caerulein-induced acute pancreatitis (AP) model in rats. Male rats were pretreated with UCN2 or stressin1 for 30 min followed by induction of AP with supraphysiologic doses of caerulein. Serum amylase and lipase activity, pancreatic tissue necrosis, immune cell infiltrate, nuclear factor (NF)-κB activity, trypsin levels, and intracellular Ca2+ ([Ca2+]i) were ascertained. UCN2, but not stressin1 attenuated the severity of AP in rats. UCN2, but not stressin1, reduced serum amylase and lipase activity, cell necrosis and inflammatory cell infiltration in AP. NF-κB activity in pancreatic nuclear extracts increased in AP and UCN2 treatment reduced caerulein-induced increases in NF-κB activity by 42%. UCN2 treatment prevented caerulein-induced degradation of IκB-α in the cytosolic fraction as well as increased levels of p65 subunit of NF-κB in the cytosolic fraction. Pancreatic UCN2 levels decreased in AP compared with saline. UCN2 evoked [Ca2+]i responses in primary acinar cells and abolished caerulein-evoked [Ca2+]i responses at 0.1nM, and decreased by ~50% at 1.0nM caerulein. UCN2 stimulation resulted in redistribution of a portion of F-actin from the apical to the basolateral pole. UCN2 prevented the massive redistribution of F-actin observed with supraphysiologic doses of caerulein. UCN2, but not stressin1 attenuated severity of an experimental pancreatitis model. The protective effects of UCN2, including anti-inflammatory and anti-necrotic effects involve activation of the CRF2 receptor, [Ca2+]i signaling, and inhibition of NF-κB activity.
Highlights
The urocortins (UCN1-3) are members of the corticotropin-releasing factor (CRF) family of neuropeptides [1]
We show that urocortin 2 (UCN2) ameliorated caerulein-induced pancreatitis measured by reductions in levels of serum amylase and lipase; and tissue measurements of cell necrosis, immune cell infiltration, as well as by inhibition of nuclear factor (NF)-κB activation
UCN2 is potent vasodilator and one possible mechanism by which it could influence pancreatic function is by increasing blood flow to the organ, which is known to be compromised in pancreatitis [42]
Summary
The urocortins (UCN1-3) are members of the corticotropin-releasing factor (CRF) family of neuropeptides [1]. UCNs play an important role in regulation of diverse processes such as vascular tone [6,7,8], cardiac function [9], visceral pain [10], immune cell activation, and gastrointestinal functions [11,12,13,14,15,16]. The urocortins exert their effects via two known receptors, CRF1 and CRF2 [17]. Localization of these ligands and receptors has been ascertained in the central nervous system as well as in the peripheral tissues [11, 15, 19,20,21,22]
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