Influence of Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs on the Evolution of Acute Pancreatitis

Abstract

Microcirculatory disturbances and leukocyte activation are main events in the pathogenesis of acute pancreatitis (AP) that is characterized by inflammatory up-regulation. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) regulate vascular function and mitigate inflammation. To investigate the influence of NO-NSAIDs on AP. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops model. Treatment with NO-flurbiprofen, NO-ibuprofen, NO-aspirin, or their parental drugs was done (i) 1 h before, (ii) 1 h after, (iii) 1 h before and 4 h after, or (iv) 4 h after surgery. The degree of severity was evaluated using biochemical and histopathological analyses. NO-NSAIDs given before and during the first hour of the noxia decreased blood levels of amylase, lipase, C-reactive protein, IL-6, IL-10, heat shock protein 72, prostaglandin E2 inactive metabolite, and 8-isoprostane, as well as pancreatic and lung myeloperoxidase and cyclooxygenase. Acinar and fat necrosis, hemorrhage, and leukocyte infiltrate were also reduced. The best protection was achieved when treatment was performed 1 h before and 4 h after triggering AP. NO-flurbiprofen was the most effective drug. AP severity was significantly ameliorated by NO-NSAIDs being the administration time essential to achieve optimal pancreatic protection that may result to be useful in the prevention of postendoscopic severe AP.

Alcohol-Induced Protein Kinase Cα Phosphorylation of Munc18c in Carbachol-Stimulated Acini Causes Basolateral Exocytosis

“…Figure 4A shows the serum alcohol levels ranging from 25 to 31 mmol/L determined at 3 weeks and at death at 6 weeks from the various ED groups, which is similar to those observed in human alcohol intoxication 21 and those used in our in vitro studies. CD or ED groups treated with IP saline did not affect serum amylase and lipase levels, which were only slightly increased in the CD ϩ Cch group, the latter of which was not sufficient to induce pancreatitis, where the histology was completely normal ( Figure 4B).…”

“…21 Histologic changes were graded in a blinded manner by 2 independent observers counting frequency of foci per field seen at 40ϫ (absent, 0; mild, 1; moderate, 2; severe, 3; overwhelming, 4).…”

VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis

“…In WT and Vamp8 -/-mice, ED plus saline treatment induced very mild edema and leukocyte infiltration of the pancreatic tissues that were more prominent in the WT group. When these ED-fed groups were treated with Cch, the WT group developed moderate to severe pancreatitis characterized by parenchymal edema, necrosis with abundant leukocyte infiltration, fat necrosis, congested blood vessels within the peripancreatic fat, and hemorrhage (24,25). Although all of these histologic changes of pancreatitis were also present in the Vamp8 -/-mice, these features were much milder in the Vamp8 -/-group.…”

“…Pancreatic and lung tissue were graded on a scale of 0-4 each for edema, hemorrhage, leukocyte infiltration, and necrosis, as previously described (8,24,25). Histologic changes were graded in a blinded manner by 2 independent observers counting the frequency of foci per field seen at ×40 (0, absent; 1, mild; 2, moderate; 3, severe; 4, overwhelming).…”

“…Cch injections) was used to block the development of pancreatitis. Figure 1 shows the representative histology, and Table 1 quantifies the pancreatic damage (24,25). In WT and Vamp8 -/-mice, ED plus saline treatment induced very mild edema and leukocyte infiltration of the pancreatic tissues that were more prominent in the WT group.…”