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Dios, Isabel De; Uruñuela, Aránzazu; Órfão, Alberto; Manso, Manuel A.

doi:10.1023/a:1016400829744

Cited by 10 publications

(2 citation statements)

References 39 publications

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“…Intra-acinar activation of trypsinogen has been proposed as the initial pathophysiological factor in AP [1, 2, 3], depending in turns on a rise in intracellular Ca 2+ concentrations [4, 5, 6]. Accordingly, premature activation of digestive enzymes [1, 2, 3, 7, 8, 9, 10]and increased cytosolic calcium levels [11, 12, 13, 14]have been found in acinar cells at early AP stages. On the other hand, the involvement of oxidative stress in the pathogenesis of AP has been widely demonstrated since the study performed by Sanfey et al [15].…”

Section: Introductionmentioning

confidence: 99%

“…However, there is no information about the effectiveness of antioxidant treatments in mitigating the pathophysiological mechanisms which lead to AP. Accordingly, our aim was to investigate to what extent administration of N-acetyl- L -cysteine (NAC) – a thiol compound with potent antioxidant and anti-inflammatory properties [23]– is able to prevent pathological events, such as the increase in cytosolic Ca 2+ levels [11, 12, 13]and the accumulation of digestive enzymes [12, 13, 24]occurring as a consequence of the exocytosis blockade which develops within acinar cells at early stages of AP induced in rats by bile and pancreatic duct obstruction (BPDO).…”

Section: Introductionmentioning

confidence: 99%

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Major Pathological Mechanisms of Acute Pancreatitis Are Prevented by N-Acetylcysteine

et al. 2003

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Aim: To analyze the capability of N-acetylcysteine (NAC) to prevent major intra-acinar pathogenic mechanisms involved in the development of acute pancreatitis (AP). Methods: AP was induced by pancreatic duct obstruction (PDO) in rats. Some animals received NAC (50 mg/kg) 1 h before and 1 h after PDO. During a 24-hour period of PDO, plasma amylase activity and pancreatic glutathione and malondialdehyde levels were measured. Cytosolic Ca²⁺ levels and enzyme (amylase and trypsinogen) load in acinar cells were also analyzed by flow cytometry, and histological analysis of the pancreas was performed by electron microscopy. Results: NAC avoided glutathione depletion at early AP stages, thereby preventing pancreatic oxidative damage, as reflected by normal malondialdehyde levels. By limiting oxidative stress, NAC treatment effectively prevented the impairment of Ca²⁺ homeostasis found in acinar cells from early AP onwards, thus protecting the pancreas from damage. In addition, lower quantities of digestive enzymes were accumulated within acinar cells. This finding, together with the significantly lower hyperamylasemia observed in these animals, suggests that NAC treatment palliates the exocytosis blockade induced by PDO. Conclusion: By preventing oxidative stress at early AP stages, NAC administration prevents other pathological mechanisms of AP from being developed inside acinar cells, thus palliating the severity of disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Major Pathological Mechanisms of Acute Pancreatitis Are Prevented by N-Acetylcysteine

et al. 2003

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Cholecystokinin Antagonists may have Detrimental Effects on Acute Pancreatitis

Dios

Manso

2006

Dig Dis Sci

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The author reviews the findings obtained with CCK antagonists in several experimental models of pancreatitis and highlights the harmful effects of L364,718-a potent CCK-receptor antagonist-on acute pancreatitis (AP) induced by bilepancreatic duct obstruction (BPDO) recently reported by De Dios et al. (2). Although the title of the paper may be appropriated for attracting the attention of readers it is highly confusing, since although L364,718 was shown to increase cytosolic calcium levels in acinar cells of control rats, no evidence of AP was found by De Dios et al. (2). In fact, it is well documented that while an increase in intracellular Ca 2+ concentration is required for the activation of trypsinogen in acinar cells exposed to supramaximal dosis of CCK (3-5), it was not sufficient, by itself, to initiate enzyme activation in the absence of the secretagogue (5). In contrast, L364,718 increased the severity of AP in rats subjected to BPDO (2), because apart from increasing citosolic calcium, it was not able to prevent the accumulation of enzymes in acinar cells at early stages of AP, when trypsinogen is highly activated in the presence of Ca 2+ .A common feature in the clinical setting and any experimental model of AP is the blockade of acinar secretion. As a result, the feedback mechanism for CCK release from duodenal mucosa is inhibited and CCK plasma levels are thereby increased. On this basis, it is thought that CCK could play an important role in the development of AP, and thereby different treatments with CCK antagonists have been extensively applied in AP models with different results. As expected a priori, CCK antagonists have been shown to decrease the severity of AP induced by supramaximal dosis of CCK or its analogue cerulein (6-10). Beneficial effects have been reported by Niedereau et al. on AP induced CDE diet (11) and BPDO (12), but CCK antagonists failed to show protective effects on AP induced by L-arginine (13), CDE diet in mice (14, 15), and BPDO (16). Niedereau (1) questions the detrimental effects of L364,718 in AP-induced by BPDO shown by De Dios et al.(2) based on the fact that the hyperamylasemia observed in BPDO rats treated with L364,718 was lower than in nontreated BPDO rats. Nevertheless, it is noteworthy that no statistically significant difference was found between either animal group. According to these observations, we could have concluded that no beneficial effect is exerted by the CCK antagonist on AP development. However, different data support the notion that L364,718 exacerbates AP induced by BPDO, such as the significantly higher values of hematocrit and ascites volume, the more severe lesions observed in blinded pancreatic sections by electron microscopy (2), and the results reported by Uruñuela et al. (17) on pancreatic fluid content (edema), plasma TNF-α levels, glutathione depletion, and oxygen free radicals within acinar cells, all of whose values were significantly higher in L364,178-treated than in nontreated BPDO rats. There is evidence to indicate that L364,718 in...

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