Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gabexate mesylate (GM; commercialized under the brand name FOY) is a nonantigenic synthetic inhibitor of plasmatic and pancreatic serine proteinases that is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for hemodialysis. The inhibitory effect of GM on nitric oxide synthase as well as serine proteinases and swine kidney copper amine oxidase, all acting on cationic substrates, has been investigated. On the basis of the available X-ray crystal structures of the enzymes considered, the possible binding mode(s) of GM has(have) been analyzed. The enzyme cross-inhibition by GM suggests that the use of this drug should be under careful control. With the aim to improve the scarce plasma stability of GM, the positively charged drug has been complexed to the surface of preformed anionic liposomes. The liposome-complexed GM half-life increases about five-fold, indicating the protective effect of liposomes on GM degradation. Moreover, the GM complexation with liposomes does not alter its inhibitory activity on NOS-I and porcine pancreatic trypsin.
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PMID:Cross-enzyme inhibition by gabexate mesylate: formulation and reactivity study. 981 86

To clarify the role of nitric oxide (NO) in the development and progression of acute pancreatitis, we investigated the effect of different NO synthase inhibitors and NO donors on experimental pancreatitis in rats. Closed duodenal loop (CDL)-induced pancreatitis was produced in male Wistar rats, and the animals were treated with normal saline, the NO-synthase substrate L-arginine, the NO donor S-nitroso-N-acetylpenicillamine, aminoguanidine, which is a more powerful inhibitor of inducible NO synthase (iNOS) than is endothelial NO synthase (eNOS), and N-nitro-L-arginine methyl ester (L-NAME), a more powerful inhibitor of eNOS than of iNOS. All drugs were infused intravenously during a period of 6 or 12 h in each group. Pancreatic tissue was removed at 6 and 12 h after creating the CDL. L-Arginine, S-nitroso-N-acetyl-penicillamine, and aminoguanidine treatment had no effect on the elevation of serum pancreatic enzymes, whereas L-NAME administration significantly exacerbated their elevation. Pathologically, L-NAME treatment resulted in a significantly worse histologic score at 6 and 12 h, especially in terms of the degree of hemorrhage, acinar cell necrosis, and microvascular thrombosis. Addition of L-arginine clearly reversed the effect of L-NAME. Neither the NO substrate nor NO donor could inhibit the progression of hemorrhagic pancreatitis in CDL-induced pancreatitis. Aminoguanidine had no effect on the severity of the pancreatitis. We therefore concluded that NO production by eNOS may play a significant role in preventing the development and progression of acute pancreatitis.
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PMID:An endothelial nitric oxide synthase inhibitor aggravates CDL-induced acute pancreatitis in rats. 1054

Coxsackievirus infection causes myocarditis and pancreatitis in humans. In certain strains of mice, Coxsackievirus causes a severe pancreatitis. We explored the role of NO in the host immune response to viral pancreatitis. Coxsackievirus replicates to higher titers in mice lacking NO synthase 2 (NOS2) than in wild-type mice, with particularly high viral titers and viral RNA levels in the pancreas. Mice lacking NOS have a severe, necrotizing pancreatitis, with elevated pancreatic enzymes in the blood and necrotic acinar cells. Lack of NOS2 leads to a rapid increase in the mortality of infected mice. Thus, NOS2 is a critical component in the immune response to Coxsackievirus infection.
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PMID:Inducible nitric oxide synthase protection against coxsackievirus pancreatitis. 1055 76

The present work critically reviews the evidence for an involvement of free radicals in the pathophysiology of acute pancreatitis and the potential of treatment with antioxidants and scavenger substances. Data originating from clinical trials, experimental pancreatitis studies and in vitro investigations are included. Enhanced free radical activities and increased concentrations of lipid peroxides in plasma and tissue have been found in both patients and experimental animals with acute pancreatitis. The individual contribution of possible sources of free radicals (e.g., invading inflammatory cells, xanthine oxidase, cytochromes P450, nitric oxide synthase) is not yet clear, however. Since prophylactic administration of antioxidants diminished, in particular, pancreatic edema formation, free radicals seem to play an important role in the genesis of edema in acute pancreatitis. An involvement of free radicals in the pathogenesis of pancreatic necrosis could not yet be proven. Thus, no antioxidant treatment has proven useful for therapy of fulminant pancreatitis in animals to date. However, in severe acute pancreatitis characterized by death occurring after 12-18 hours, the seleno-organic compound Ebselen, which has a glutathione peroxidase-like activity, and the membrane permeable ascorbic acid derivative CV-3611 have been demonstrated to be effective. To date, controlled clinical studies have failed to demonstrate the therapeutic efficacy of antioxidant selenium or glutathione precursor supplementation. Therefore, further controlled clinical trials are needed to determine whether supplements of antioxidants can alter the clinical course of acute pancreatitis. Since the nitric oxide radical may even protect the pancreas, a purely negative discussion of the role of free radicals on the pancreas is not justified. The actual role of free radicals in acute pancreatitis, i.e. serving the body's defense against infection, being an epiphenomenon of the inflammatory process without pathophysiological relevance, or having true pathogenic significance, is not yet clear. Lipid peroxidation may perhaps not be the cause but rather the sequel of pancreatic inflammation and may likely reflect the severity of the systemic inflammatory response rather than that of pancreatic parenchyma damage. In vitro, exposure of isolated pancreatic acinar cells to oxidative stress caused rapid cell damage and death. Such knowledge from cellular studies might help to plan therapeutical trials to evaluate potentially effective therapies in the experimental animal, as well as in patients suffering from pancreatitis. Thus, to further clarify the role of oxidative stress in acute pancreatitis, an integrated approach is needed, including investigations at various biological levels, from isolated cells or even organelles to laboratory animals and, finally, clinical studies in man.
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PMID:Oxidative stress in acute pancreatitis. 1057 39

Nitric oxide (NO) as a unique biological mediator that has been implicated in many physiological and pathophysiological processes may have a significant influence on the course of acute pancreatitis and the recovery process. The aim of the study was to evaluate the effect of a NO synthase inhibitor or a substrate for NO endogenous production on the ultrastructural features of the acinar cells in the course of caerulein-induced acute pancreatitis. Acute pancreatitis was induced in the rats by a supramaximal dose of caerulein. During acute pancreatitis induction, the rats were treated with L-arginine (the substrate for NO synthesis), NG-nitro-L-arginine (L-NNA, NO synthase inhibitor), L-arginine + L-NNA or saline. Light and electron microscopy examinations were performed in all groups after pancreatitis induction and additionally after 7 and 14 days of recovery. The study demonstrated that the NO synthase inhibitor given during pancreatitis induction in rats enhances the damage to the acinar cells, detected ultrastructurally, and increases the cellular inflammatory infiltration. In the later period, the considerable damage to the mitochondria and the changes in secretory compartment were observed, including dilated cisternae of Golgi apparatus, focal degranulation of rough endoplasmic reticulum, and reduced number of zymogen granules and condensing vacuoles. L-arginine reversed to some extent the deleterious effect of L-NNA, although when administered alone it had no apparent effect on the ultrastructure of pancreatic acinar cells compared with untreated animals. The obtained results indicate that the NO synthase inhibitor enhances the ultrastructural degenerative alterations in the pancreatic acinar cells in the course of caerulein-induced acute pancreatitis and confirm the protective role of endogenous nitric oxide in this disease.
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PMID:Nitric oxide protects the ultrastructure of pancreatic acinar cells in the course of caerulein-induced acute pancreatitis. 1063 81

To clarify the roles of nitric oxide (NO) in acute pancreatitis (AP), we examined the effects of NO on the endothelial activation induced by ascitic fluids from rats with experimental severe AP. Necrotizing hemorrhagic pancreatitis was induced in male Wistar rats with sodium taurocholate. Six hours later, peritoneal exudates were collected, centrifuged, and human umbilical vein endothelial cells were treated with the supernatants. Then (a) the mRNA level of endothelial-type NO synthase (ecNOS) was examined by reverse transcription-polymerase chain reaction; (b) effects of an NO donor, sodium nitroprusside (SNP) and an inhibitor of NOS, N(omega)-nitro-L-arginine (L-NNA) on the ascitic fluids-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin-8 were assessed by enzyme-linked immunoassay; (c) nuclear translocation of nuclear factor-kappa B (NF-kappaB) was examined by electrophoretic mobility shift assay; and (d) effects of SNP and L-NNA on the adhesion of U937 cells to endothelial monolayer were assessed. The ecNOS mRNA level was decreased by the ascitic fluids; ascitic fluids-induced expression of adhesion molecules and interleukin-8 as well as the nuclear translocation of NF-kappaB were attenuated by SNP, whereas L-NNA augmented them; and the effects on the endothelial activation were paralleled by the altered adhesion of U937 cells to endothelium. The ability of NO to limit endothelial activation and inhibit leukocyte adhesion might contribute to its antiinflammatory properties in AP.
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PMID:Nitric oxide decreases endothelial activation by rat experimental severe pancreatitis-associated ascitic fluids. 1076 57

Lipopolysaccharide (LPS) derived from the bacterial cell wall activates the inflammatory response in the tissue but the role of LPS in the pathogenesis of pancreatic damage and in the activation of NO system in the pancreas has not been fully explained. The aim of this study was to investigate the effect of repeated administration of LPS to the rats on the integrity of the pancreas, on the ability of isolated pancreatic acini to secrete the amylase and on the plasma level of tumor necrosis factor alpha (TNFalpha). The role of NO in the pancreatic resistance to the damage was assessed in animals subjected to repeated administration of LPS. To induce pancreatic damage one group of rats received intraperitoneal (i.p.) injection of LPS (from E. coli) every day during 5 consecutive days (10 mg/kg--day). Another groups of animals were given N(G)-nitro-L-arginine (L-NNA), an inhibitor of NO synthase (NOS) (20 mg/kg i.p.) alone or in combination with L-arginine (100 mg/kg i.p.), 30 min prior to each LPS injection. Plasma level of TNFalpha was determined by ELISA kit. Repeated administration of LPS produced mild pancreatic inflammation that was most pronounced at day 5 of LPS treatment and manifested as edema, neutrophil infiltration and hemorrhage of the pancreas. The survival rate after 5 days treatment with LPS was 87.5%. Pancreatic weight, plasma levels of TNFalpha and amylase, pancreatic blood flow (PBF) and NO generation by pancreatic acini were markedly increased in rats subjected to repeated administration of LPS whereas the amylase response of isolated pancreatic acini to pancreatic secretagogues was significantly attenuated. Suppression of NOS by L-NNA resulted in a dramatic increase in the mortality of the animals reaching 50% and significantly increased inflammatory changes in the pancreatic tissue, decreased PBF, abolished the ability of pancreatic acini to release NO and to secrete amylase. Pancreatic weight and plasma levels of amylase and TNFalpha significantly increased in the group of rats treated with combination of LPS+L-NNA as compared to the animals received LPS alone. Addition of L-arginine to L-NNA+LPS administration reversed all harmful effects produced by L-NNA in the pancreas. We conclude that repeated administration of high doses of bacterial LPS to the rats could induce pancreatic tissue damage by itself, however, it is not able to produce severe pancreatitis. Suppression of NO generation significantly aggravates the pancreatic lesion produced by LPS leading to the dramatic mortality in treated rats. The rise of plasma level of TNFalpha corresponds to the severity of pancreatic inflammation.
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PMID:Protective role of endogenous nitric oxide (NO) in lipopolysaccharide--induced pancreatic damage (a new experimental model of acute pancreatitis). 1076 53

Lipopolysaccharides (LPS), the component of the cell wall of gram-negative bacteria, have been implicated in the pathogenesis of acute pancreatitis, but the mechanism of their action on the pancreas has not been fully explored. The aim of this study was to investigate the effects of various doses of LPS on the integrity of intact pancreas and that involved in acute caerulein-induced pancreatitis (CIP) in the rat and to compare these effects with those of nitric oxide (NO) donor, S-nitrose-acetylpenicillamine (SNAP). The expression of constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) mRNA was also examined in the isolated pancreatic acini obtained from the inflamed pancreas of rats treated with LPS. CIP was produced by subcutaneous (s.c.) infusion of caerulein (5 microg/kg.h for 5 h) to conscious rats. Bolus injections of various doses of LPS (0.1, 1, 10, 20 or 40 mg/kg) or SNAP (1.5, 3 or 6 mg/kg) were made intraperitoneally (i.p.) either alone or 30 min prior to s.c. infusion of caerulein to induce CIP. Infusion of caerulein produced acute pancreatitis confirmed by histological examination and manifested by an increase of pancreatic mass (by about 200%). Blood levels of amylase and lipase were augmented by 400 and 800% respectively, whereas the pancreatic blood flow (PBF) was decreased by 50% in rats with CIP. Injection of low doses of LPS (0.1-1 mg/kg i.p.) or SNAP (1.5-3 mg/kg i.p.) 30 min prior to caerulein infusion reversed the harmful effects of pancreatic overstimulation with caerulein and reduced significantly the histological manifestations of CIP such as edema, neutrophil infiltration and vacuolization of the acinar cells. These protective effects of low doses of LPS pretreatment on the pancreas were completely antagonized by the suppression of the activity of NO synthase (NOS) with N(G)-nitro-L-arginine (L-NNA) applied (20 mg/kg i.p.) 15 min prior to the LPS injection. Combination of L-arginine (100 mg/kg i.p.), a substrate for NOS, with L-NNA given prior to low doses of LPS, restored the LPS-induced protection of the pancreas in rats with CIP. In contrast, higher doses of LPS (20-40 mg/kg i.p.) or SNAP (6 mg/kg i.p.), which produced a significant fall of the PBF, did not protect the pancreas against CIP. Administration of various doses of LPS to rats with CIP resulted in significant and dose-dependent stimulation of NO biosynthesis in the isolated acini obtained from the pancreas of these animals. LPS enhanced the expression of both cNOS and iNOS in the pancreatic acini obtained from rats subjected to CIP. The signal for cNOS mRNA was detected in all samples, reaching peak at the protective dose of LPS (1 mg/kg i. p.), while iNOS was overexpressed only at the highest doses of LPS that failed to exhibit the protective activity. We conclude that the pretreatment with low doses of LPS protects the pancreas against the damage provoked by CIP and this effect could be attributed, at least in part, to the activation of L-arginine-NO system in the pancreas.
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PMID:Protective action of lipopolysaccharidesin rat caerulein-induced pancreatitis: role of nitric oxide. 1089 19

We investigated the effects of nafamostat mesilate, a synthetic protease inhibitor clinically used for patients with pancreatitis or disseminated intravascular coagulopathy, on NO synthesis and apoptosis in lipopolysaccharide (LPS)-treated human trophoblasts. Nafamostat mesilate or aminoguanidine, an inhibitor of NO synthase, suppressed NO synthesis and apoptosis in trophoblasts induced by LPS. Both agents also suppressed matrix metalloproteinase-2 activity induced by LPS. LPS also stimulated secretion of IL-6 and IL-8 in cultured trophoblasts, which was suppressed by nafamostat mesilate. Protease inhibitors including nafamostat mesilate may be therapeutic agents for chorioamnionitis and various diseases including septic shock, ischemia-reperfusion injury in brain and heart, graft rejection, and acute phase inflammatory diseases, in which overproduction of NO or peroxynitrite is involved in tissue injury.
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PMID:Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts. 1095 57

Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitric oxide synthase (NOS2), in viral clearance and pancreatic beta-cell maintenance. Mice deficient in NOS2 (NOS2-/- mice) and their wild-type (wt) counterparts were injected with CB4, after which both groups developed severe pancreatitis, hepatitis, and hypoglycemia within 3 days. Within 4 to 7 days postinfection (p.i.), most of the NOS2-/- mice died and at a strikingly higher mortality rate than wt mice. Histological examination of pancreata from both infected NOS2-/- and infected wt mice revealed early and complete destruction of the pancreatic acinar tissue, but intact, insulin-stained islets. When examined up to 8 weeks p.i., neither surviving NOS2-/-mice nor surviving wt mice developed hyperglycemia. However, the clearance of infectious CB4 was different between the mice. The spleens of NOS2-/- survivors were cleared of infectious virus with kinetics similar to that of wt mice, but the livers, pancreata, kidneys, and hearts of the NOS2-/- groups cleared virus more slowly than those of the wt group. This delayed clearance was particularly prominent in the livers of infected NOS2-/- mice, which also showed prolonged histopathological features of viral hepatitis. Taken together, this outcome suggests that NOS2 (and NO) is not required for the prevention of pancreatic beta-cell depletion after CB4 infection. Instead the critical actions of NOS2 apparently occur early in the host immune response, allowing mice to survive and clear virus. Moreover, the data support the existence of an organ-specific dependency on NO for a rapid clearance of CB4.
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PMID:A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. 1127 93


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