Oxidative Stress In Acute Pancreatitis Research Articles

Assessment of Add-On Therapy of N-Acetylcysteine in the Management of Acute Pancreatitis

Abstract Background Acute pancreatitis (AP) is an inflammation of the pancreas. The conservative therapeutic options include enteral nutrition, antibiotics, and/or surgery. Oxidative stress in AP has been pathologically linked with the systemic inflammatory response. N-acetylcysteine (NAC), an antioxidant, attenuates oxidative stress-induced cell injury and other potential pathological events in AP. Objective This article evaluates the treatment outcome of NAC combined with conventional therapy in AP patients and assesses the difference in the duration of hospital stay between the NAC with conventional therapy group and the conventional therapy group. Materials and Methods This observational study was conducted in a tertiary care hospital with 65 AP patients above 18 years of age. The effect of adding NAC with conventional therapy (intravenous hydration 0.9% normal saline, pancreatin, optional antibiotics) was assessed in patients by comparing serum amylase, lipase, Acute Physiology and Chronic Health Examination (APACHE) II score, and Ranson's score, before and after therapy and the difference in duration of hospital stay was assessed using the independent t-test. Results Of the 65 AP patients, 62% (n = 40) were on conventional therapy and 38% (n = 25) were on NAC along with conventional therapy. The difference in mean values of reduced serum amylase between the two treatment groups indicates a significant difference (p = 0.01). However, the variance in mean serum lipase values was statistically insignificant (p = 0.1). The mean scores of Ranson's criteria showed no significant difference between both groups (p = 0.4). There was a significant difference in APACHE II severity scores after 24 (p = 0.04) and 48 hours (p = 0.01), respectively. Similarly, the mean duration of hospital stay in both treatment groups was found to be statistically insignificant (p = 0.4). Conclusion Both treatment options, conventional therapy and NAC combined with conventional therapy, resulted similar treatment outcomes for AP patients, with no additional benefits observed.

Natural Compounds for the Treatment of Acute Pancreatitis: Novel Anti-Inflammatory Therapies.

Acute pancreatitis remains a serious public health problem, and the burden of acute pancreatitis is increasing. With significant morbidity and serious complications, appropriate and effective therapies are critical. Great progress has been made in understanding the pathophysiology of acute pancreatitis over the past two decades. However, specific drugs targeting key molecules and pathways involved in acute pancreatitis still require further study. Natural compounds extracted from plants have a variety of biological activities and can inhibit inflammation and oxidative stress in acute pancreatitis by blocking several signaling pathways, such as the nuclear factor kappa-B and mitogen-activated protein kinase pathways. In this article, we review the therapeutic effects of various types of phytochemicals on acute pancreatitis and discuss the mechanism of action of these natural compounds in acute pancreatitis, aiming to provide clearer insights into the treatment of acute pancreatitis.

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway.

Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.

Role of antioxidants and oxidative stress in the evolution of acute pancreatitis (Review).

Acute pancreatitis (AP) is a severe disease with a high prevalence and 3 to 15% mortality worldwide, which can represent an important challenge for the physician. Oxidative stress and antioxidants are involved in AP progression. The mechanisms responsible for the onset and progression of AP are still poorly understood. Previous studies have highlighted the important contribution of antioxidants and oxidative stress in AP. The existence of a relationship between oxidative stress and antioxidants in AP is unquestionable, although a more accurate understanding of the mechanistic pathways involved is required to create a solid basis for potential prevention or treatment strategies. Further investigation is needed to clarify the role of antioxidant status and the severity of AP and to determine the association between oxidative stress and pancreatic enzyme activities. Antioxidant therapy may represent an interesting option for the management of patients with AP, although additional information about the effectiveness of this potential treatment is required.

Characterization of oxidative stress in acute pancreatitis

Characterization of oxidative stress in acute pancreatitis

Evaluation of oxidative stress in acute pancreatitis

Evaluation of oxidative stress in acute pancreatitis

Association between antioxidants and mild acute pancreatitis

Background and study aimsThe mechanisms underlying acute pancreatitis have not been well elucidated. Over the last 20 years, there has been increasing awareness regarding the role played by oxidative stress in acute pancreatitis, but it is less well defined in human clinical trials. The aim of this study was to identify the relationship between antioxidants and acute pancreatitis. Patients and methodsWe performed a cross-sectional trial on patients with mild acute pancreatitis. The study population consisted of 53 patients with mild acute pancreatitis and 55 healthy controls. Serum paraoxonase, arylesterase activity, total antioxidant status, total oxidant status and thiol levels were measured, and oxidative stress index was calculated. ResultsParaoxonase, arylesterase activity, thiol and total antioxidant status levels were significantly lower in the acute pancreatitis group than in the control group (p = .024, p < .001, p < .001, p = .010, respectively). Oxidative stress index and total oxidant status levels were higher in the acute pancreatitis group than in the control group, but the difference was not statistically significant (p = .135, p = .253, respectively). ConclusionsThis study demonstrates that decreased antioxidant levels are associated with mild acute pancreatitis. No association was observed between mild acute pancreatitis and total oxidant status.

PP12 - γ-Glutamyl cysteine modulates the inflammatory response via protein phosphatases

Acute pancreatitis (AP) is an acute inflammatory process of the pancreatic gland that may lead to severe systemic complications. Cytokines and oxidative stress play a role in the early pathophysiological events of the disease. Previous studies have shown the antioxidant properties of γ-glutamyl cysteine (γ–GC), a metabolic precursor for the synthesis of glutathione. C57BL/6 mice were treated with cerulein (7 injections each with 50 μg/kg bw). To evaluate the effects of γ-GC, a group of mice with AP was treated with γ-GC (75 mg/kg bw) administered in two doses at 4 and 7 hours after the first cerulein injection. Plasma lipase activity was measured and histological studies were performed to confirm the induction of AP. The aim of this work was to assess the role of γ-GC in the modulation of the inflammatory response and oxidative stress in AP. The activity of pancreatic lipase in plasma increased after induction of acute pancreatitis, but this increase was lower with γ-GC treatment. The histopathological study showed that the inflammatory process and tissue edema were reduced with the γ-GC treatment. The increase in pancreatic myeloperoxydase activity and TNF-α mRNA levels were abrogated in mice treated with γ-GC after AP induction. Moreover, the c-Jun N-terminal kinase (JNK) pathway activation was blocked upon γ-GC treatment. On the contrary, protein levels of protein tyrosine phosphatases SHP-1, SHP-2 and protein serine threonine phosphatase PP2A, which were reduced upon AP induction, were recovered after γ-GC administration. Redox pairs, such as reduced glutathione/oxidized glutathione, and cysteine/cystine were not affected by the γ-GC treatment. In conclusion, our results show the anti-inflammatory properties of the γ-GC in AP, which seem to be mediated by recovering protein phosphatase levels and avoiding the activation of the JNK pathway, independently of the redox thiol status.

Disulfide stress: a novel type of oxidative stress in acute pancreatitis

Glutathione oxidation and protein glutathionylation are considered hallmarks of oxidative stress in cells because they reflect thiol redox status in proteins. Our aims were to analyze the redox status of thiols and to identify mixed disulfides and targets of redox signaling in pancreas in experimental acute pancreatitis as a model of acute inflammation associated with glutathione depletion. Glutathione depletion in pancreas in acute pancreatitis is not associated with any increase in oxidized glutathione levels or protein glutathionylation. Cystine and homocystine levels as well as protein cysteinylation and γ-glutamyl cysteinylation markedly rose in pancreas after induction of pancreatitis. Protein cysteinylation was undetectable in pancreas under basal conditions. Targets of disulfide stress were identified by Western blotting, diagonal electrophoresis, and proteomic methods. Cysteinylated albumin was detected. Redox-sensitive PP2A and tyrosine protein phosphatase activities diminished in pancreatitis and this loss was abrogated by N-acetylcysteine. According to our findings, disulfide stress may be considered a specific type of oxidative stress in acute inflammation associated with protein cysteinylation and γ-glutamylcysteinylation and oxidation of the pair cysteine/cystine, but without glutathione oxidation or changes in protein glutathionylation. Two types of targets of disulfide stress were identified: redox buffers, such as ribonuclease inhibitor or albumin, and redox-signaling thiols, which include thioredoxin 1, APE1/Ref1, Keap1, tyrosine and serine/threonine phosphatases, and protein disulfide isomerase. These targets exhibit great relevance in DNA repair, cell proliferation, apoptosis, endoplasmic reticulum stress, and inflammatory response. Disulfide stress would be a specific mechanism of redox signaling independent of glutathione redox status involved in inflammation.

Drivers of Oxidative Stress in Acute Pancreatitis

Severe acute pancreatitis is a disease process distinguished by increasing oxidative stress and potential destruction of the pancreatic gland. An initial injury to the acinar cell initiates a sentinel event, which leads to a vicious cycle of inflammation and cell death by either apoptosis or necrosis. Whether the acute inflammation resolves or goes on to a pattern of chronicity may be related to genetic predisposition, failure to remove injurious agents, and innate systems for antioxidant defense. The degree to which nutrition therapy can modulate oxidative stress, maintain intestinal function, and preserve the structure of the acinar cell is truly amazing. Understanding the mechanisms involved in this complex disease process and the manner in which these mechanisms are influenced by dietary agents affords new and exciting therapeutic options for the future.

Malondialdehyde in early phase of acute pancreatitis

to assess oxidative stress in acute pancreatitis, its evolution over time and its relationship with the severity of the disease. during a two-year period, patients with acute pancreatitis with less than 24 hours of pain were evaluated. Serum was obtained the first, second and fourth day from admittance, if complications were detected, and after recovery. Malondialdehyde was determined by high performance liquid chromatography. Twenty healthy volunteers constituted the control group. Malondialdehyde between groups was compared with Mann-Whitney and Kruskal-Wallis tests; malondialdehyde evolution was studied with Wilcoxon test. one hundred and sixty-nine patients were included (91 women, median age 67 years, range 20-95); 33 suffered a severe episode. Malondialdehyde decreased from first to fourth day (0.600 vs. 0.451 vs. 0.343 M, respectively, p < 0.05). When complications were detected, malondialdehyde level was similar to that of first and second day (0.473 M, p > 0.05). In severe attacks malondialdehyde was higher than in control group at day 2 (severe: 0.514; mild: 0.440; control: 0.347 M, p < 0.05 severe vs. control). an early oxidative stress is observed in acute pancreatitis. In severe attacks, oxidative stress remains high longer than in mild episodes. The onset of complications is associated with high malondialdehyde concentration.

Molecular mechanisms of pancreatic injury

Despite being a subject of much scientific scrutiny, the pathogenesis of acute pancreatitis is still not well understood. This article reviews recent advances in our understanding of acute pancreatitis. Zymogen activation, observed within acini early during acute pancreatitis for a long time, was shown to be sufficient to induce acute pancreatitis. Another key early event, NFκB activation, has previously been shown to induce acute pancreatitis. The relationship between these two key early steps is beginning to be clarified. Mechanisms of zymogen activation - pathologic calcium signaling, pH changes, colocalization and autophagy, and of NFκB activation have been investigated intensively along with potential therapeutic targets both upstream and downstream of these key events. Additional key findings have been elucidation of the role of bioenergetics and the dual role of oxidative stress in acute pancreatitis, recognition of endoplasmic reticulum stress as an early step and the status of duct cells as important entities in pancreatic injury. Current findings have provided further insight into the roles and mechanisms of zymogen activation and inflammatory pathways in pancreatic injury. Future studies, which will be of great importance in identifying therapeutic targets, are being undertaken to establish the relative contributions of these pathways during acute pancreatitis.

Antioxidant Therapy in Acute Pancreatitis: Experimental and Clinical Evidence

Oxidative stress plays an important role in the pathogenesis of both acute and chronic pancreatitis. Although its impact is well investigated and has been studied clinically in chronic pancreatitis, it is less well defined for acute pancreatitis. Pathophysiological aspects of oxidative stress in acute pancreatitis have shown that reactive oxidative species (ROS) participate in the inflammatory cascade, and mediate inflammatory cell adhesion and consecutive tissue damage. Furthermore, ROS are involved in the generation of pain as another important clinical feature of patients suffering from acute pancreatitis. Despite sufficient basic and experimental knowledge and evidence, the step from bench to bedside has not been successfully performed. Only a limited number of clinical studies are available that can give convincing evidence for the use of antioxidants in the clinical setting of acute pancreatitis. Future studies are required to evaluate potential benefits of antioxidative substances to attenuate the severity of acute pancreatitis. Special focus should be put on the aspect of pain generation and the progression from mild to severe acute pancreatitis in the clinical setting.

The Combined Effects of Etanercept Plus Methylprednisolone on Pancreatic Oxidative Stress in Acute Pancreatitis Induced by Cerulein

ABSTRACT Whether etanercept plus metylprednisolone reduce pancreatic oxidative stress and injury during pancreatitis is unknown well. The aim of this study was to examine the therapeutic effects of etanercept and methylprednisolone (MP) on acute pancreatitis and oxidative stress in acute pancreatitis (AP) induced by cerulein in a rat model. The study was performed with 48 rats divided into 6 groups (n = 8/group): 1-sham, 2-cerulein-induced pancreatitis (over 10 hours), 3- cerulein-pancreatitis (over 20 hours), 4-etanercept (5 mg/kg, i.p.), 5-methylprednisolone (10 mg/kg, i.m.), 6-etanercept plus methylprednisolone. Also, the rats in groups 4, 5, and 6 were cerulein-induced pancreatitis at 20 hours. After the treatment, the pancreas and blood were taken for histopathological and biochemical analysis. All cerulein-treated rats developed biochemical and pathological acute pancreatitis after 10-20 hours. The markers of oxidative stress such as protein carbonyls, lipid peroxidation, and myeloperoxidase (mpo) in the pancreas tissues were increased in the group 2 and 3, but these were lower in etanercept and MP-treated rats compared to groups 3. Pancreatic mpo activity was considerably reduced in pancreas tissues at 20 h after the administration of etanercept plus metylprednisolone in the group 6 compared to group 3. In AP induced by cerulein, the treatment of etanercept plus methylprednisolone may ameliorate pancreatic oxidative stress in rats. J. Exp. Clin. Med., 2011; 28:12-16

The Combined Effects of Etanercept Plus Methylprednisolone on Pancreatic Oxidative Stress in Acute Pancreatitis Induced by Cerulein

The Combined Effects of Etanercept Plus Methylprednisolone on Pancreatic Oxidative Stress in Acute Pancreatitis Induced by Cerulein

Reactive Oxygen Species Induced by Bile Acid Induce Apoptosis and Protect Against Necrosis in Pancreatic Acinar Cells

Oxidative stress is implicated in the pathogenesis of pancreatitis, but clinical trials of antioxidants have produced conflicting results. We examined the role of intracellular reactive oxygen species (ROS) in pancreatic acinar cell injury. Freshly isolated murine and human pancreatic acinar cells were studied using confocal microscopy to measure changes in intracellular and mitochondrial ROS concentrations ([ROS]I and [ROS]M), cytosolic and mitochondrial calcium concentrations ([Ca2+]C and [Ca2+]M), reduced nicotinamide adenine dinucleotide phosphate levels, and death pathways in response to taurolithocholate acid sulfate (TLC-S) or the oxidant menadione. Ca2+-activated Cl- currents were measured using whole-cell patch clamp, with or without adenosine triphosphate (ATP). TLC-S induced prolonged increases in [Ca2+]C and [Ca2+]M, which led to dose-dependent increases in [ROS]I and [ROS]M, impaired production of ATP, apoptosis, and necrosis. Inhibition of the antioxidant reduced nicotinamide adenine dinucleotide phosphate quinine oxidoreductase by 2,4-dimethoxy-2-methylnaphthalene potentiated the increases in [ROS]I and apoptosis but reduced necrosis, whereas the antioxidant N-acetyl-L-cysteine reduced [ROS]I and apoptosis but increased necrosis. Inhibition of mitochondrial ROS production prevented apoptosis but did not alter necrosis; autophagy had no detectable role. Patched ATP prevented sustained increases in [Ca2+]C and necrosis. Increases in [ROS]M and [ROS]I during bile acid injury of pancreatic acinar cells promote apoptosis but not necrosis. These results indicate that alternative strategies to antioxidants are required for oxidative stress in acute pancreatitis.

Ultrastructural Clues for the Protective Effect of Ascorbic Acid and N-Acetylcysteine against Oxidative Damage on Caerulein-Induced Pancreatitis

Background: Oxygen free radicals (OFR) have been implicated in the induction of acute pancreatitis (AP). Aims: The aim of this study was to determine the effect of ascorbic acid and N-acetylcysteine (NAC), potent antioxidants, against oxidative stress in AP. Methods: AP was induced by two i.p. injections of caerulein at 2-hour intervals (50 µg/kg BW). One group received additionally an antioxidant mixture composed of L(+)-ascorbic acid (14.3 mg/kg BW) and NAC (181 mg/kg BW) i.p. The rats were sacrificed 12 h after the last injection. Oxidative stress markers were evaluated. Light-microscopic and ultrastructural examination was performed. Results: Formation of vacuoles, mitochondrial damage, and dilatation of rough endoplasmic reticulum, margination and clumping of chromatin were major ultrastructural alterations in AP group. Ascorbic acid + NAC prevented these changes. Small vacuoles were present within the cytoplasm of some of the acinar cells. Pancreas damage was accompanied by an increase in tissue malondialdehyde (MDA) levels (p < 0.05), whereas a decrease was seen in catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and total glutathione (GSH) levels (p < 0.005). Ascorbic acid + NAC decreased MDA levels but increased CAT, SOD, GPx activities and GSH levels (p < 0.005). Conclusion: These results suggest that ascorbic acid + NAC is potentially capable of limiting pancreatic damage produced during AP via protecting fine structure of acinar cells and tissue antioxidant enzyme activities.

Interaction Between Cytokines and Oxidative Stress in Acute Pancreatitis

Acute pancreatitis is an inflammation initially localized in the pancreatic gland which may lead to local and systemic complications. The development of severe acute pancreatitis is mediated by pathophysiological mechanisms involved in the systemic inflammatory response, cytokines and oxidative stress being their components of major importance. Nevertheless, it is still unknown why an episode of acute pancreatitis remains mild or progresses to a severe form. Activated leukocytes are the main source of cytokines. Interleukin 1beta and tumor necrosis factor alpha (TNF-alpha) initiate and propagate almost all the consequences of the systemic inflammatory response syndrome, leading to amplification of the inflammatory response. It is noteworthy that the systemic inflammatory response is restrained and the rate of mortality decreased in acute pancreatitis when TNF-alpha is blocked with specific antibodies or in knock-out mice deficient in its receptors. A synergy between pro-inflammatory cytokines and oxidative stress occurs in the development of the inflammatory response in acute pancreatitis. Pro-inflammatory cytokines and oxidative stress trigger common signal transduction pathways that lead to amplification of the inflammatory cascade, mainly through activation of mitogen-activated protein kinases (MAPK) and nuclear factor kappaB (NF-kappaB). Furthermore, pro-inflammatory cytokines, particularly TNF-alpha, and oxidative stress promote each other generating a vicious circle in acute pancreatitis. This cross-talk that arises between pro-inflammatory cytokines and oxidative stress greatly contributes to amplification of the uncontrolled inflammatory cascade through MAPK and NF-kappaB.

Melatonin protects against pancreaticobiliary inflammation and associated remote organ injury in rats: role of neutrophils.

Although the role of oxidative stress in acute pancreatitis (AP) has been studied in several animal models, little data are available regarding AP induced by pancreatic duct obstruction. We characterized the protective effects of melatonin on pancreaticobiliary inflammation and associated remote organ injury. In Sprague-Dawley rats, either the common pancreaticobiliary duct (PBDL; n = 28) or bile duct (BDL; n = 28) was ligated or a sham operation was applied (n = 14). Either melatonin (10 mg/kg) or vehicle (saline; 1 mL/kg) was administered intraperitoneally (i.p.) immediately before the surgery and twice a day until the rats were decapitated at 6 or 72 h. The pancreas, liver, kidneys and lungs were removed and tissue samples were stored for the determination of malondialdehyde (MDA) and glutathione (GSH) levels and myelopreoxidase activity. The results demonstrate that pathogenesis of acute obstructive pancreatitis involves not only the oxidative damage of the pancreatic and hepatic tissues, as assessed by increased MDA and reduced GSH levels, but the lungs and kidneys are also challenged by oxidant injury. Similarly, hepatic oxidative injury caused by cholestasis was also accompanied by pulmonary, renal and even pancreatic damage. The biochemical findings were also verified histologically. Melatonin, probably because of its free-radical scavenging and antioxidant activity, which involves an inhibitory effect on tissue neutrophil infiltration, protected all the affected tissues.

Elevated Protein Carbonyls as Plasma Markers of Oxidative Stress in Acute Pancreatitis

Background: Experimental studies have demonstrated that protein and lipid oxidation is a feature of acute pancreatitis and that antioxidant pretreatment can ameliorate the severity of the disease. Justification for a clinical trial of antioxidant therapy requires stronger evidence for oxidative stress in patients. Aims: To determine if oxidative stress is evident in patients with acute pancreatitis on admission to hospital, if it increases after admission and if it is related to disease severity. Methods: Measurement of plasma concentrations of protein carbonyls and malondialdehyde as markers of protein oxidation and lipid peroxidation, respectively, in a consecutive series of 85 patients with acute pancreatitis 0, 2 and 5 days after admission. Results: Patients with acute pancreatitis had significantly increased concentrations of protein carbonyls in plasma on recruitment (median 27 h after the onset of symptoms) that persisted over 5 days. Protein carbonyls were higher in severe compared with mild disease (median 0.099 and 0.043 nmol/mg protein, respectively, p = 0.0016). They were higher at day 0 in patients recruited with more established pancreatitis than in those presenting early. No increases in malondialdehyde were seen. Receiver operator characteristic curve analysis demonstrated that protein carbonyls at day 0 were comparable with C-reactive protein at predicting pancreatitis severity. Conclusion: Our demonstration of substantial protein oxidation provides further evidence for oxidative stress in patients with severe pancreatitis. Our results suggest that there could be a window for early antioxidant intervention and that protein carbonyls could be a useful plasma marker of oxidative injury.