Damage In Acute Pancreatitis Research Articles

Serum markers of myocardial damage in acute pancreatitis. A prospective time course study

Serum markers of myocardial damage in acute pancreatitis. A prospective time course study

Serum Markers of Myocardial Damage in Acute Pancreatitis

Serum Markers of Myocardial Damage in Acute Pancreatitis

Histone deacetylase regulates trypsin activation, inflammation, and tissue damage in acute pancreatitis in mice.

The onset of acute pancreatitis (AP) is characterized by early protease activation followed by inflammation and organ damage, but the mechanisms are poorly understood. We hypothesized that histone deacetylase (HDAC) inhibition might exert protective effects on AP and investigated the role of HDAC in trypsin activation, inflammation, and tissue damage in severe AP. Male C57Bl/6 mice were treated i.p. with the HDAC inhibitor trichostatin A (2 mg/kg) prior to retrograde infusion of taurocholic acid (5 %) into the pancreatic duct. Serum levels of amylase and interleukin (IL)-6, pancreatic levels of macrophage inflammatory protein-2 (MIP-2) as well as tissue morphology and myeloperoxidase activity in the pancreas and lung were determined 24 h after taurocholate challenge. Trypsin activation was analyzed in isolated acinar cells. Quantitative RT-PCR was used to examine the expression of pro-inflammatory mediators in the pancreas. Pretreatment with trichostatin A decreased amylase levels by 70 % and protected against tissue injury in the pancreas. Moreover, HDAC inhibition reduced systemic IL-6 by more than 95 % and pulmonary myeloperoxidase activity by 75 %. Notably, inhibition of HDAC abolished taurocholate-induced gene expression of cyclooxygenase-2, MIP-2, monocyte chemotactic protein-1, IL-6, and IL-1β in the pancreas. In addition, HDAC inhibition reduced cerulein-induced trypsinogen activation in isolated acinar cells. Our findings show that HDAC regulates trypsin activation, inflammation, and tissue damage in AP. Thus, targeting HDAC could serve as novel therapeutic approach in the management of severe AP.

Farnesyltransferase Regulates Neutrophil Recruitment and Tissue Damage in Acute Pancreatitis

The signaling mechanisms controlling organ damage in the pancreas in severe acute pancreatitis (AP) remain elusive. Herein, we examined the role of farnesyltransferase signaling in AP. Pancreatitis was provoked by the infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a farnesyltransferase inhibitor FTI-277 (25 mg/kg) before pancreatitis induction. FTI-277 decreased the blood amylase levels, pancreatic neutrophil infiltration, hemorrhage, and edema formation in the pancreas in mice challenged with taurocholate. Farnesyltransferase inhibition reduced the myeloperoxidase levels in the pancreas and lungs in response to taurocholate infusion. However, FTI-277 had no effect on the taurocholate-provoked formation of macrophage inflammatory protein-2 in the pancreas. Interestingly, farnesyltransferase inhibition abolished the neutrophil expression of macrophage-1 antigen in mice with pancreatitis. In addition, FTI-277 decreased the taurocholate-induced activation of the rat sarcoma protein in the pancreas. An important role of farnesyltransferase was confirmed in L-arginine-induced pancreatitis. These results demonstrate that farnesyltransferase signaling plays a significant role in AP by regulating neutrophil infiltration and tissue injury via the neutrophil expression of macrophage-1 antigen. Thus, our findings not only elucidate novel signaling mechanisms in pancreatitis but also suggest that farnesyltransferase might constitute a target in the management of severe AP.

Oxidative stress and inflammatory signaling in cerulein pancreatitis.

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.

Neuronostatin Ameliorates Sodium Taurocholate-Induced Acute Pancreatitis in Rats

Neuronostatin is encoded in the preprosomatostatin gene and exerts important physiological actions on neuronal and cardiovascular regulation and metabolism in diverse tissues. An intraperitoneal injection of neuronostatin can induce c-Jun expression in the periphery of pancreatic islets. Because of the relatively high amount of neuronostatin present in the pancreas, it is necessary to investigate the effects of neuronostatin on pancreas. Furthermore, little is known about the effect of neuronostatin on acute pancreatitis. Neuronostatin (30, 60, and 120 nmol) was injected in to the external jugular vein 30 min before retrograde infusion of 2 % sodium taurocholate into the pancreaticobiliary duct. After 6 h, histological damage of the pancreas was evaluated by pancreas weight and paraffin section. A blood sample was collected to determine the serum amylase and lipase activities. In our findings, neuronostatin groups had a reduction in interstitial edema, acinar cell vacuolization, and inflammatory infiltration of the pancreas compared with the model group. Biochemical data showed that serum amylase and lipase activities were significantly decreased in neuronostatin-pretreated groups by comparison with the model group. Histopathologic examination suggests that neuronostatin ameliorated the histological damage of sodium taurocholate-induced acute pancreatitis in rats. The biochemical analysis was consistent with that obtained from histopathologic examination, which was toward a trend of attenuating acute pancreatitis. In summary, neuronostatin might be potentially capable of ameliorating pancreatic damage in acute pancreatitis in rats.

Nitric oxide synthase inhibition reduces albumin induced lung damage in acute pancreatitis

Background/objectivesColloid resuscitation in acute pancreatitis (AP) is a matter of controversy due to the possible deleterious effect on lung function. A previous study demonstrates that albumin administration increases lung damage in burns and this effect can be reversed by inducible nitric oxide synthase (iNOS) inhibition. This study evaluates the effects of S-methylisothiourea (SMT), a specific iNOS inhibitor, on lungs and pancreas of rats with AP receiving intravenous albumin. MethodsAP was induced in Wistar rats by intraductal 5% taurocholate injection. To evaluate the effect of albumin on lung damage, animals received IV saline or human albumin immediately after AP (Groups: Saline and Albumin). To evaluate the effect of iNOS inhibition on lung damage, SMT was given immediately after AP (Group Saline+SMT, and Group Albumin+SMT). At 12 h after AP induction, serum amylase activity, lung vascular permeability and myeloperoxidase (MPO) activity were evaluated. Lung and pancreas histological analysis were performed. ResultsSerum amylase activity, pancreatic edema, lung vascular permeability, MPO activity, and inflammatory infiltration were significantly increased after AP. Albumin administration increased lung vascular permeability, inflammatory infiltration, and pancreatic edema compared to saline administration (p < 0.05). Albumin administration with SMT reduced lung vascular permeability, MPO activity, and inflammatory infiltration compared to albumin administration alone (p < 0.05). ConclusionLung and pancreatic damage induced by albumin administration for restoration of plasma volume in AP are reduced by iNOS inhibition. Awareness of this fact may be useful in high-risk patients who need to receive albumin for volume replacement.

The impact of early goal-directed fluid management on survival in an experimental model of severe acute pancreatitis

Severe acute pancreatitis (SAP) remains a life-threatening disease with classic etiology of systemic inflammatory response and mortality between 30 and 50 %. The aim of the present study is to compare two different treatment strategies of goal-directed hemodynamic management and evaluate their impact on survival, microcirculation, tissue oxygenation, and histopathologic damage in acute pancreatitis in a prospective animal study. Thirty-four domestic pigs were randomly assigned to two different treatment groups. After induction of acute pancreatitis, in group 1 volume administration was guided by central venous pressure (CVP >12 mmHg) and mean arterial pressure (MAP). In group 2, hemodynamic management was guided primarily by left-ventricular stroke volume variation (SVV <10 %), MAP, and cardiac output (CO). Treatment according to randomization was performed for 6 h, and tissue oxygen tension in the pancreas and pancreatic microcirculation were evaluated. Thereafter, animals were observed for 7 days and then sacrificed. Standardized tissue specimens were taken post mortem, and histopathologic scoring was performed. Survival after 7 days was 29.4 % in group 2 versus 11.8 % in group 1 (p < 0.05). Pancreatic oxygen tension (138.0 ± 89.5 mmHg versus 71.1 ± 35.3 mmHg; p < 0.05) and pancreatic microcirculation (1,209.9 ± 630 AU versus 732 ± 315 AU; p < 0.05) were significantly higher in group 2. Significantly less histopathologic damage within the pancreas could be analyzed post mortem in group 2. Goal-directed hemodynamic management guided by stroke volume variation led to improved survival, tissue oxygenation, and microcirculatory perfusion, as well as less histopathologic damage in an animal model of severe acute pancreatitis.

NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice

The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice. We measured levels of myeloperoxidase and macrophage inflammatory protein 2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 hours after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an l-arginine-induced model of AP. Reverse-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target.

Platelets regulate P-selectin expression and leukocyte rolling in inflamed venules of the pancreas

Recent data suggest that platelets regulate inflammatory changes and tissue damage in acute pancreatitis although the role of platelets in leukocyte–endothelium interactions in the pancreatic microcirculation is not known. The aim of this study was to define the impact of platelets on leukocyte rolling and adhesion in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by caerulein challenge. Mice were treated with an anti-GP1bα (CD42b) antibody, which depletes platelets, or a control antibody before caerulein. Leukocyte rolling and adhesion were determined by the use of intravital fluorescence microscopy 18h after the last dose of caerulein. In separate experiments, leukocyte–endothelium interactions were determined before and after administration of an anti-P-selectin, anti-PSGL-1 and a control antibody in mice with caerulein pancreatitis. Circulating platelet–neutrophil aggregates and pancreatic P-selectin mRNA were quantified 1 and 6h respectively after caerulein challenge. Caerulein administration increased leukocyte and platelet interactions in the pancreatic microvasculature, increased tissue damage and expression of P-selectin mRNA in the pancreas as well as platelet–neutrophil complexes in the circulation. Notably, platelet depletion markedly reduced caerulein-provoked leukocyte rolling and adhesion in postcapillary venules. Interestingly, depletion of platelets significantly decreased caerulein-induced gene expression of P-selectin in the pancreas. Moreover, immunoneutralization of P-selectin and PSGL-1 abolished leukocyte rolling in the pancreatic venules triggered by caerulein. Our novel findings demonstrate that platelets regulate leukocyte rolling in acute pancreatitis via induction of P-selectin, which was critical in supporting leukocyte rolling in inflamed venules of the pancreas.

Oxidative and nitrosative stress in acute pancreatitis. Modulation by pentoxifylline and oxypurinol

Reactive oxygen species are considered mediators of the inflammatory response and tissue damage in acute pancreatitis. We previously found that the combined treatment with oxypurinol – as inhibitor of xanthine oxidase- and pentoxifylline – as inhibitor of TNF-α production-restrained local and systemic inflammatory response and decreased mortality in experimental acute pancreatitis. Our aims were (1) to determine the time-course of glutathione depletion and oxidation in necrotizing pancreatitis in rats and its modulation by oxypurinol and pentoxifylline; (2) to determine whether TNF-α is responsible for glutathione depletion in acute pancreatitis; and (3) to elucidate the role of oxidative stress in the inflammatory cascade in pancreatic AR42J acinar cells. We report here that oxidative stress and nitrosative stress occur in pancreas and lung in acute pancreatitis and the co-treatment with oxypurinol and pentoxifylline prevents oxidative stress in both tissues. Oxypurinol was effective in preventing glutathione oxidation, whereas pentoxifylline abrogated glutathione depletion. This latter effect was independent of TNF-α since glutathione depletion occurred in mice deficient in TNF-α or its receptors after induction of pancreatitis. The beneficial effects of oxypurinol in the inflammatory response may also be ascribed to a partial inhibition of MEK1/2 activity. Pentoxifylline markedly reduced the expression of Icam1 and iNos induced by TNF-α in vitro in AR42J cells. Oxidative stress significantly contributes to the TNF-α-induced up-regulation of Icam and iNos in AR42J cells. These results provide new insights into the mechanism of action of oxypurinol and pentoxifylline as anti-inflammatory agents in acute pancreatitis.

TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate

Neutrophil infiltration is a key regulator in the pathophysiology of acute pancreatitis (AP), although the impact of Toll-like receptors (TLRs) in AP remains elusive. The aim of this study was to define the role of TLR2 and TLR4 in leukocyte recruitment and tissue damage in severe AP. AP was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in wild-type, TLR2- and TLR4-deficient mice. Samples were collected 24h after induction of AP. Taurocholate challenge caused a clear-cut pancreatic damage characterized by increased acinar cell necrosis, neutrophil infiltration, focal hemorrhage and edema formation, as well as increased levels of blood amylase and CXCL2 (macrophage inflammatory protein-2) in the pancreas and serum. Moreover, challenge with taurocholate increased activation of trypsinogen in the pancreas. Notably, TLR2 gene-deficient mice exhibited a similar phenotype to wild-type mice after challenge with taurocholate. In contrast, tissue damage, pancreatic and lung myeloperoxidase (MPO) activity, serum and pancreatic levels of CXCL2 as well as blood amylase were significantly reduced in TLR4-deficient mice exposed to taurocholate. However, taurocholate-induced activation of trypsinogen was intact in TLR4-deficient mice. Our data suggest a role for TLR4 but not TLR2 in the pathogenesis of severe AP in mice.

Interleukin 22: A novel mediator of inflammatory inhibition and tissue damage in acute pancreatitis

Interleukin 22: A novel mediator of inflammatory inhibition and tissue damage in acute pancreatitis

Lymphocyte function antigen‐1 regulates neutrophil recruitment and tissue damage in acute pancreatitis

Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillary venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas. Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas.

Deletion of TRPC3 in Mice Reduces Store-Operated Ca 2+ Influx and the Severity of Acute Pancreatitis

Receptor-stimulated Ca(2+) influx is a critical component of the Ca(2+) signal and mediates all cellular functions regulated by Ca(2+). However, excessive Ca(2+) influx is highly toxic, resulting in cell death, which is the nodal point in all forms of pancreatitis. Ca(2+) influx is mediated by store-operated channels (SOCs). The identity and function of the native SOCs in most cells is unknown. Here, we determined the role of deletion of Trpc3 in mice on Ca(2+) signaling, exocytosis, intracellular trypsin activation, and pancreatitis. Deletion of TRPC3 reduced the receptor-stimulated and SOC-mediated Ca(2+) influx by about 50%, indicating that TRPC3 functions as an SOC in vivo. The reduced Ca(2+) influx in TRPC3(-/-) acini resulted in reduced frequency of the physiologic Ca(2+) oscillations and of the pathologic sustained increase in cytosolic Ca(2+) levels caused by supramaximal stimulation and by the toxins bile acids and palmitoleic acid ethyl ester. Consequently, deletion of TRPC3 shifted the dose response for receptor-stimulated exocytosis and prevented the pathologic inhibition of digestive enzyme secretion at supramaximal agonist concentrations. Accordingly, deletion of TRPC3 markedly reduced intracellular trypsin activation and excessive actin depolymerization in vitro and the severity of pancreatitis in vivo. These findings establish the native TRPC3 as an SOC in vivo and a role for TRPC3-mediated Ca(2+) influx in the pathogenesis of acute pancreatitis and suggest that TRPC3 should be considered a target for prevention of pancreatic damage in acute pancreatitis.

Dual, time-dependent deleterious and protective effect of anandamide on the course of cerulein-induced acute pancreatitis. Role of sensory nerves

Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 μmol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.

ATTENUATION BY SELECTIVE KALLIKREIN INHIBITORS OF HEMORRHAGIC LESIONS INDUCED BY BRADYKININ B2 ANTAGONISTS IN CERULEIN-INDUCED PANCREATITIS

Introduction: Kinin B2 receptor antagonists effectively prevent edema formation in cerulein-induced acute pancreatitis. However, this is complicated by hemorrhagic lesions in the pancreas at later time points. We have investigated whether this is due to a reduced influx of endogenous protease inhibitors into the pancreas and a concomitant excessive augmentation of tissue kallikrein activity. Methods: Pancreatitis was induced in anaesthetized rats by i.v. infusion of cerulein. The animals were pretreated with the B2 receptor antagonist icatibant and/or selective inhibitors of tissue kallikrein (tKI) and plasma kallikrein (pKI) (Evans et al., Immunopharmacology, 1996; 32: 115-116 and 117-118 ). Six hours later, tissue samples were excised, assessed histologically, and analyzed for hemoglobin in the pancreatic tissue. Results: Cerulein alone did not induce signs of vascular damage. Tissue hemoglobin levels were similar to those of controls without pancreatitis. Pretreatment with icatibant produced an about 10-fold elevation (p < 0.01) in tissue hemoglobin concentrations. Although tKI inhibited the edema to an extent similar to icatibant, signs of vascular damage were absent. The hemorrhage induced by icatibant was largely attenuated by a concomitant treatment with tKI and pKI (p < 0.05). Influx of endogenous inhibitors of kallikreins (α1-antitrypsin, α2-macroglobulin) was significantly (p < 0.05) reduced by icatibant and tKI. However, tissue kallikrein activity was increased 10-100 fold by icatibant (p < 0.01), whereas it was strongly inhibited (p < 0.05) by tKI. Conclusions: Our results suggest that increased levels of kallikrein activity in the pancreas in the absence of edema formation are involved in the induction of hemorrhagic lesions induced by icatibant in this model. Inhibition of tissue and plasma kallikrein thus seems to be a highly interesting strategy for the prevention of this kind of tissue damage in acute pancreatitis.

3. Internationales Symposium: „Autologe Transfusion - Von der Euphorie zur Ratio: Praktisches Handeln aus wissenschaftlicher Sicht” (Teil IV)Künstliche Sauerstoffträger: Hämoglobinlösungen - Stand 2004

Because of an impending shortfall of allogeneic blood products within the next decades and ongoing problems such as transfusion reactions, immunomodulating side effects and the risk of bacterial, viral and prion transmission associated with relevant costs for testing and storage of banked RBC units which, additionally, suffer from aging processes, the development of alternatives has been intensified during the last 15 years. Modern chemically modified hemoglobin-based oxygen carriers (HBOC) are free of red blood cell membrane remnants eliminating renal toxicity, and they do not possess AB0 antigens which allows transfusion without knowledge of the respective blood group of a patient. Bovine polymerized cell-free hemoglobin can be stored at room temperature for three years. In contrast to the perfluorocarbon solutions, HBOC can be applied at room air oxygen concentrations. Animal experiments have shown that HBOC can compensate for intravascular volume deficits in hemorrhagic shock, including restoration of colloid osmotic pressure and organ perfusion, and deliver oxygen to organs and tissues during nearly complete blood exchange. Chemical modifications of HBOC are able to reduce the vasoconstrictive side-effect of HBOC which is caused by NO scavenging. In spite of vasoconstriction the increased oxygen extraction in presence of HBOC in combination with the plasmatic oxygen transport provides enhanced tissue oxygenation even in post-stenotic tissues. HBOC seem to improve the diffusive oxygen transport at the microcirculatory site thus decreasing tissue damage in acute pancreatitis and the heart and brain after ischemia/reperfusion injury. Clinical studies have shown that the peri-operative use of different HBOC (Hemopure, PolyHeme, Hemolink and HemAssist) can reduce the number of allogeneic RBC units and increase the avoidance rate of allogeneic transfusion in emergency bleeding, vascular, cardiac and non-cardiac surgery. Polymerized HBOC appear to have a lower potential of side effects in comparison to intra-molecularly cross-linked preparations. However, HBOC-201 (Hemopure) is the only substance which has been licensed for the treatment of patients with acute peri-operative anemia in South Africa until now.

Nitric oxide protects against pancreatic subcellular damage in acute pancreatitis.

Oxidative stress involvement in damage to the pancreas in acute pancreatitis (AP) is well documented. However, little is known about oxidative damage occurring in the different subcellular fractions of pancreatic cells. The aim of this study was to ascertain the main targets of oxidative damage inside cells after AP and the role of endogenous nitric oxide (NO) in it. A model of cerulein-induced AP in rats was used and N-nitro-l-arginine methyl ester (l-NAME) was administered as an NO production inhibitor. After pancreatitis induction, indicative parameters of lipid peroxidation and protein oxidation together with some enzymatic and nonenzymatic endogenous free radical scavengers were assessed in serum and pancreatic subcellular fractions. In pancreatitic rats, malondialdehyde and protein carbonyl group concentrations were significantly increased (P < 0.05) in serum and some fractions. The increases were higher in l-NAME-treated rats (P < 0.05). Superoxide dismutase and catalase activities were also increased (P < 0.05) but were decreased (P < 0.05) with l-NAME. The alpha-tocopherol concentration diminished (P < 0.05) in serum and all the studied subcellular fractions and the decrease was stronger in l-NAME-treated rats. Our data suggest that microsomes followed by lysosomal + mitochondrial are the fractions most susceptible to oxidative damage in AP. Endogenous NO plays a protective role against oxidative damage to subcellular fractions.

Bacterial analysis of infected pancreatic necrosis and its prevention (Symposium 8: Pancreatobiliary infection (IHPBA)).

In severe acute pancreatitis, sepsis mainly due to pancreatic or peripancreatic infection have emerged as the most serious complications and now accounts for more than 80% of deaths. Collective review of organisms associated with secondary pancreatic infection in patients with acute pancreatitis has revealed that most of them are intestinal flora. Several experimental studies including ours have revealed that acute pancreatitis promotes bacterial translocation (BT), which in turn leads to infection of the pancreas and septic complications. Prophylactic antibiotics given intravenously have been demonstrated to be beneficial in reducing the rate of pancreatic infection, but their survival benefit remains unclear. We have demonstrated that continuous regional arterial infusion (CRAI) of an antibiotic is more effective than intravenous administration in preventing pancreatic infection and improving survival, in a canine model of acute necrotizing pancreatitis. Our recent experimental study has revealed that CRAI of an antibiotic via the superior mesenteric artery (SMA) is effective in mitigating intestinal mucosal damage and preventing BT in acute pancreatitis, thereby improving survival. BT aggravates pancreatic necrosis and remote organ damage in acute pancreatitis, and SMA infusion of antibiotics is effective in preventing BT and is practical for clinical use.