Acinar Cell Necrosis Research Articles

Experimental models of pancreatitis.

Acute pancreatitis is an inflammatory disease characterized by interstitial edema, inflammatory cell infiltration, and acinar cell necrosis, depending on its severity. Regardless of the extent of tissue injury, acute pancreatitis is a completely reversible process with evident normal tissue architecture after recovery. Its pathogenic mechanism has been known to be closely related to intracellular digestive enzyme activation. In contrast to acute pancreatitis, chronic pancreatitis is characterized by irreversible tissue damage such as acinar cell atrophy and pancreatic fibrosis that results in exocrine and endocrine insufficiency. Recently, many studies of chronic pancreatitis have been prompted by the discovery of the pancreatic stellate cell, which has been identified and distinguished as the key effector cell of pancreatic fibrosis. However, investigations into the pathogenesis and treatment of pancreatitis face many obstacles because of its anatomical location and disparate clinical course. Due to these difficulties, most of our knowledge on pancreatitis is based on research conducted using experimental models of pancreatitis. In this review, several experimental models of pancreatitis will be discussed in terms of technique, advantages, and limitations.

Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis

Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration of sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.

The Effects of Glycyrrhizin in a Rat Model of Sodium Taurocholate-Induced Acute Pancreatitis: Presidential Poster

Purpose: Although physiopathology of acute pancreatitis (AP) is not fully understood, the roles of reactive oxygen species (ROS) and changes of cytokines have been determined. The aim of this study was to investigate anti-inflammatory and anti-oxidant effects of glycyrrhizin (GL) on taurocholate-induced AP in rats. Methods: Thirty six rats were randomly divided into three groups: group I, group II, and group III were enrolled as sham, AP and AP+GL, respectively (n=12 per group). AP was induced by 1 ml/kg body weight using 5% taurocholate injection into the biliopancreatic duct in groups II and III after clamping the hepatic duct. In groups III, GL (20 mg/kg) was given by oral gavage twice daily for 4 days. Group I and II did not receive any treatment. On the fifth day of induction, the rats were killed; blood samples were taken to measure amylase, lipase, calcium, albumin, urea, glucose, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) assays before killing. Pancreatic tissue samples were also taken for biochemical analyses and histopathology. Results: The serum amylase, lipase, AST and urea levels were significantly lower in the AP+GL group than in the AP group. The serum cytokines including IL-6, TNF-α and MPO levels were significantly lower in the AP+GL group than in the AP group. Even so there is no statistically difference between in the AP+GL group and the AP group in terms of pancreatic tissue IL-1β, IL-6 and TNF-α levels. GL treatment significantly decreased pancreatic tissue MPO activities and MDA levels in the AP+GL group compared with the other groups (p=0.001 and p=0.05, respectively). The histopathologic evaluations of the groups determined that acinar cell necrosis, hemorrhage, and edema were significantly lower in the AP+GL group than in the AP group (p<0.001).Table 1: Biochemical parameters in the all experimental groupsConclusion: GL treatment following taurocholate-induced acute necrotizing pancreatitis in rats suppressed the levels of pro-inflammatory cytokines, and caused a clear recovery of histological changes.

Infected Pancreatic Necrosis Increases the Severity of Experimental Necrotizing Pancreatitis in Mice

Infection of pancreatic necrosis in necrotizing pancreatitis increases the lethality of patients with acute pancreatitis. To examine mechanisms underlying this clinical observation, we developed and tested a model, in which primary infection of necrosis is achieved in taurocholate-induced pancreatitis in mice. Sterile necrosis of acute necrotizing pancreatitis was induced by retrograde injection of 4% taurocholate into the common bile duct of Balb/c mice. Primary infection of pancreatic necrosis was induced by coinjecting 10 colony-forming units of Escherichia coli. Animals were killed after 6, 12, 24, 48, and 120 hours, and pancreatic damage and pancreatitis-associated systemic inflammatory response were assessed. Mice with pancreatic acinar cell necrosis had an increased bacterial concentration in all tissues and showed sustained bacteremia. Acute pancreatitis was induced only by coinjection of taurocholate and not by bacterial infection alone. Infection of pancreatic necrosis increased pancreatic damage and the pulmonary vascular leak. Serum glucose concentrations serving as a parameter of hepatic function were reduced in mice with infected pancreatic necrosis. Primary infection of pancreatic necrosis with E. coli increases both pancreatic damage and pulmonary and hepatic complications in acute necrotizing pancreatitis in mice.

Necro-inflammatory response of pancreatic acinar cells in the pathogenesis of acute alcoholic pancreatitis.

The role of pancreatic acinar cells in initiating necro-inflammatory responses during the early onset of alcoholic acute pancreatitis (AP) has not been fully evaluated. We investigated the ability of acinar cells to generate pro- and anti-inflammatory mediators, including inflammasome-associated IL-18/caspase-1, and evaluated acinar cell necrosis in an animal model of AP and human samples. Rats were fed either an ethanol-containing or control diet for 14 weeks and killed 3 or 24 h after a single lipopolysaccharide (LPS) injection. Inflammasome components and necro-inflammation were evaluated in acinar cells by immunofluorescence (IF), histology, and biochemical approaches. Alcohol exposure enhanced acinar cell-specific production of TNFα, IL-6, MCP-1 and IL-10, as early as 3 h after LPS, whereas IL-18 and caspase-1 were evident 24 h later. Alcohol enhanced LPS-induced TNFα expression, whereas blockade of LPS signaling diminished TNFα production in vitro, indicating that the response of pancreatic acinar cells to LPS is similar to that of immune cells. Similar results were observed from acinar cells in samples from patients with acute/recurrent pancreatitis. Although morphologic examination of sub-clinical AP showed no visible signs of necrosis, early loss of pancreatic HMGB1 and increased systemic levels of HMGB1 and LDH were observed, indicating that this strong systemic inflammatory response is associated with little pancreatic necrosis. These results suggest that TLR-4-positive acinar cells respond to LPS by activating the inflammasome and producing pro- and anti-inflammatory mediators during the development of mild, sub-clinical AP, and that these effects are exacerbated by alcohol injury.

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Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis

Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP.

Effects of trimetazidine in acute pancreatitis induced by L-arginine

In acute pancreatitis, oxygen free radicals (OFRs) and cytokines have been shown to play a role in the failure of pancreatic microcirculation and the development of local tissue damage. We studied the effects of trimetazidine (TMZ), a potent antioxidant and anti-ischemic agent, on acute pancreatitis. Rats were randomized into 3 groups: a control group (n = 15), a study group (n = 15) in which acute pancreatitis was induced with with L-arginine, and a treatment group (n = 15) in which pancreatitis was induced and treated with TMZ intraperitoneally. The rats were followed for 24 hours. At the 24th hour we determined serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, lactate dehydrogenase (LDH), interleukin 1-β (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α), and the pancreatic tissues were analyzed histopathologically. The AST (p < 0.001), ALT (p < 0.01), amylase (p < 0.001), LDH (p < 0.01), TNF-α (p < 0.01), IL-1β (p < 0.001) and IL-6 (p < 0.001) levels, and pancreatic tissue edema (p < 0.01), hemorrhage (p < 0.05), acinar cell necrosis (p < 0.001) and level of perivascular inflammation (p < 0.01), were significantly lower in the treatment group than the study group. Trimetazidine markedly decreases biochemical and histopathologic changes during the early stages of acute pancreatitis, thus preserving the pancreas histologically.

Fibrosis Reduces Severity of Acute-on-Chronic Pancreatitis in Humans

Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. We reviewed records from the University of Pittsburgh Medical Center/Presbyterian Hospital Autopsy Database (1998-2008) for patients with a diagnosis of AP (n = 23), CP (n = 35), or both (AP-on-CP; n = 15). Pancreatic histology samples from these patients and 50 randomly selected controls (no pancreatic disease) were analyzed, and IPF data were correlated with computed tomography data. An adipocyte and acinar cell Transwell coculture system, with or without collagen type I, was used to study the effects of fibrosis on acinar-adipocyte interactions. We studied the effects of nonesterified fatty acids (NEFAs) and adipokines on acinar cells in culture. Levels of IPF were significantly higher in nonobese patients with CP than in nonobese controls. In patients with CP or AP-on-CP, areas of IPF were surrounded by significantly more fibrosis than in controls or patients with AP. Fat necrosis-associated peri-fat acinar necrosis (PFAN, indicated by NEFA spillage) contributed to most of the necrosis observed in samples from patients with AP; however, findings of peri-fat acinar necrosis and total necrosis were significantly lower in samples from patients with CP or AP-on-CP. Fibrosis appeared to wall off the fat necrosis and limit peri-fat acinar necrosis, reducing acinar necrosis. In vitro, collagen I limited the lipolytic flux between acinar cells and adipocytes and prevented increases in adipokines in the acinar compartment. This was associated with reduced acinar cell necrosis. However, NEFAs, but not adipokines, caused acinar cell necrosis. Based on analysis of pancreatic samples from patients with CP, AP, or AP-on-CP and in vitro studies, fibrosis reduces the severity of acute exacerbations of CP by reducing lipolytic flux between adipocytes and acinar cells.

887 Intraluminal Release of Galectin 4 in EHEC Infection Provides a Novel Host Defense Mechanism

G A A b st ra ct s no significant difference in pancreatic MPO (unit mg of protein) in wild type 2981+734; CB(-/-)3042+767;T7(-/-) 3070+292 (P.0.05) treated with L-arginine, but it was significantly higher compared to saline treated animals(149+12). We also did not find a significant difference in lung MPO in unit /mg of protein in (Wild type 7766+1852; CB(-/)6234+602 and T7(-/-)7185+1236 treated with L-arginine HCL(P .0.05) but significantly higher than saline treated(2555+285) animals. These findings correlate with our finding in cerulein model of acute pancreatitis. Conclusion: Regardless of the model of acute pancreatitis trypsinogen activation significantly decreases acinar cell necrosis, but local and systemic inflammation is independent of trypsin activation.

884 Bile Acids Cause Pancreatic Acinar Cell NF-κB Activation and Injury Through an Interplay of PKC and Calcineurin

G A A b st ra ct s no significant difference in pancreatic MPO (unit mg of protein) in wild type 2981+734; CB(-/-)3042+767;T7(-/-) 3070+292 (P.0.05) treated with L-arginine, but it was significantly higher compared to saline treated animals(149+12). We also did not find a significant difference in lung MPO in unit /mg of protein in (Wild type 7766+1852; CB(-/)6234+602 and T7(-/-)7185+1236 treated with L-arginine HCL(P .0.05) but significantly higher than saline treated(2555+285) animals. These findings correlate with our finding in cerulein model of acute pancreatitis. Conclusion: Regardless of the model of acute pancreatitis trypsinogen activation significantly decreases acinar cell necrosis, but local and systemic inflammation is independent of trypsin activation.

888 Biological Oximetry Using Phosphorescence Quenching Reveals a Dynamic Oxygen Equilibrium Maintained Between the Gut Microbiota and the Host

G A A b st ra ct s no significant difference in pancreatic MPO (unit mg of protein) in wild type 2981+734; CB(-/-)3042+767;T7(-/-) 3070+292 (P.0.05) treated with L-arginine, but it was significantly higher compared to saline treated animals(149+12). We also did not find a significant difference in lung MPO in unit /mg of protein in (Wild type 7766+1852; CB(-/)6234+602 and T7(-/-)7185+1236 treated with L-arginine HCL(P .0.05) but significantly higher than saline treated(2555+285) animals. These findings correlate with our finding in cerulein model of acute pancreatitis. Conclusion: Regardless of the model of acute pancreatitis trypsinogen activation significantly decreases acinar cell necrosis, but local and systemic inflammation is independent of trypsin activation.

Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

Although females suffer twice as much as males from stress-related disorders, sex-specific participating and pathogenic cellular stress mechanisms remain uncharacterized. Using corticotropin-releasing factor receptor 2-deficient (Crhr2-/-) and wild-type (WT) mice, we show that CRF receptor type 2 (CRF2) and its high-affinity ligand, urocortin 1 (Ucn1), are key mediators of the endoplasmic reticulum (ER) stress response in a murine model of acute pancreatic inflammation. Ucn1 was expressed de novo in acinar cells of male, but not female WT mice during acute inflammation. Upon insult, acinar Ucn1 induction was markedly attenuated in male but not female Crhr2-/- mice. Crhr2-/- mice of both sexes show exacerbated acinar cell inflammation and necrosis. Electron microscopy showed mild ER damage in WT male mice and markedly distorted ER structure in Crhr2-/- male mice during pancreatitis. WT and Crhr2-/- female mice showed similarly distorted ER ultrastructure that was less severe than distortion seen in Crhr2-/- male mice. Damage in ER structure was accompanied by increased ubiquitination, peIF2, and mistargeted localization of vimentin in WT mice that was further exacerbated in Crhr2-/- mice of both sexes during pancreatitis. Exogenous Ucn1 rescued many aspects of histological damage and cellular stress response, including restoration of ER structure in male WT and Crhr2-/- mice, but not in females. Instead, females often showed increased damage. Thus, specific cellular pathways involved in coping and resolution seem to be distinct to each sex. Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics.

Parasitic Castration in Freshwater Snail Melanoides tuberculatus (Mollusca: Gastropoda)

Structure of ovotestis and its parasitic castration were observed histologically in hermaphrodite freshwater snail Melanoides tuberculatus (Mollusca, Gastropoda). In mature healthy snail ovotestis was found to be closely associated with posterior region of digestive gland. It was composed of numerous oval to pear-shaped acini intermingled with loose inter-acinar connective tissue. Each acinus was found to be made up of two unequal zones, the larger testicular zone comprising of male germ cells and the smaller one with the female germ cells. Both of them were lined by germinal epithelium. Oocytes were generally found towards the periphery of ovotestis enclosed by the membrane tunica propria. In infected snails ovotestis was found to be invaded by the larval trematode parasites (sporocysts and xiphidiocercariae) but the larvae were restricted to the connective tissue of ovotestis and did not invade the acini. Except ovotestis no other organ was found to be infected with these larvae. Histopathological changes in the acini of infected ovotestis were associated with the severity of infection. Degenerative changes, hypotrophy and destruction of individual acinus were found in mild infection. In severe infection, autolysis and necrosis of acinar cells were found and ultimately these were completely replaced by parthenitae. In such parasitic castration no sex conversion was detected. In the present communication structure of ovotestis along with parasitic castration and its evolutionary significance are discussed.

Diagnosing infected necrotizing pancreatitis: Clinical signs, gas bubbles or routine fine-needle aspiration?

Introduction: Infection of pancreatic necrosis in necrotizing pancreatitis increases the lethality. Aims/objectives: To examine the mechanisms underlying this clinical circumstance we used a model of primary infected pancreatic necrosis in taurocholate induced pancreatitis in mice. Materials and methods: Acute necrotizing pancreatitis with sterile necrosis (SN) was induced by retrograde injection of 4% taurocholate in the common bile duct of Balb/c mice, infected pancreatic necrosis (IN) was induced by co-injecting 108 CFU E. coli. For antibiotic therapy 10 mg/kg bodyweight moxifloxacin were administered intravenously (AIN). After 6, 12, 24, 48 and 120 hours animals were sacrificed and serum as well as SIRS related organs were examined. Results: Prolonged bacteremia occurred when infected acinar cell necrosis was induced (24h CFU E. coli in blood; bacteria only not detected, IN 121 63). Infection of pancreatic necrosis with E. coli further increased the pancreatic damage (histology score 24h: SN 17.8 2.6 vs. IN 23.7 2.2; p<0.001) and the systemic complications such as the pulmonary vascular leak (albumin in bronchoalveolary lavage 6h: SN 151.0 57.7 mg/ml vs. IN 219.5 76.2 mg/ml; p<0.05). Additionally, infected necrosis induced impaired hepatic function with reduced serum glucose concentrations (24h: SN 167.0 35.6 mg/dl vs. IN 106.9 12.7 mg/dl; p<0.001). Moxifloxacin treatment reduced the systemic inflammatory response (serum IL-6: IN 330.5 336.6 vs. AIN 38.7 25.5 pg/ml; p<0.001) and restored liver function (serum glucose: IN 105.8 12.7 vs. AIN 155.7 39.5 mg/dl; p<0.001). Conclusion: Infection of pancreatic necrosis induces sustained bacteremia and increases the systemic complications in acute necrotizing pancreatitis. Initial antibiotic therapy reduces the inflammatory response and restores liver function.

Involvement of Interleukin-17A in Pancreatic Damage in Rat Experimental Acute Necrotizing Pancreatitis

Interleukin (IL)-17A is a proinflammatory cytokine, which has recently attracted much interest due to its pathogenic role in various inflammatory conditions such as ischemia/reperfusion injury, chronic inflammation, and autoimmune diseases, but the role of IL-17A in acute pancreatitis remains unclear. This study aimed to investigate the role of IL-17A in experimental acute necrotizing pancreatitis (ANP). We analyzed the expression of IL-17A during the pathogenesis of ANP in vivo induced by 3 % sodium taurocholate (NaTc), by microarray test, quantitative real-time PCR, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. The effects of IL-17A on pancreatic acinar cells and pancreatic stellate cells (PSCs) were further investigated in vitro using recombinant rat IL-17A (rIL-17A). Expression of IL-17A was significantly increased following experimental acute pancreatitis. In addition, rIL-17A induced rat pancreatic acinar cell necrosis and promoted expression of several target genes, including IL-6, IL-1β, CXCL1, CXCL2, and CXCL5, in acinar cells and PSCs. These findings suggest that IL-17A may be involved in pancreatic damage by regulating the expression of inflammatory cytokines and chemokines during experimental 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.

The role of phosphatidylinositide 3-kinase gamma (P13Kγ) in mediating acinar cell necrosis in rat models with acute pancreatitis

Objective To study the role and mechanism of phosphatidylinositide 3-kinase gamma (P13Kγ) in mediating acinar cell necrosis in rat models with acute pancreatitis.Methods Twelve male C57BL/6 wild-type and twelve male P13Ky knockout mice were randomly divided into saline group and pancreatitis group.The pancreatitis group received an intraperitoneal injection of cerulean (50 μg/kg) to induce acute panreatitis.Pathologic changes in the two groups were observed by measuring the trypsin,cathepsin B,and cathepsin L activity.The protein expressions of cathepsin B and cathepsin L were detected by the Western blot assay.Results Compared with the wild-type mice,the P13Kγγknockout mice had fewer acinar cell necrosis [(2.25± 0.54)/HP vs (5.14±0.85)/HP] and vacuoles [(1.24±0.21)/HP vs (2.36± 0.34)/HP]according to histology.The cathepsin B activity [(1232± 21)pmolAMC/min/mg vs (1891 ±35)pmolAMC/min/mg] and trypsin activity [(0.358± 0.098)pmol/mg vs (0.827± 0.126)pmol/mg] were significantly decreased in the pancreatitis group (P＜0.05) compared to the saline group.However,the cathepsin L activity [ (415 ±11 ) pmolAMC/ min/mg vs (346 ± 6)pmolAMC/min/mg] was significantly higher in P13Kγγ knockout mice than in wild-type mice(P＜0.01).Conclusions P13Kγmay promote cell necrosis in acute pancreatitis by possibly changing the balance between eathepsin B and cathepsin L levels to promote the activation of trypsinogen. Key words: Phosphatidylinositide 3 kinase gamma; Cerulean; Acute pancreatitis; Cell necrosis

Desferrioxamine Attenuates Pancreatic Injury after Major Hepatectomy under Vascular Control of the Liver: Experimental Study in Pigs

Introduction. Pancreatic injury can manifest after major hepatectomy under vascular control. The main mechanism involved seems to be remote oxidative injury due to “spillage” of reactive oxygen species and cytokines from the liver. The aim of this study is to evaluate the role of desferrioxamine in the prevention of pancreatic injury following major hepatectomy. Methods. Twelve Landrace pigs were subjected to a combination of major hepatectomy (70–75%), using the Pringle maneuver for 150 minutes, after constructing a porta-caval side-to-side anastomosis. The duration of reperfusion was 24 hours. Animals were randomly divided into a control group (n = 6) and a desferrioxamine group (DFX, n = 6). DFX animals were treated with continuous IV infusion of desferrioxamine 100 mg/kg. Pancreatic tissue injury, c-peptide and amylase concentrations, and pancreatic tissue oxidative markers were evaluated. Results. Desferrioxamine-treated animals showed decreased c-peptide levels, decreased acinar cell necrosis, and decreased tissue malondialdehyde levels 24 hours after reperfusion compared with the control group. There was no difference in portal pressure or serum amylase levels between the groups. Conclusions. Desferrioxamine seems to attenuate pancreatic injury after major hepatectomy under vascular control possibly by preventing and reversing production and circulation of oxidative products.

Involvement of thrombopoietin in acinar cell necrosis in l-arginine-induced acute pancreatitis in mice

Thrombopoietin (TPO) plays an important role in injuries of different tissues. However, the role of TPO in acute pancreatitis (AP) is not yet known. The aim of the study was to determine the involvement of TPO in AP. Serum TPO was assayed in necrotizing pancreatitis induced by l-arginine in mice. Recombinant TPO and anti-TPO antibody were given to mice with necrotizing pancreatitis. Amylase, lipase, lactate dehydrogenase, myeloperoxidase activity and pancreatic water content were assayed in serum and tissue samples. Pancreas and lung tissue samples were also collected for histological evaluation. Immunohistochemistry of amylase α and PCNA were applied for the study of acinar regeneration and TUNEL assay for the detection of apoptosis in the pancreas. Increased levels of serum TPO were found in necrotizing pancreatitis. After TPO administration, more severe acinar necrosis was found and blockade of TPO reduced the acinar necrosis in this AP model. Acinar regeneration and apoptosis in the pancreas were affected by TPO and antibody treatment in necrotizing pancreatitis. The severity of pancreatitis-associated lung injury was worsened after TPO treatment, but attenuated after Anti-TPO antibody treatment. In conclusion, serum TPO is up-regulated in the necrotizing pancreatitis induced by l-arginine in mice and may be a risk factor for the pancreatic acinar necrosis in AP. As a pro-necrotic factor, blockade of TPO can attenuate the acinar necrosis in AP and may be a possible therapeutic intervention for AP.