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  • 1.
    Björnsson, Bergthor
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Winbladh, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Trulsson, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gullstrand, Per
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Remote or Conventional Ischemic Preconditioning -Local Liver Metabolism in Rats Studied with Microdialysis2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 176, no 1, p. 55-62Article in journal (Refereed)
    Abstract [en]

    Background. Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. Material and Methods. Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceeded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. Results. Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC = 759 (84) mu M] and the IRI = 732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. Conclusions. IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.

  • 2.
    Lutgendorff, Femke
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nijmeijer, Rian M
    Utrecht University Medical Center.
    Sandström, Per A
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Trulsson, Lena M
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Timmerman, Harro M
    Utrecht University Medical Center.
    van Minnen, L Paul
    Utrecht University Medical Center.
    Rijkers, Ger T
    Utrecht University Medical Center.
    Gooszen, Hein G
    Utrecht University Medical Center.
    Akkermans, Louis M A
    Utrecht University Medical Center.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Probiotics prevent intestinal barrier dysfunction in acute pancreatitis in rats via induction of ileal mucosal glutathione biosynthesis.2009In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 2, p. e4512-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. METHODOLOGY/PRINCIPAL FINDINGS: Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and (51)Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4+/-33.5 vs. placebo 223.7+/-93.7 a.u.; P<0.001), (51)Cr-EDTA flux (16.7+/-10.1 vs. 32.1+/-10.0 cm/s10(-6); P<0.005), apoptosis, lipid peroxidation (0.42+/-0.13 vs. 1.62+/-0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33+/-1.47 vs. 8.82+/-1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33+/-1.47 vs. 10.70+/-1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88+/-1.21 vs. placebo 1.94+/-0.55 nmol/min/mg protein; P<0.05) coinciding with an increase in mRNA expression of glutamate-cysteine-ligase catalytic (GCLc) and modifier (GCLm) subunits. CONCLUSIONS: Probiotic pre-treatment diminished AP-induced intestinal barrier dysfunction and prevented oxidative stress via mechanisms mainly involving mucosal glutathione biosynthesis.

  • 3.
    Lutgendorff, Femke
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    van Minnen, L. Paul
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Rijkers, Ger T.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Timmerman, Harro M.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Franzén, Lennart E.
    3Department of Pathology and Cytology Aleris Medilab, Täby.
    Gooszen, Hein G.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Akkermans, Louis M. A.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sandström, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Probiotics enhance pancreatic glutathione biosynthesis and reduce oxidative stress in experimental acute pancreatitis2008In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 295, no 5Article in journal (Refereed)
    Abstract [en]

    Factors determining severity of acute pancreatitis (AP) are poorly understood. Oxidative stress causes acinar cell injury and contributes to the severity, whereas prophylactic probiotics ameliorate experimental pancreatitis. Our objective was to study how probiotics affect oxidative stress, inflammation, and acinar cell injury during the early phase of AP. Fifty-three male Sprague-Dawley rats were randomly allocated into groups: 1) control, 2) sham procedure, 3) AP with no treatment, 4) AP with probiotics, and 5) AP with placebo. AP was induced under general anesthesia by intraductal glycodeoxycholate infusion (15 mM) and intravenous cerulein (5 μg·kg-1·h-1, for 6 h). Daily probiotics or placebo were administered intragastrically, starting 5 days prior to AP. After cerulein infusion, pancreas samples were collected for analysis including lipid peroxidation, glutathione, glutamate-cysteine-ligase activity, histological grading of pancreatic injury, and NF-κB activation. The severity of pancreatic injury correlated to oxidative damage (r = 0.9) and was ameliorated by probiotics (1.5 vs. placebo 5.5, P = 0.014). AP-induced NF-κB activation was reduced by probiotics (0.20 vs. placebo 0.53 OD 450nm/mg nuclear protein, P < 0.001). Probiotics attenuated AP-induced lipid peroxidation (0.25 vs. placebo 0.51 pmol malondialdehyde/mg protein, P < 0.001). Not only was AP-induced glutathione depletion prevented (8.81 vs. placebo 4.1 μmol/mg protein, P < 0.001), probiotic pretreatment even increased glutathione compared with sham rats (8.81 vs. sham 6.18 μmol/mg protein, P < 0.001). Biosynthesis of glutathione (glutamate-cysteine-ligase activity) was enhanced in probiotic-pretreated animals. Probiotics enhanced the biosynthesis of glutathione, which may have reduced activation of inflammation and acinar cell injury and ameliorated experimental AP, via a reduction in oxidative stress. Copyright © 2008 the American Physiological Society.

  • 4.
    Sandström, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    von Dobeln, U.
    Department of Laboratory Medicine Karolinska University Hospital Huddinge, Stockholm.
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Serum amino acid profile in patients with acute pancreatitis2008In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 35, no 1, p. 225-231Article in journal (Refereed)
    Abstract [en]

    Patients in the early phase of acute pancreatitis (AP) have reduced serum levels of arginine and citrulline. This may be of patho-biological importance, since arginine is the substrate for nitric oxide, which in turn is involved in normal pancreatic physiology and in the inflammatory process. Serum amino acid spectrum was measured daily for five days and after recovery six weeks later in 19 patients admitted to the hospital for acute pancreatitis. These patients had abnormal levels of most amino acids including arginine, citrulline, glutamine and glutamate. Phenylalanine and glutamate were increased, while arginine, citrulline, ornithine and glutamine were decreased compared to levels after recovery. NO2/NO3 concentration in the urine, but not serum arginase activity, was significantly increased day 1 compared to day 5 after admission. Acute pancreatitis causes a disturbance of the serum amino acid spectrum, with possible implications for the inflammatory process and organ function both in the pancreas and the gut. Supplementation of selected amino acids could possibly be of value in this severe condition. © 2007 Springer-Verlag.

  • 5.
    Smeds, Staffan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: endokir.
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Garovay, M
    Gumpert, M
    Clark, OH
    Survival of human parathyroid tissue transplanted in nude mice after 9 to 55 months' cryopreservation.1999In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 107, p. 445-450Article in journal (Refereed)
  • 6.
    Trulsson, Lena
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Influence of cholecystokinin and nitric oxide on growth regulation in exocrine pancreas of the rat2002Licentiate thesis, comprehensive summary (Other academic)
  • 7.
    Trulsson, Lena
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    The influence of nitric oxide and cholecystokinin on tissue homeostasis in exocrine pancreas: an experimental study in rats2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Growth of the pancreas is stimulated by cholecystokinin (CCK) in rats. Nitric oxide (NO), which is synthesized from the amino acid L-arginine by NO-synthases (NOS), interferes with CCK in modulating the pancreatic secretion. Both pro- and anti-apoptotic influences of NO have been observed in other tissues, but its importance for pancreatic tissue homeostasis has not been studied.

    Cell proliferation and death rates were studied in the rat pancreas during different experimental conditions. CCK-octapeptide (CCK-8) was given in different doses either intermittently or continuously for three days and the pancreatic growth response was studied. Exogenous CCK-8 caused dose-dependent pancreatic atrophy when given intermittently and hyperplasia when given continuously.

    The influence of NO on cell death and proliferation was studied during: 1) basal conditions, 2) CCK-8 induced hyperplasia, and 3) CCK-8 induced atrophy. The NO level was manipulated either by NOS inhibition (L-NNA) or by exogenous NO supply (SNAP). NO-metabolism was assessed in the basal situation by analysis of nitrite/nitrate excretion in urine (which was decreased by L-NNA and increased by SNAP), and L-arginine in serum (which increased by L-NNA) and L-citrulline in serum.

    1) During basal conditions NOS inhibition (NO↓) increased apoptosis and decreased cell proliferation.

    2) During CCK-8 induced hyperplasia NOS inhibition (NO↓) increased both apoptosis and cell proliferation. The apoptosis dominated as indicated by decreased DNA content. SNAP administration (NO↑) did neither influence apoptosis nor cell proliferation.

    3) During CCK-8 induced atrophy (DNA↓, apoptosis↑, cell proliferation↑, and cytoplasmic vacuolization) NOS inhibition further increased apoptosis, reduced cell proliferation and abolished vacuole formation. SNAP administration (NO↑) decreased the DNA content, and increased both apoptosis and cell proliferation. The vacuole formation was still present. Hence, NO influences both the basal and the disturbed homeostasis in hyperplastic and atrophic rat pancreatic tissue.

    Early events of a load of L-arginine, known to induce pancreatitis within 48 hrs, was studied at 8, 16 and 24 hrs by analysis of serum L-arginine and L-citrulline, pancreatic tissue ATP, apoptosis and cell proliferation. The initially increased serum L-arginine and L-citrulline decreased to levels below control at 24 hrs. Administration of L-arginine was correlated to a biphasic ATP production and formation of small vacuoles (mitochondrial swelling) in the acinar cells, most prominent at 8 hrs and followed by a gradually increased apoptosis rate. The cell proliferation decreased. At 24 hrs there was pronounced cell degeneration, but no evident necrosis. Another 20 amino acids in serum were also analysed at 24 hrs. Twelve amino acids (including the 'glutamate family') were significantly reduced. After an L-arginine load the augmented A TP production correlates to the initiation of pancreatic cell death. The disturbed amino acid metabolism seems to be of importance for development of experimental pancreatitis.

    List of papers
    1. Cholecystokinin octapeptide induces both proliferation and apoptosis in the rat pancreas
    Open this publication in new window or tab >>Cholecystokinin octapeptide induces both proliferation and apoptosis in the rat pancreas
    2001 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 98, no 1-2, p. 41-48Article in journal (Refereed) Published
    Abstract [en]

    Cholecystokinin-8 (CCK-8) causes exocrine pancreatic hypertrophy and hyperplasia. High doses of the CCK analogue cerulein causes necrosis and an inflammatory response in the pancreas. We have studied the pancreatic growth response in rats after administration of CCK-8 for 3 days, given either intermittently (20–80 μg/kg) twice a day, or continuously (2.4–48 μg/kg per 24 h). Plasma CCK-8 levels, pancreatic wet weight, water, protein and DNA contents and the pancreatic caspase-3 activity were measured. Cell proliferation was visualized by [3H]thymidine incorporation and apoptosis by TUNEL reaction. Continuous administration of CCK-8 dose-dependently increased the plasma CCK levels, the pancreatic wet weight, protein and DNA contents as well as thymidine labeling index, apoptotic index and caspase-3 activity. Intermittent injections of CCK-8 caused transient raises in plasma CCK, increased apoptotic index and caspase-3 activity, a dose-dependent increase in thymidine labeling but caused a dose-dependent reduction of pancreatic wet weight, protein, and DNA contents. It is concluded that CCK-8 causes both increased proliferation and apoptosis in the pancreas. In case of continuous administration of CCK-8, the proliferation outweighs the apoptosis causing hyperplasia but in the case of intermittent administration the opposite effect is seen.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25028 (URN)10.1016/S0167-0115(00)00223-8 (DOI)9451 (Local ID)9451 (Archive number)9451 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    2. The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas
    Open this publication in new window or tab >>The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas
    2002 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 106, no 1-3, p. 97-104Article in journal (Refereed) Published
    Abstract [en]

    Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by Nω-nitro-l-arginine (l-NNA) reduced the urinary excretion of NO2/NO3 and raised serum l-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO2/NO3. The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, l-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of l-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25029 (URN)10.1016/S0167-0115(02)00056-3 (DOI)9452 (Local ID)9452 (Archive number)9452 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    3. Cholecystokinin-8-induced atrophy in the rat pancreas: influence of nitric oxide on proliferation, programmed cell death and NF-κB activation
    Open this publication in new window or tab >>Cholecystokinin-8-induced atrophy in the rat pancreas: influence of nitric oxide on proliferation, programmed cell death and NF-κB activation
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The mechanisms involved in cholecystokinin-8-induced atrophy in the pancreas are not known and in this study the roles of nitric oxide (NO) and NF-κB were studied in rats. CCK-8 was injected for 4 days, in a mode known to cause atrophy, and the NO formation was either decreased by Nω-nitro-L-arginine (L-NNA) or increased by S-nitroso-N-acetylpencillamine (SNAP). Activation of NF-κB was quantified by ELISA detection, apoptosis with caspase-3 and histone associated DNA-fragmentation and mitotic activity in the acinar, centroacinar and ductal cells was visualized by incorporation of [3H]-thymidine. Pancreatic histology, weight, protein- and DNA contents were studied.

    Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and NF-κB activation. It also caused vacuolisation of the acinar cells. Inhibition of endogenous NO formation by L-NNA further increased apoptosis and NF-κB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK-8 increased both apoptosis and proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Further, it caused vacuolisation in the acinar cells and these findings together indicate cell death by other pathways besides apoptosis. Histological examination showed no inflammation in any group.

    During CCK-8 induced pancreatic atrophy endogenous NO suppresses apoptosis and stimulates regeneration of acinar cells but increases cell death by non-apoptotic pathways. Exogenous NO enhances the acinar cell turnover by increases of both proliferation and apoptotic and non-apoptotic cell deaths. NF-κB activation, in this situation, seems not to inhibit apoptosis or promote cell proliferation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85071 (URN)
    Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2012-11-01
    4. The influence of a load of L-arginine on serum amino acids and pancreatic apoptosis/proliferation and ATP levels in the rat
    Open this publication in new window or tab >>The influence of a load of L-arginine on serum amino acids and pancreatic apoptosis/proliferation and ATP levels in the rat
    Show others...
    2004 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 29, no 4, p. 113-120Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    Administration of high doses of amino acids like ethionine, methionine, and arginine causes pancreatic tissue damage. The initial mechanism behind these effects is not known. The aim of this study was to show the early effects of a load of L-arginine on programed cell death/proliferation and ATP levels in the pancreas.

    METHODS:

    We analyzed in rats the effects of intraperitoneal administration of L-arginine on serum amino acids, pancreatic cell apoptosis/proliferation, and ATP levels at 8, 16, and 24 hours. Serum amino acid concentrations were measured with HPLC, tissue ATP was measured fluorometrically, apoptosis was studied with caspase-3 activity and histone-associated DNA-fragments, and proliferation was studied with thymidine autoradiography.

    RESULTS:

    After a load of l-arginine, there were initially increased serum levels of L-arginine and L-citrulline, but these fell below control levels after 24 hours as well as amino acids in the glutamate family (ornithine, proline, histidine, and glutamine). Initially, increased ATP levels in the pancreatic tissue returned to control levels at 24 hours. The acinar cells proliferation was suppressed and the apoptosis rate strongly increased at 16 and 24 hours. Pancreatic histology showed vacuole formation in the acinar cells at 8 hours. At 16 hours, there was less vacuolization, but apoptotic bodies were seen, and at 24 hours there was cell degeneration but no necrosis.

    CONCLUSIONS:

    After a load of l-arginine, amino acid metabolism causes a high ATP production in the pancreatic tissue that may cause mitochondrial initiation of cell death.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-23748 (URN)15502637 (PubMedID)3258 (Local ID)3258 (Archive number)3258 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
  • 8.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Permerth, J
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    The balance of mitogenesis and apoptosis in the rat pancreas in response to CCK-8.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 5324-Conference paper (Other academic)
  • 9.
    Trulsson, Lena
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Gasslander, Thomas
    Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas2002In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 106, no 1-3, p. 97-104Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by Nω-nitro-l-arginine (l-NNA) reduced the urinary excretion of NO2/NO3 and raised serum l-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO2/NO3. The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, l-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of l-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.

  • 10.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Cholecystokinin-8-induced hypoplasia of the rat pancreas: Influence of nitric oxide on cell proliferation and programmed cell death2004In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 95, no 4, p. 183-190Article in journal (Refereed)
    Abstract [en]

    The background of cholecystokinin-8 (CCK-8)-induced hypoplasia in the pancreas is not known. In order to increase our understanding we studied the roles of nitric oxide and NF-κB in rats. CCK-8 was injected for 4 days, in a mode known to cause hypoplasia, and the nitric oxide formation was either decreased by means of Nω-nitro-L-arginine (L-NNA) or increased by S-nitroso-N-acetylpencillamine (SNAP). The activation of NF-κB was quantified by ELISA detection, apoptosis with caspase-3 and histone-associated DNA-fragmentation and mitotic activity in the acinar, centroacinar and ductal cells were visualized by the incorporation of [3H]-thymidine. Pancreatic histology and weight as well as protein- and DNA contents were also studied. Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and nuclear factor κB (NF-κB) activation. It also caused vacuolisation of acinar cells. The inhibition of endogenous nitric oxide formation by L-NNA further increased apoptosis and NF-κB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK-8 increased apoptosis and other pathways of cell death, raised proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Histological examination showed no inflammation in any group. We conclude that during CCK-8-induced pancreatic hypoplasia, endogenously formed nitric oxide suppresses apoptosis but increases cell death along non-apoptotic pathways and stimulates regeneration of acinar cells. Exogenous nitric oxide enhances the acinar cell turnover by increasing both apoptotic and non-apoptotic cell death and cell renewal. In this situation NF-κB activation seems not to inhibit apoptosis nor promote cell proliferation.

  • 11.
    Trulsson, Lena M.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Gasslander, Thomas
    Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden.
    Svanvik, Joar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Cholecystokinin-8-induced atrophy in the rat pancreas: influence of nitric oxide on proliferation, programmed cell death and NF-κB activationManuscript (preprint) (Other academic)
    Abstract [en]

    The mechanisms involved in cholecystokinin-8-induced atrophy in the pancreas are not known and in this study the roles of nitric oxide (NO) and NF-κB were studied in rats. CCK-8 was injected for 4 days, in a mode known to cause atrophy, and the NO formation was either decreased by Nω-nitro-L-arginine (L-NNA) or increased by S-nitroso-N-acetylpencillamine (SNAP). Activation of NF-κB was quantified by ELISA detection, apoptosis with caspase-3 and histone associated DNA-fragmentation and mitotic activity in the acinar, centroacinar and ductal cells was visualized by incorporation of [3H]-thymidine. Pancreatic histology, weight, protein- and DNA contents were studied.

    Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and NF-κB activation. It also caused vacuolisation of the acinar cells. Inhibition of endogenous NO formation by L-NNA further increased apoptosis and NF-κB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK-8 increased both apoptosis and proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Further, it caused vacuolisation in the acinar cells and these findings together indicate cell death by other pathways besides apoptosis. Histological examination showed no inflammation in any group.

    During CCK-8 induced pancreatic atrophy endogenous NO suppresses apoptosis and stimulates regeneration of acinar cells but increases cell death by non-apoptotic pathways. Exogenous NO enhances the acinar cell turnover by increases of both proliferation and apoptotic and non-apoptotic cell deaths. NF-κB activation, in this situation, seems not to inhibit apoptosis or promote cell proliferation.

  • 12.
    Trulsson, Lena M.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Permert, Johan
    Department of Surgery, Karolinska Institute at Huddinge, Huddinge University Hospital, Stockholm, Sweden.
    Gasslander, Thomas
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Cholecystokinin octapeptide induces both proliferation and apoptosis in the rat pancreas2001In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 98, no 1-2, p. 41-48Article in journal (Refereed)
    Abstract [en]

    Cholecystokinin-8 (CCK-8) causes exocrine pancreatic hypertrophy and hyperplasia. High doses of the CCK analogue cerulein causes necrosis and an inflammatory response in the pancreas. We have studied the pancreatic growth response in rats after administration of CCK-8 for 3 days, given either intermittently (20–80 μg/kg) twice a day, or continuously (2.4–48 μg/kg per 24 h). Plasma CCK-8 levels, pancreatic wet weight, water, protein and DNA contents and the pancreatic caspase-3 activity were measured. Cell proliferation was visualized by [3H]thymidine incorporation and apoptosis by TUNEL reaction. Continuous administration of CCK-8 dose-dependently increased the plasma CCK levels, the pancreatic wet weight, protein and DNA contents as well as thymidine labeling index, apoptotic index and caspase-3 activity. Intermittent injections of CCK-8 caused transient raises in plasma CCK, increased apoptotic index and caspase-3 activity, a dose-dependent increase in thymidine labeling but caused a dose-dependent reduction of pancreatic wet weight, protein, and DNA contents. It is concluded that CCK-8 causes both increased proliferation and apoptosis in the pancreas. In case of continuous administration of CCK-8, the proliferation outweighs the apoptosis causing hyperplasia but in the case of intermittent administration the opposite effect is seen.

  • 13.
    Trulsson, Lena
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Smeds, Staffan
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Gasslander, Thomas
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Svanvik, Joar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    The influence of a load of L-arginine on serum amino acids and pancreatic apoptosis/proliferation and ATP levels in the rat2004In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 29, no 4, p. 113-120Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Administration of high doses of amino acids like ethionine, methionine, and arginine causes pancreatic tissue damage. The initial mechanism behind these effects is not known. The aim of this study was to show the early effects of a load of L-arginine on programed cell death/proliferation and ATP levels in the pancreas.

    METHODS:

    We analyzed in rats the effects of intraperitoneal administration of L-arginine on serum amino acids, pancreatic cell apoptosis/proliferation, and ATP levels at 8, 16, and 24 hours. Serum amino acid concentrations were measured with HPLC, tissue ATP was measured fluorometrically, apoptosis was studied with caspase-3 activity and histone-associated DNA-fragments, and proliferation was studied with thymidine autoradiography.

    RESULTS:

    After a load of l-arginine, there were initially increased serum levels of L-arginine and L-citrulline, but these fell below control levels after 24 hours as well as amino acids in the glutamate family (ornithine, proline, histidine, and glutamine). Initially, increased ATP levels in the pancreatic tissue returned to control levels at 24 hours. The acinar cells proliferation was suppressed and the apoptosis rate strongly increased at 16 and 24 hours. Pancreatic histology showed vacuole formation in the acinar cells at 8 hours. At 16 hours, there was less vacuolization, but apoptotic bodies were seen, and at 24 hours there was cell degeneration but no necrosis.

    CONCLUSIONS:

    After a load of l-arginine, amino acid metabolism causes a high ATP production in the pancreatic tissue that may cause mitochondrial initiation of cell death.

  • 14.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Velin, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Herder, Anders
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Rüter, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Telomerase activity in surgical specimens and fine-needle aspiration biopsies from hyperplastic and neoplastic human thyroid tissues2003In: American Journal of Surgery, ISSN 0002-9610, E-ISSN 1879-1883, Vol. 186, no 1, p. 83-88Article in journal (Refereed)
    Abstract [en]

    Background: Telomerase activity (TA) indicates malignancy, but activated lymphocytes also express TA. Correlation between TA in thyroid tissues and fine-needle aspiration (FNA) samples and knowledge about TA in adjacent tissue are of importance. Methods: The telomeric repeat amplification protocol assay followed by enzyme-linked immunosorbent assay detection was performed on 78 thyroid cases including 53 suspected malignancies, preoperative and perioperative FNA specimens, and adjacent tissue. Results: Benign lesions in cancer-suspected cases were TA negative. Eight of 13 papillary (62%) and 4 of 5 follicular (80%) tumors were TA positive (TA+). Lower TA was observed in conventional papillary cancer than in follicular, tall cell variant of papillary and anaplastic cancers. Adjacent tissues with lymphocyte infiltration were TA+ in 9 of 17 cases (53%). Nine of 65 adjacent tissues (14%) were TA+. Three of 6 preoperative and 9 of 11 perioperative FNA samples from malignant tumors corresponded to the tissue TA. Conclusions: High TA may reflect more severe thyroid cancer. Telomerase activity in FNA biopsies does not add reliable diagnostic information, and presence of lymphocytes can give false-positive results.

  • 15.
    Velin, Åsa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Ander, Stefan
    Johansson, Kenth
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: endokir.
    Inverse relation between mRNA synthesis and secretion of parathyroid hormone in athymic mice grafted with human parathyroid tissue2001In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 109, no 3, p. 235-240Article in journal (Refereed)
    Abstract [en]

    Parathyroid hormone (PTH) mRNA in original and transplanted human adenomatous parathyroid tissue and human serum intact PTH (S-iPTH) was measured in athymic mice at 4, 7, 14, and 28 days after transplantation. Parathyroid tissue was obtained during surgery for hyperparathyroidism and implanted subcutaneously. PTH mRNA detection was done with RT-PCR followed by membrane blot and hybridisation and S-iPTH was analysed using a human specific immunoradiometric method. At 4 days, PTH mRNA was 79.6 ▒ 5.3% (mean ▒ SE) of that in original tissue whereas S-iPTH was only 5.4 ng/l. At 28 days, PTH mRNA was significantly reduced to 60.7▒4.1% whereas S-iPTH was increased to 192 ng/l. The reduced PTH mRNA expression in the transplants at 28 days may be explained by an inhibited DNA transcription. The presence of human S-iPTH in transplanted mice at 4 days may be due to cell disintegration and diffusion. The gradual increase in S-iPH during the experimental period probably reflects increased transplant cell volume and improved graft revascularisation.

  • 16.
    Velin, Åsa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Herder, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Johansson, Kenth
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: endokir.
    Telomerase is not activated in human hyperplastic and adenomatous parathyroid tissue2001In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 145, no 2, p. 161-164Article in journal (Refereed)
    Abstract [en]

    Background: Telomerase is a specific enzyme that appears to have a key role in cellular senescence and the progression of neoplastic tissue. High telomerase activity has been found in several cancers, but not in most normal and benign tissue. Little is known about the influence of telomerase on the abnormal growth associated with hyperparathyroidism. Objective: To analyse telomerase activity in parathyroid tissue obtained from 29 patients undergoing surgery for primary hyperparathyroidism. Design: Tissue for telomerase activity measurements was collected from six hyperplastic, 20 adenomatous and 22 normal parathyroid glands. Methods: The highly sensitive PCR-based telomeric repeat amplification protocol, TRAP, combined with ELISA, was used to detect telomerase activity in tissue extracts containing 3.0 ╡g protein. Result: Telomerase was not activated in any of the analysed tissue by 3 ╡g protein. Reassay of 12 samples containing 6.0 ╡g protein verified these negative TRAP results. Conclusion: Our findings indicate that telomerase is not a part of the mechanism promoting parathyroid proliferation and the underlying conditions remain to be determined.

  • 17.
    Winbladh, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Trulsson, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gullstrand, Per
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    N-acetyl cysteine improves glycogenesis after segmental liver ischemia and reperfusion injury in pigs2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 47, no 2, p. 225-236Article in journal (Refereed)
    Abstract [en]

    Abstract Objective. N-acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion (IR). Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in IR injury. Material and Methods. In an experimental model, 80 min of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 min. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously. Results. AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC-treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysates, indicating that NAC scavenges radical nitrosative species. Conclusions. NAC treatment improves glycogenesis after liver IR injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of radical nitrosative species.

  • 18.
    Winbladh, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Trulsson, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gullstrand, Per
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
    N-Acetylcysteine Improves Glycogenesis after Segmental Liver Ischemia and Reperfusion Injury in PigsManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: N-Acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion. Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in ischemia-reperfusion injury.

    Material and Methods: In an experimental model, 80 minutes of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 minutes. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously.

    Results: AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysate, indicating that NAC scavenges radical nitrosative species (RNS).

    Conclusions: NAC treatment improves glycogenesis after liver ischemia and reperfusion injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of RNS.

  • 19.
    Winbladh, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Trulsson, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Offenbartl, Karsten
    Höglandssjukhuset, Eksjö.
    Gullstrand, Per
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
    Ischemic Preconditioning Prior to Intermittent Pringles Maneuver in Liver Resections2012In: Journal of Hepato-Biliary-Pancreatic Sciences, ISSN 1868-6982, Vol. 19, no 2, p. 159-170Article in journal (Refereed)
    Abstract [en]

    Background: Continuous inflow vascular occlusion during liver resections causes less severe ischemia and reperfusion injury (IRI) if it is preceded by ischemic preconditioning (IP) or if intermittent inflow occlusion is used during the resection. No previous clinical trial has studied the effects of adding IP to intermittent inflow occlusion.

    Methods: Consecutive patients (n=32) with suspicion of malignant liver disease had liver resections (minimum 2 segments) performed with inflow occlusion 15/5. Half of the patients were randomized to receive IP (10/10). The patients were stratified according to volume of resection and none had chronic liver disease. The patients were followed for 5 days with microdialysis (μD).

    Results: All patients completed the study and there were no deaths. No differences were seen between the groups regarding demographics or perioperative parameters (bleeding, duration of ischemia, resection volume, complications and serum lab tests). There were no differences in ALT, AST, Bilirubin or PT-INR levels, but μD revealed lower levels of lactate, pyruvate and glucose in the IP group having major liver resections (ANOVA). Nitrite and nitrate levels in μD decreased postoperatively but no differences were seen between the groups. In one patient an elevated μDglycerol curve was seen before the diagnosis of a stroke was made.

    Conclusions: IP before intermittent vascular occlusion does not reduce the serum parameters used to assess IRI. IP seems to improve aerobic glucose metabolism as the levels of glucose, pyruvate and lactate locally in the liver were reduced compared to controls in patients having resected >3 segments. μD may be used to monitor metabolism locally.

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