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Influence of PACAP on Oxidative Stress and Tissue Injury Following Small-Bowel Autotransplantation

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Abstract

Tissue injury caused by cold preservation and reperfusion remains an unsolved problem during small-bowel transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present and plays a central role in the intestinal physiology. This study investigated effect of PACAP-38 on the oxidative stress and tissue damage in autotransplanted intestine. Sham-operated, ischemia/reperfusion, and autotransplanted groups were established in Wistar rats. In ischemia/reperfusion groups, 1 h (group A), 2 h (group B), and 3 h (group C) ischemia followed by 3 h of reperfusion was applied. In autotransplanted groups, total orthotopic intestinal autotransplantation was performed. Grafts were preserved in University of Wisconsin (UW) solution and in UW containing 30 μg PACAP-38 for 1, 2, 3, and 6 h. Reperfusion lasted 3 h in all groups. Endogenous PACAP-38 concentration was measured by radioimmunoassay. To determine oxidative stress parameters, malondialdehyde, reduced glutathione, and superoxide dismutase were measured in tissue samples. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. Concentration of endogenous PACAP-38 significantly decreased in groups B and C compared to sham-operated group. Preservation solution containing PACAP-38 ameliorated bowel tissue oxidative injury induced by cold ischemia and reperfusion. Histological results showed that preservation caused destruction of the mucous, submucous, and muscular layers, which were further deteriorated by the end of reperfusion. In contrast, PACAP-38 significantly protected the intestinal structure. Ischemia/reperfusion decreased the endogenous PACAP-38 concentration in the intestinal tissue. Administration of PACAP-38 mitigated the oxidative injury and histological lesions in small-bowel autotransplantation model.

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References

  • Abad, C., Gomariz, R. P., & Waschek, J. A. (2006). Neuropeptide mimetics and antagonists in the treatment of inflammatory disease: Focus on VIP and PACAP. Current Topics in Medicinal Chemistry, 6, 151–163.

    Article  PubMed  CAS  Google Scholar 

  • Arimura, A. (2007). PACAP: The road to discovery. Peptides, 28, 1617–1619.

    Article  PubMed  CAS  Google Scholar 

  • Atlasz, T., Babai, N., Kiss, P., et al. (2007). Pituitary adenylate cyclase activating polypeptide is protective in bilateral carotid occlusion-induced retinal lesion in rats. General and Comparative Endocrinology, 153, 108–114.

    Article  PubMed  CAS  Google Scholar 

  • Azuma, Y. T., Hagi, K., Shintani, N., et al. (2008). PACAP provides colonic protection against dextran sodium sulfate induced colitits. Journal of cellular physiology, 216, 111–119.

    Article  PubMed  CAS  Google Scholar 

  • Balaz, P., Kudla, M., Lodererova, A., Oliverius, M., & Adamec, M. (2007). Preservation injury to the human small bowel graft: Jejunum vs. ileum. Annals of Transplantation, 12, 15–18.

    PubMed  Google Scholar 

  • Beath, S. V. (2006). Closure and summary of Ninth International Small Bowel Transplantation Symposium. Transplantation Proceedings, 38, 1657–1658.

    Article  PubMed  CAS  Google Scholar 

  • Chen, Y., Samal, B., Hamelink, C. R., et al. (2006). Neuroprotection by endogenous and exogenous PACAP following stroke. Regulatory Peptides, 137, 4–19.

    Article  PubMed  CAS  Google Scholar 

  • Ekblad, E., Jongsma, H., Brabet, P., Bockaert, J., & Sundler, F. (2000). Characterization of intestinal receptors for VIP and PACAP in rat and in PAC1 receptor knockout mouse. Annals of the New York Academy of Sciences, 921, 137–147.

    Article  PubMed  CAS  Google Scholar 

  • Ferencz, A., Racz, B., Gasz, B., et al. (2006). Intestinal ischemic preconditioning in rats and NF-kappaB activation. Microsurgery, 26, 54–57.

    Article  PubMed  Google Scholar 

  • Ferencz, A., Szanto, Z., Borsiczky, B., et al. (2002). The effects of preconditioning on the oxidative stress in small-bowel autotransplantation. Surgery, 132, 877–884.

    Article  PubMed  Google Scholar 

  • Foda, H. D., Sharaf, H. H., Absood, A., & Said, S. I. (1995). Pituitary adenylate cyclase-activating peptide (PACAP), a VIP-like peptide, has prolonged airway smooth muscle relaxant activity. Peptides, 16, 1057–1061.

    Article  PubMed  CAS  Google Scholar 

  • Fraczek, M., Hevelke, P., Kotulski, M., et al. (2007). Small bowel transplantation-harvesting technique and graft preparation in pigs. Annals of Transplantation, 12, 19–26.

    PubMed  Google Scholar 

  • Fujimoto, Y., Olson, D. W., Madsen, K. L., et al. (2002). Defining the role of a tailored luminal solution for small bowel preservation. American Journal of Transplantation, 2, 229–236.

    Article  PubMed  CAS  Google Scholar 

  • Girard, B. M., Young, B. A., Buttolph, T. R., White, S. L., & Parsons, R. L. (2007). Regulation of neuronal pituitary adenylate cyclase-activating polypeptide expression during culture of guinea-pig cardiac ganglia. Neuroscience, 146, 584–593.

    Article  PubMed  CAS  Google Scholar 

  • Hannibal, J., Ekblad, E., Mulder, H., Sundler, F., & Fahrenkrug, J. (1998). Pituitary adenylate cyclase activating polypeptide (PACAP) in the gastrointestinal tract of the rat: Distribution and effects of capsaicin or denervation. Cell & Tissue Research, 291, 65–79.

    CAS  Google Scholar 

  • Inuzuka, K., Unno, N., Yamamoto, N., et al. (2007). Effect of hyperbarically oxygenated-perfluorochemical with University of Wisconsin solution on preservation of rat small intestine using an original pressure-resistant portable apparatus. Surgery, 142, 57–66.

    Article  PubMed  Google Scholar 

  • Jakab, B., Reglodi, D., Jozsa, R., et al. (2004). Distribution of PACAP-38 in the central nervous system of various species determined by a novel radioimmunoassay. Journal of Biochemical and Biophysical Methods, 61, 189–198.

    Article  PubMed  CAS  Google Scholar 

  • Koves, K., Arimura, A., Vigh, S., Somogyvari-Vigh, A., & Miller, J. (1993). Immunohistochemical localization of PACAP in the ovine digestive system. Peptides, 14, 449–455.

    Article  PubMed  CAS  Google Scholar 

  • Lauffer, J. M., Modlin, I. M., & Tang, L. H. (1999). Biological relevance of pituitary adenylate cyclase activating polypeptide (PACAP) in the gastrointestinal tract. Regulatory Peptide, 84, 1–12.

    Article  CAS  Google Scholar 

  • Lelievre, V., Favrais, G., Abad, C., et al. (2007). Gastrointestinal dysfunction in mice with a targeted mutation in the gene encoding vasoactive intestinal polypeptide: A model for the study of intestinal ileus and Hirschsprung's disease. Peptides, 28, 1688–1699.

    Article  PubMed  CAS  Google Scholar 

  • Leuvenink, H. G., van Dijk, A., Freund, R. L., Ploeg, R. J., & van Goor, H. (2005). Luminal preservation of rat small intestine with University of Wisconsin or Celsior solution. Transplantation Proceedings, 37, 445–447.

    Article  PubMed  CAS  Google Scholar 

  • Mei, Q., & Sundler, F. (1998). Changes in pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide innervation of rat oxyntic mucosa during ulcer healing. Neuropeptides, 32, 527–535.

    Article  PubMed  CAS  Google Scholar 

  • Minor, T., & Isselhard, W. (1998). Cellular signal level of cyclic AMP and functional integrity of the small bowel after ischemic preservation: An experimental pilot study in the rat. European Surgical Research, 30, 144–148.

    Article  PubMed  CAS  Google Scholar 

  • Miyata, A., Arimura, A., Dahl, R. R., et al. (1989). Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in the pituitary cells. Biochemical and Biophysical Research Communications, 164, 567–574.

    Article  PubMed  CAS  Google Scholar 

  • Mueller, A. R., Platz, K. P., Neuhaus, P., Lee, K. K., & Schraut, W. H. (1996). Goals of small bowel preservation. Transplantation Proceedings, 28, 2633–2635.

    PubMed  CAS  Google Scholar 

  • Muhlbacher, F., Langer, F., & Mittermayer, C. (1999). Preservation solutions for transplantation. Transplantation Proceedings, 31, 2069–2070.

    Article  PubMed  CAS  Google Scholar 

  • Nakao, A., Toyokawa, H., Tsung, A., et al. (2006). Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. American Journal of Transplantation, 6, 2243–2255.

    Article  PubMed  CAS  Google Scholar 

  • Oh, D. S., Lieu, S. N., Yamaguchi, D. J., et al. (2005). PACAP regulation of secretion and proliferation of pure populations of gastric ECL cells. Journal of Molecular Neuroscience, 26, 85–98.

    Article  PubMed  CAS  Google Scholar 

  • Ohtaki, H., Nakamachi, T., Dohi, K., et al. (2006). Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proceedings of the National Academy of Sciences of the United States of America, 103, 7488–7493.

    Article  PubMed  CAS  Google Scholar 

  • Olson, D. W., Jijon, H., Madsen, K. L., et al. (2003). Human small bowel storage: The role for luminal preservation solutions. Transplantation, 76, 709–714.

    Article  PubMed  Google Scholar 

  • Park, P. O., Haglund, U., Bulkley, G. B., & Falt, K. (1990). The sequence of development of intestinal tissue injury after strangulation ischemia and reperfusion. Surgery, 107, 574–580.

    PubMed  CAS  Google Scholar 

  • Racz, B., Gasz, B., Gallyas Jr., F., et al. (2008). PKA-Bad-14-3-3 and Akt-Bad-14-3-3 signaling pathways are involved in the protective effects of PACAP against ischemia/reperfusion-induced cardiomyocyte apoptosis. Regulatory Peptide, 145, 105–115.

    Article  CAS  Google Scholar 

  • Reglodi, D., Fabian, Z., Tamas, A., et al. (2004). Effects of PACAP on in vitro and in vivo neuronal cell death, platelet aggregation, and production of reactive oxygen radicals. Regulatory Peptide, 123, 51–59.

    Article  CAS  Google Scholar 

  • Riera, M., Torras, J., Cruzado, J. M., et al. (2001). The enhancement of endogenous cAMP with pituitary adenylate cyclase activating polypeptide protects rat kidney against ischemia through the modulation of inflammatory response. Transplantation, 72, 1217–1223.

    Article  PubMed  CAS  Google Scholar 

  • Salehi, P., Madsen, K., Zhu, J., et al. (2004). Alleviating ischemia-reperfusion injury in small bowel. American Journal of Transplantation, 4, 728–737.

    Article  PubMed  CAS  Google Scholar 

  • Salehi, P., Walker, J., Madsen, K. L., et al. (2007). Relationship between energetic stress and pro-apoptotic/cytoprotective kinase mechanisms in intestinal preservation. Surgery, 141, 795–803.

    Article  PubMed  Google Scholar 

  • Salehi, P., Walker, J., Madsen, K., & Churchill, T. A. (2006). Control of oxidative stress in small bowel: Relevance to organ preservation. Surgery, 139, 317–323.

    Article  PubMed  Google Scholar 

  • Salehi, P., Zhu, L. F., Sigurdson, G. T., Jewell, L. D., & Churchill, T. A. (2005). Nutrient-related issues affecting successful experimental orthotopic small bowel transplantation. Transplantation, 80, 1261–1268.

    Article  PubMed  Google Scholar 

  • Salomon, R., Couvineau, A., Rouyer-Fessard, C., et al. (1993). Characterization of a common VIP-PACAP receptor in human small intestinal epithelium. American Journal of Physiology, 264, 294–300.

    Google Scholar 

  • Schulz, S., Rocken, C., Mawrin, C., Weise, W., Hollt, V., & Schulz, S. (2004). Immunocytochemical identification of VPAC1, VPAC2, and PAC1 receptors in normal and neoplastic human tissues with subtype-specific antibodies. Clinical Cancer Research, 10, 8235–8242.

    Article  PubMed  CAS  Google Scholar 

  • Sherwood, N. M., Krueckl, S. L., & McRory, J. E. (2000). The origin and function of the pituitary adenylate cyclase activating polypeptide (PACAP)/glucagon superfamily. Endocrine Reviews, 21, 619–670.

    Article  PubMed  CAS  Google Scholar 

  • Shioda, S., Ohtaki, H., Nakamachi, T., et al. (2006). Pleiotropic functions of PACAP in the CNS: Neuroprotection and neurodevelopment. Annals of the New York Academy of Sciences, 1070, 550–560.

    Article  PubMed  CAS  Google Scholar 

  • Shioda, S., Ozawa, H., Dohi, K., et al. (1998). PACAP protects hippocampal neurons against apoptosis: Involvement of JNK/SAPK signaling pathway. Annals of the New York Academy of Sciences, 865, 111–117.

    Article  PubMed  CAS  Google Scholar 

  • Somogyvari-Vigh, A., & Reglodi, D. (2004). Pituitary adenylate cyclase activating polypeptide: A potential neuroprotective peptide. Current Pharmaceutical Design, 10, 2861–2889.

    Article  PubMed  CAS  Google Scholar 

  • Szakaly, P., Kiss, P., Magyarlaki, T., et al. (2008). Effects of PACAP on survival and renal morphology in rats subjected to renal ischemia. Journal of Molecular Neuroscience (in press, PMID: 18478450).

  • Takeyoshi, I., Zhang, S., Nomoto, M., et al. (2001). Mucosal damage and recovery of the intestine after prolonged preservation and transplantation in dogs. Transplantation, 71, 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Tornoe, K., Hannibal, J., Georg, B., et al. (2001). PACAP 1-38 as neurotransmitter in the porcine antrum. Regulatory Peptide, 101, 109–121.

    Article  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., Yon, L., Fournier, A., & Vaudry, H. (2000). Pituitary adenylate cyclase activating polypeptide and its receptors: From structure to functions. Pharmacological Reviews, 52, 269–324.

    PubMed  CAS  Google Scholar 

  • Waschek, J. A. (2002). Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Developmental Neuroscience, 24, 14–23.

    Article  PubMed  CAS  Google Scholar 

  • Wei, L., Hata, K., Doorschodt, B. M., Büttner, R., Minor, T., & Tolba, R. H. (2007). Experimental small bowel preservation using Polysol: A new alternative to University of Wisconsin solution, Celsior and histidine-tryptophan-ketoglutarate solution? World Journal of Gastroenterology, 13, 3684–3691.

    PubMed  CAS  Google Scholar 

  • Yan, S. F., Ogawa, S., Stern, D. M., & Pinsky, D. J. (1997). Hypoxia-induced modulation of endothelial cell properties: Regulation of barrier function and expression on interleukin-6. Kidney International, 51, 419–425.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Hungarian Scientific Research Fund (Grant OTKA F046593 and T046589, F67830, K72592, ETT439/2006), and Bolyai János Scholarship of the Hungarian Academy of Sciences.

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Authors and Affiliations

  1. Department of Surgical Research and Techniques, University of Pécs, Medical Faculty, Kodály Zoltán Street 20, 7624, Pecs, Hungary

    Andrea Ferencz, Boglarka Racz, Klara Nedvig, Gyorgy Weber & Erzsebet Roth

  2. Department of Surgery, University of Pecs, 1fjusag Street 13, Pecs, 7624, Hungary

    Karoly Kalmar-Nagy & Ors Peter Horvath

  3. Department of Anatomy, University of Pecs, Szigeti Street 12, Pecs, 7624, Hungary

    Andrea Tamas, Dora Reglodi & Andrea Lubics

  4. Department of Pharmacology and Pharmacotherapy, University of Debrecen, Nagyerdei Street 94, Debrecen, 4012, Hungary

    Jozsef Nemeth

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  1. Andrea Ferencz
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Correspondence to Andrea Ferencz.

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Ferencz, A., Racz, B., Tamas, A. et al. Influence of PACAP on Oxidative Stress and Tissue Injury Following Small-Bowel Autotransplantation. J Mol Neurosci 37, 168–176 (2009). https://doi.org/10.1007/s12031-008-9132-0

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