Skip to main content

Advertisement

SpringerLink
Log in

Pyrrolidine Dithiocarbamate Reduces Lung Injury Caused by Mesenteric Ischemia/Reperfusion in a Rat Model

  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

Pyrrolidine dithiocarbamate (PDTC) is a low-molecular thiol antioxidant and potent inhibitor of nuclear factor-κB (NF-κB) activation. It has been shown to attenuate local harmful effects of ischemia/reperfusion (I/R) injury in many organs. In this study, we aimed to study the effect of PDTC on lung reperfusion injury induced by superior mesenteric occlusion.

Methods

Male Wistar-albino rats randomized into three groups: (1) sham-operated control group (n = 12), laparotomy without I/R injury; (2) intestinal ischemia/reperfusion (I/R) group (n = 12), 60 min of ischemia by superior mesenteric occlusion followed by 2 h of reperfusion; and (3) I/R+PDTC-treated group (n = 12), 100 mg/kg injection of PDTC intravenously, 30 min after the commencement of reperfusion. Evans blue dye was injected to half of rats in all groups before the induction of I/R. We assessed the degree of pulmonary tissue injury biochemically by measuring malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) levels, and histopathologically by establishing pulmonary neutrophil sequestration and acute lung injury scoring. Pulmonary edema was evaluated by Evans blue dye extravasation, as well as lung tissue wet/dry weight ratios.

Results

Pyrrolidine dithiocarbamate treatment significantly reduced the MDA and NO levels, and increased the GSH levels in the lung parenchyma, biochemically (p < 0.05), and atteneuated the pulmonary parenchymal damage, histopathologically (p < 0.05). However, pulmonary neutrophil sequestration was not affected by postischemic treatment with PDTC (p > 0.05). Pyrrolidine dithiocarbamate administration also significantly alleviated the formation of pulmonary edema, as evidenced by the decreased Evans blue dye extravasation and organ wet/dry weight ratios (p < 0.05).

Conclusions

This study showed that postischemic treatment with PDTC significantly attenuated the lung reperfusion injury. Further clinical studies are needed for better understanding of the specific mechanisms of PDTC protection against I/R-related organ injury and to clarify whether PDTC may be a useful therapeutic agent during particular operations where remote organ I/R injury occurs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sisley AC, Desai T, Harig JM, et al. (1994) Neutrophil depletion attenuates human intestinal reperfusion injury. J Surg Res 57:192–196

    Article  PubMed  CAS  Google Scholar 

  2. McMillen MA, Huribal M, Sumpio B. (1993) Common pathway of endothelial-leukocyte interaction in shock, ischemia, and reperfusion. Am J Surg 166:557–562

    Article  PubMed  CAS  Google Scholar 

  3. Aytekin FO, Tekin K, Kabay B, et al. (2005) Antithrombin III attenuates pulmonary tissue injury caused by mesenteric ischemia-reperfusion. Am J Surg 189:161–166

    Article  PubMed  CAS  Google Scholar 

  4. Koike K, Moore EE, Moore FA, et al. (1994) Gut ischemia/reperfusion produces lung injury independent of endotoxin. Crit Care Med 22:1438–1444

    Article  PubMed  CAS  Google Scholar 

  5. Kuzu MA, Koksoy C, Kuzu I, et al. (2002) Role of integrins and intracellular adhesion molecule-1 in lung injury after intestinal ischemia-reperfusion. Am J Surg 183:70–74

    Article  PubMed  CAS  Google Scholar 

  6. Schmeling DJ, Caty MG, Oldham KT, et al. (1989) Evidence for neutrophil-related acute lung injury after intestinal ischemia-reperfusion. Surgery 106:195–201

    PubMed  CAS  Google Scholar 

  7. Lucchesi BR. (1994) Complement, neutrophils and free radicals: mediators of reperfusion injury. Arzneimittelforschung 44:420–432

    PubMed  CAS  Google Scholar 

  8. Abraham E. (2003) Neutrophils and acute lung injury. Crit Care Med 31:195–199

    Article  Google Scholar 

  9. de Perrot M, Liu M, Waddell TK, et al. (2003) Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 167:490–511

    Article  PubMed  Google Scholar 

  10. Swank DW, Moore SB. (1989) Roles of the neutrophil and other mediators in adult respiratory distress syndrome. Mayo Clin Proc 64:1118–1132

    PubMed  CAS  Google Scholar 

  11. Beutler B, Cerami A. (1989) The biology of cachectin/TNF-α primary mediator of the host response. Annu Rev Immunol 7:625–655

    PubMed  CAS  Google Scholar 

  12. Burgess AW, Metcalf D. (1980) The nature and action of granulocyte-macrophage colony stimulating factors. Blood 56:947–958

    PubMed  CAS  Google Scholar 

  13. Jones KL, Bryan TW, Jinkins PA, et al. (1998) Superoxide release from neutrophils causes a reduction in nitric oxide gas. Am J Physiol Lung Cell Mol Physiol 275:1120–1126

    Google Scholar 

  14. Nakazawa H, Fukuyama N, Takizawa S, et al. (2001) Nitrotyrosine formation and its role in various pathological conditions. Free Radic Res 33:771–784

    Article  Google Scholar 

  15. Haddad IY, Ischiropoulos H, Holm BA, et al. (1993) Mechanisms of peroxynitrite-induced injury to pulmonary surfactant. Am J Physiol 265:555–564

    Google Scholar 

  16. Li C, Jackson RM. (2002) Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol 282:227–241

    Google Scholar 

  17. Orrenius S, Nobel CS, van den Dobbelsteen DJ, et al. (1996) Dithiocarbamates and the redox regulation of cell death. Biochem Soc Trans 24:1032–1038

    PubMed  CAS  Google Scholar 

  18. Li C, Browder W, Kao RL. (1999) Early activation of transcription factor NF-κB during ischemia in perfused rat heart. Am J Physiol 276:543–552

    Google Scholar 

  19. Iseki A, Kambe F, Okumura K, et al. (2000) Pyrrolidine dithiocarbamate inhibits TNF-α-dependent activation of NF-kappaB by increasing intracellular copper level in human aortic smooth muscle cells. Biochem Biophys Res Commun 276:88–92

    Article  PubMed  CAS  Google Scholar 

  20. Ross SD, Kron IL, Gangemi JJ, et al. (2000) Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB. Am J Physiol Lung Cell Mol Physiol 297:528–536

    Google Scholar 

  21. Muller DN, Dechend R, Mervaala EMA, et al. (2000) NF-κB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 35:193–201

    PubMed  CAS  Google Scholar 

  22. Liu SF, Ye X, Malik AB. (1999) Inhibition of NF-κB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100:1330–1337

    PubMed  CAS  Google Scholar 

  23. Schreck R, Meier B, Mannel DN, et al. (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 175:1181–1194

    Article  PubMed  CAS  Google Scholar 

  24. Borrello S, Demple B. (1997) NF kappa B-independent transcriptional induction of the human manganese superoxide dismutase gene. Arch Biochem Biophys 348:289–294

    Article  PubMed  CAS  Google Scholar 

  25. Hartsfield CL, Alam J, Choi AMK. (1998) Transcriptional regulation of the heme oxygenase 1 gene by pyrrolidine dithiocarbamate. FASEB J 12:1675–1682

    PubMed  CAS  Google Scholar 

  26. Willis D, Moore AR, Frederick R, et al. (1996) Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2:87–90

    Article  PubMed  CAS  Google Scholar 

  27. Balla G, Jacob HS, Balla J, et al. (1992) Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 67:18128–18153

    Google Scholar 

  28. Yang L, Quan S, Abraham NG. (1999) Retrovirus-mediated HO gene transfer into endothelial cells protects against oxidant-induced injury. Am J Physiol 277:127–133

    Google Scholar 

  29. Otterbein L, Sylvester SL, Choi AM. (1995) Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1. Am J Respir Cell Mol Biol 13:595–601

    PubMed  CAS  Google Scholar 

  30. Kuzu MA, Tanik A, Kale IT, et al. (2000) Effect of ischemia/reperfusion as a systemic phenomenon on anastomotic healing in the left colon. World J Surg 24:990–994

    Article  PubMed  CAS  Google Scholar 

  31. Chatterjee PK, di Villa Bianca RD, Sivarajah A, et al. (2003) Pyrrolidine dithiocarbamate reduces renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney. Eur J Pharmacol 482:271–280

    Article  PubMed  CAS  Google Scholar 

  32. El Eter E, Hagar HH, Al-Tuwaijiri A, et al. (2005) Nuclear factor-kappa B inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats. Can J Physiol Pharmacol 83:483–492

    Article  PubMed  CAS  Google Scholar 

  33. Chen J, Wang G. (2004) Role of nuclear factor kappa B in intestine injury induced by hepatic ischemia reperfusion. J Huazhong Univ Sci Technol Med Sci 24:284–291

    Article  PubMed  CAS  Google Scholar 

  34. Turnage RH, Kadesky KM, Bartula L, et al. (1995) Intestinal reperfusion up-regulates inducible nitric oxide synthase activity within the lung. Surgery 118:288–293

    Article  PubMed  CAS  Google Scholar 

  35. Koksoy C, Kuzu MA, Kuzu I, et al. (2001) Role of tumour necrosis factor in lung injury caused by intestinal ischaemia-reperfusion. Br J Surg 88:464–468

    Article  PubMed  CAS  Google Scholar 

  36. Nishina K, Mikawa K, Takao Y, et al. (1997) ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits. Anesth Analg 84:1097–1103

    Article  PubMed  CAS  Google Scholar 

  37. Ohkawa H, Ohishi N, Yagi K. (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  PubMed  CAS  Google Scholar 

  38. Ellman GL. (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  39. Cortas NK, Wakid NW. (1990) Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 36:1440–1443

    PubMed  CAS  Google Scholar 

  40. Hill J, Lindsay TF, Ortiz F, et al. (1992) Soluble complement receptor type-1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat. J Immunol 149:1723–1728

    PubMed  CAS  Google Scholar 

  41. Tekin K, Aytekin OF, Ozden A, et al. (2002) Antithrombin III prevents deleterious effects of remote ischemia-reperfusion injury on healing of colonic anastomoses. Am J Surg 184:160–165

    Article  PubMed  CAS  Google Scholar 

  42. Mallick IH, Yang WX, Winslet MC, et al. (2005) Pyrrolidine dithiocarbamate reduces ischemia-reperfusion injury of the small intestine. World J Gastroenterol 11:7308–7313

    PubMed  CAS  Google Scholar 

  43. Radi R, Beckman JS, Bush KKM, et al. (1991) Peroxynitrite-induced lipid peroxidation: the cytoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288:481–487

    Article  PubMed  CAS  Google Scholar 

  44. Hidaka S, Funakoshi T, Shimada H, et al. (1995) Protective effect of N-benzyl-D-glucamine dithiocarbamate against renal toxicity in rats during repeated cis-diamminedichloroplatinum administrations. Renal Failure 17:539–550

    PubMed  CAS  Google Scholar 

  45. Kojima S, Sugimura Y, Ono H, et al. (1993) N-benzyl-D-glucamine dithiocarbamate and N-p-isopropylbenzyl-D-glucamine dithiocarbamate improve the protective effect of diethyldithiocarbamate against cadmium-induced testicular toxicity in rats. Biol Pharmaceut Bull 16:244–247

    CAS  Google Scholar 

  46. Turnage RH, Wright JK, Iglesias J, et al. (1998) Intestinal reperfusion-induced pulmonary edema is related to increased pulmonary inducible nitric oxide synthase activity. Surgery 124:457–463

    PubMed  CAS  Google Scholar 

  47. Cuzzocrea S, Chatterjee PK, Mazzon E, et al. (2002) Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation. Br J Pharm 135:496–510

    Article  CAS  Google Scholar 

  48. Okboy N, Yegen C, Aktan AO, et al. (1992) The effect of iloprost and NDGA in ischemia reperfusion injury in rat liver. Prostaglandins Leukot Essent Fatty Acids 47:291–295

    Article  PubMed  CAS  Google Scholar 

  49. Dosluoglu HH, Aktan AO, Yegen C, et al. (1993) The cytoprotective effects of verapamil and iloprost (ZK 36374) on ischemia/reperfusion injury of kidneys. Transpl Int 6:138–142

    Article  PubMed  CAS  Google Scholar 

  50. Otamiri T. (1989) Oxygen radicals, lipid peroxidation, and neutrophil infiltration after small-intestinal ischemia and reperfusion. Surgery 105:593–597

    PubMed  CAS  Google Scholar 

  51. Satriano J, Schlondorff D. (1994) Activation and attenuation of transcription factor NF-κB in mouse glomerular mesangial cells in response to tumor necrosis factor-α, immunoglobulin G, and adenosine 3′:5′-cyclic monophosphate. Evidence for involvement of reactive oxygen species. J Clin Invest 94:1629–1636

    Article  PubMed  CAS  Google Scholar 

  52. Schmidt KN, Traeckner EB, Meier B, et al. (1995) Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-κB. J Biol Chem 270:136–142

    Google Scholar 

  53. Liu SF, Ye X, Malik AB. (1997) In vivo inhibition of nuclear factor-κB activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J Immunol 159:3976–3983

    PubMed  CAS  Google Scholar 

  54. Jefferies H, Coster J, Khalil A, et al. (2003) Glutathione. Aust N Z J Surg 73:517–522

    Article  Google Scholar 

  55. Nakamura S, Sugiyama S, Fujioka D, et al. (2003) Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Circulation 108:1425–1427

    Article  PubMed  CAS  Google Scholar 

  56. Nathan C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J 6:3051–3062

    PubMed  CAS  Google Scholar 

  57. Kozlov AV, Staniek K, Nohl H. (1999) Nitrite reductase activity is a novel function of mammalian mitochondria. FEBS Lett 454:127–130

    Article  PubMed  CAS  Google Scholar 

  58. Griscavage JM, Wilk S, Ignarro LJ. (1995) Serine and cysteine proteinase inhibitors prevent nitric oxide production by activated macrophages by interfering with transcription of inducible NO synthase gene. Biochem Biophys Res Commun 215:721–729

    Article  PubMed  CAS  Google Scholar 

  59. Long SM, Laubach VE, Tribble CG, et al. (2003) Pyrrolidine dithiocarbamate reduces lung reperfusion injury. J Surg Res 112:12–18

    Article  PubMed  CAS  Google Scholar 

  60. Salvemini D, Wang ZQ, Wyatt P. (1996) Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 118:829–838

    PubMed  CAS  Google Scholar 

  61. Sherman MP, Aeberhard EE, Wong VZ, et al. (1993) Pyrrolidine dithiocarbamate inhibits induction of nitric oxide synthase activity in rat alveolar macrophages. Biochem Biophys Res Commun 199:1301–1308

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Surgery, Pamukkale University, School of Medicine, 20070, Denizli, Turkey

    Burhan Kabay, Zafer Teke, Faruk Onder Aytekin, Ergun Erdem & Akin Ozden

  2. Department of Biochemistry, Adnan Menderes University, School of Medicine, 09100, Aydin, Turkey

    Cigdem Yenisey

  3. Department of Pathology, Pamukkale University, School of Medicine, 20070, Denizli, Turkey

    Ferda Bir

  4. Department of Cardiovascular Surgery, Pamukkale University, School of Medicine, 20070, Denizli, Turkey

    Mustafa Sacar

Authors
  1. Burhan Kabay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zafer Teke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Faruk Onder Aytekin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cigdem Yenisey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ferda Bir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mustafa Sacar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ergun Erdem
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akin Ozden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zafer Teke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kabay, B., Teke, Z., Aytekin, F.O. et al. Pyrrolidine Dithiocarbamate Reduces Lung Injury Caused by Mesenteric Ischemia/Reperfusion in a Rat Model. World J Surg 31, 1707–1715 (2007). https://doi.org/10.1007/s00268-007-9112-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-007-9112-5

Keywords

Search

Navigation