Skip to main content
SpringerLink
Log in

Lung inflammation is induced by renal ischemia and reperfusion injury as part of the systemic inflammatory syndrome

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Introduction

Ischemia and reperfusion injury (IRI) are mainly caused by leukocyte activation, endothelial dysfunction and production of reactive oxygen species. Moreover, IRI can lead to a systemic response affecting distant organs, such as the lungs.

Aim

The objective was to study the pulmonary inflammatory systemic response after renal IRI.

Methods

Male C57Bl/6 mice were subjected to 45 min of bilateral renal ischemia, followed by 4, 6, 12, 24 and 48 h of reperfusion. Blood was collected to measure serum creatinine and cytokine concentrations. Bronchoalveolar lavage fluid (BALF) was collected to determine the number of cells and PGE2 concentration. Expressions of iNOS and COX-2 in lung were determined by Western blot. Gene analyses were quantified by real time PCR.

Results

Serum creatinine increased in the IRI group compared to sham mainly at 24 h after IRI (2.57 ± 0.16 vs. 0.43 ± 0.07, p < 0.01). The total number of cells in BAL fluid was higher in the IRI group in comparison with sham, 12 h (100 × 104 ± 15.63 vs. 18.1×104 ± 10.5, p < 0.05) 24 h (124 × 104 ± 8.94 vs. 23.2×104 ± 3.5, p < 0.05) and 48 h (79 × 104 ± 15.72 vs. 22.2 × 104 ± 4.2, p < 0.05), mainly by mononuclear cells and neutrophils. Pulmonary COX-2 and iNOS were up-regulated in the IRI group. TNF-α, IL-1β, MCP-1, KC and IL-6 mRNA expression were up-regulated in kidney and lungs 24 h after renal IRI. ICAM-1 mRNA was up-regulated in lungs 24 h after renal IRI. Serum TNF-α, IL-1β and MCP-1 and BALF PGE2 concentrations were increased 24 h after renal IRI.

Conclusion

Renal IRI induces an increase of cellular infiltration, up-regulation of COX-2, iNOS and ICAM-1, enhanced chemokine expression and a Th1 cytokine profile in lung demonstrating that the inflammatory response is indeed systemic, possibly leading to an amplification of renal injury.

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. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. 1996;334:1448.

    Article  CAS  PubMed  Google Scholar 

  2. Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 2004;66:480.

    Article  CAS  PubMed  Google Scholar 

  3. Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int. 2004;66:486.

    Article  PubMed  Google Scholar 

  4. Thornton MA, Winn R, Alpers CE, Zager RA. An evaluation of the neutrophil as a mediator of in vivo renal ischemic-reperfusion injury. Am J Pathol. 1989;135:509.

    CAS  PubMed  Google Scholar 

  5. Paller MS. Effect of neutrophil depletion on ischemic renal injury in the rat. J Lab Clin Med. 1989;113:379.

    CAS  PubMed  Google Scholar 

  6. Rabb H, Daniels F, O’Donnell M, Haq M, Saba SR, Keane W, Tang WW. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol. 2000;279:F525.

    CAS  PubMed  Google Scholar 

  7. Ysebaert DK, De Greef KE, De Beuf A, Van Rompay AR, Vercauteren S, Persy VP, De Broe ME. T cells as mediators in renal ischemia/reperfusion injury. Kidney Int. 2004;66:491.

    Article  CAS  PubMed  Google Scholar 

  8. Yokota N, Burne-Taney M, Racusen L, Rabb H. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2003;285:F319.

    CAS  PubMed  Google Scholar 

  9. Marques VP, Goncalves GM, Feitoza CQ, Cenedeze MA, Fernandes Bertocchi AP, Damiao MJ, Pinheiro HS, Antunes Teixeira VP, dos Reis MA, Pacheco-Silva A, Saraiva Camara NO. Influence of TH1/TH2 switched immune response on renal ischemia-reperfusion injury. Nephron Exp Nephrol. 2006;104:e48.

    Article  CAS  PubMed  Google Scholar 

  10. Daha MR, van Kooten C. Is the proximal tubular cell a proinflammatory cell? Nephrol Dial Transplant. 2000;15(Suppl 6):41.

    Article  PubMed  Google Scholar 

  11. Kapper S, Beck G, Riedel S, Prem K, Haak M, van der Woude FJ, Yard BA. Modulation of chemokine production and expression of adhesion molecules in renal tubular epithelial and endothelial cells by catecholamines. Transplantation. 2002;74:253.

    Article  CAS  PubMed  Google Scholar 

  12. Safirstein R, Megyesi J, Saggi SJ, Price PM, Poon M, Rollins BJ, Taubman MB. Expression of cytokine-like genes JE and KC is increased during renal ischemia. Am J Physiol. 1991;261:F1095.

    CAS  PubMed  Google Scholar 

  13. Segerer S, Nelson PJ, Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol. 2000;11:152.

    CAS  PubMed  Google Scholar 

  14. Kuzu MA, Koksoy C, Kuzu I, Gurhan I, Ergun H, Demirpence E. Role of integrins and intracellular adhesion molecule-1 in lung injury after intestinal ischemia-reperfusion. Am J Surg. 2002;183:70.

    Article  CAS  PubMed  Google Scholar 

  15. Schmeling DJ, Caty MG, Oldham KT, Guice KS, Hinshaw DB. Evidence for neutrophil-related acute lung injury after intestinal ischemia-reperfusion. Surgery. 1989;106:195.

    CAS  PubMed  Google Scholar 

  16. Foulds S, Mireskandari M, Kalu P, Jackson W, Cheshire NJ, Mansfield AO, Schachter M. Visceral ischemia and neutrophil activation in sepsis and organ dysfunction. J Surg Res. 1998;75:170.

    Article  CAS  PubMed  Google Scholar 

  17. Desai SR. Acute respiratory distress syndrome: imaging of the injured lung. Clin Radiol. 2002;57:8.

    Article  PubMed  Google Scholar 

  18. Zhou JL, Jin GH, Yi YL, Zhang JL, Huang XL. Role of nitric oxide and peroxynitrite anion in lung injury induced by intestinal ischemia-reperfusion in rats. World J Gastroenterol. 2003;9:1318.

    CAS  PubMed  Google Scholar 

  19. Kelly KJ, Williams W W Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci USA. 1994;91:812.

    Article  CAS  PubMed  Google Scholar 

  20. Pradelles P, Grassi J, Maclouf J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal Chem. 1985;57:1170.

    Article  CAS  PubMed  Google Scholar 

  21. Tilney NL, Guttmann RD. Effects of initial ischemia/reperfusion injury on the transplanted kidney. Transplantation. 1997;64:945.

    Article  CAS  PubMed  Google Scholar 

  22. Humes HD. Acute renal failure: prevailing challenges and prospects for the future. Kidney Int Suppl. 1995;50:S26.

    CAS  PubMed  Google Scholar 

  23. Deng J, Hu X, Yuen PS, Star RA. Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med. 2004;169:749.

    Article  PubMed  Google Scholar 

  24. Kelly KJ. Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol. 2003;14:1549.

    Article  CAS  PubMed  Google Scholar 

  25. Koksoy C, Kuzu MA, Kuzu I, Ergun H, Gurhan I. Role of tumour necrosis factor in lung injury caused by intestinal ischaemia-reperfusion. Br J Surg. 2001;88:464.

    Article  CAS  PubMed  Google Scholar 

  26. Alves-Filho JC, Freitas A, Souto FO, Spiller F, Paula-Neto H, Silva JS, Gazzinelli RT, Teixeira MM, Ferreira SH, Cunha FQ. Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis. Proc Natl Acad Sci USA. 2009;106:4018.

    Article  CAS  PubMed  Google Scholar 

  27. Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol Suppl. 1997;49:15.

    CAS  PubMed  Google Scholar 

  28. Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001;2:907.

    Article  CAS  PubMed  Google Scholar 

  29. Feitoza CQ, Camara NO, Pinheiro HS, Goncalves GM, Cenedeze MA, Pacheco-Silva A, Santos OF. Cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury. Int Immunopharmacol. 2005;5:79.

    Article  CAS  PubMed  Google Scholar 

  30. Cavriani G, Oliveira-Filho RM, Trezena AG, da Silva ZL, Domingos HV, de Arruda MJ, Jancar S, Tavares de Lima W. Lung microvascular permeability and neutrophil recruitment are differently regulated by nitric oxide in a rat model of intestinal ischemia-reperfusion. Eur J Pharmacol. 2004;494:241.

    Article  CAS  PubMed  Google Scholar 

  31. Turnage RH, Wright JK, Iglesias J, LaNoue JL, Nguyen H, Kim L, Myers S. Intestinal reperfusion-induced pulmonary edema is related to increased pulmonary inducible nitric oxide synthase activity. Surgery. 1998;124:457.

    CAS  PubMed  Google Scholar 

  32. Turnage RH, Kadesky KM, Bartula L, Myers SI. Intestinal reperfusion up-regulates inducible nitric oxide synthase activity within the lung. Surgery. 1995;118:288.

    Article  CAS  PubMed  Google Scholar 

  33. Matsuyama M, Yoshimura R, Hase T, Kawahito Y, Sano H, Nakatani T. Study of cyclooxygenase-2 in renal ischemia-reperfusion injury. Transplant Proc. 2005;37:370.

    Article  CAS  PubMed  Google Scholar 

  34. Kosaka H, Yoneyama H, Zhang L, Fujii S, Yamamoto A, Igarashi J. Induction of LOX-1 and iNOS expressions by ischemia-reperfusion of rat kidney and the opposing effect of l-arginine. FASEB J. 2003;17:636.

    Article  CAS  PubMed  Google Scholar 

  35. Mehta S. The effects of nitric oxide in acute lung injury. Vascul Pharmacol. 2005;43:390.

    Article  CAS  PubMed  Google Scholar 

  36. Farley KS, Wang LF, Law C, Mehta S. Alveolar macrophage inducible nitric oxide synthase-dependent pulmonary microvascular endothelial cell septic barrier dysfunction. Microvasc Res. 2008;76:208.

    Article  CAS  PubMed  Google Scholar 

  37. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol Rev. 1998;50:515.

    CAS  PubMed  Google Scholar 

  38. Gauvreau GM, Watson RM, O’Byrne PM. Protective effects of inhaled PGE2 on allergen-induced airway responses and airway inflammation. Am J Respir Crit Care Med. 1999;159:31.

    CAS  PubMed  Google Scholar 

  39. Sestini P, Armetti L, Gambaro G, Pieroni MG, Refini RM, Sala A, Vaghi A, Folco GC, Bianco S, Robuschi M. Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma. Am J Respir Crit Care Med. 1996;153:572.

    CAS  PubMed  Google Scholar 

  40. Pavord ID, Ward R, Woltmann G, Wardlaw AJ, Sheller JR, Dworski R. Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med. 1999;160:1905.

    CAS  PubMed  Google Scholar 

  41. Peacock CD, Misso NL, Watkins DN, Thompson PJ. PGE 2 and dibutyryl cyclic adenosine monophosphate prolong eosinophil survival in vitro. J Allergy Clin Immunol. 1999;104:153.

    Article  CAS  PubMed  Google Scholar 

  42. Profita M, Sala A, Bonanno A, Riccobono L, Siena L, Melis MR, Di Giorgi R, Mirabella F, Gjomarkaj M, Bonsignore G, Vignola AM. Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia. J Allergy Clin Immunol. 2003;112:709.

    Article  CAS  PubMed  Google Scholar 

  43. Landgraf RG, Nossi DF, Sirois P, Jancar S. Prostaglandins, leukotrienes and PAF selectively modulate lymphocyte subset and eosinophil infiltration into the airways in a murine model of asthma. Prostaglandins Leukot Essent Fatty Acids. 2007;77:163.

    Article  CAS  PubMed  Google Scholar 

  44. Kielar ML, John R, Bennett M, Richardson JA, Shelton JM, Chen L, Jeyarajah DR, Zhou XJ, Zhou H, Chiquett B, Nagami GT, Lu CY. Maladaptive role of IL-6 in ischemic acute renal failure. J Am Soc Nephrol. 2005;16:3315.

    Article  CAS  PubMed  Google Scholar 

  45. Cavriani G, Domingos HV, Soares AL, Trezena AG, Ligeiro-Oliveira AP, Oliveira-Filho RM, Sudo-Hayashi LS, Tavares de Lima W. Lymphatic system as a path underlying the spread of lung and gut injury after intestinal ischemia/reperfusion in rats. Shock. 2005;23:330.

    Article  PubMed  Google Scholar 

  46. Cavriani G, Domingos HV, Oliveira-Filho RM, Sudo-Hayashi LS, Vargaftig BB, de Lima WT. Lymphatic thoracic duct ligation modulates the serum levels of IL-1beta and IL-10 after intestinal ischemia/reperfusion in rats with the involvement of tumor necrosis factor alpha and nitric oxide. Shock. 2007;27:209.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by Conselho Nacional de Desenvolvimento Científiproco e Tecnológico (CNPq) and FAPESP (06/06236-2, 06/03982-5, 07/07139-3).

Conflict of interest statement

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, Av. Prof. Lineu Prestes, 1730, São Paulo, SP, 05508-900, Brazil

    G. Campanholle, G. M. Gonçalves, V. N. Paiva & Niels Olsen Saraiva Camara

  2. Department of Biological Sciences, Federal University of São Paulo, Campus Diadema, Diadema, Brazil

    R. G. Landgraf

  3. Laboratory of Immunopharmacology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil

    J. O. Martins & S. Jancar

  4. Laboratory of Clinical and Experimental Immunology, Division of Nephrology, UNIFESP, São Paulo, Brazil

    P. H. M. Wang, R. M. M. Monteiro, R. C. Silva, M. A. Cenedeze, A. Pacheco-Silva & Niels Olsen Saraiva Camara

  5. Department of Pathology, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil

    V. P. A. Teixeira & M. A. Reis

Authors
  1. G. Campanholle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. G. Landgraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. M. Gonçalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. N. Paiva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. O. Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. H. M. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. M. M. Monteiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. C. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. A. Cenedeze
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. V. P. A. Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. A. Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A. Pacheco-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S. Jancar
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Niels Olsen Saraiva Camara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niels Olsen Saraiva Camara.

Additional information

Responsible Editor: M. Katori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campanholle, G., Landgraf, R.G., Gonçalves, G.M. et al. Lung inflammation is induced by renal ischemia and reperfusion injury as part of the systemic inflammatory syndrome. Inflamm. Res. 59, 861–869 (2010). https://doi.org/10.1007/s00011-010-0198-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-010-0198-0

Keywords

Search

Navigation