Skip to main content
Log in

Angiotensin Receptors as Sensitive Markers of Acute Bronchiole Injury After Lung Transplantation

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Background

Although lung transplantation is the only means of survival for patients with end-stage pulmonary disease, outcomes from this intervention are inferior to other solid organ transplants. The reason for the poor outcomes may be linked to an early reaction, such as primary graft dysfunction, and associated with marked inflammatory response, bronchiole injury, and later fibrotic responses. Mediators regulating these effects include angiotensin II and matrix metalloproteinases (MMPs).

Methods

We investigated changes to these mediators over the course of cardiopulmonary bypass (CPB) and up to 72 h after lung transplantation, using immunohistochemistry, Western blot, and ELISA techniques.

Results

We found 4- and 16-fold increases in plasma angiotensin II and MMP-9, respectively, from pre-CPB to post-CPB. MMP-9 levels remained elevated 1 h after transplantation. MMP-2 levels were elevated 6–24 h after lung transplantation. Type 2 angiotensin II receptor (ATR2) expression was 3.5-fold higher in bronchoalveolar cells 1–6 h after transplantation than in controls.

Conclusions

The study suggests that the combination of cardiopulmonary bypass and lung transplantation is associated with early changes in the angiotensin II receptor system and in MMPs, and that altered expression of these mediators may be a useful marker to examine pathological changes that occur in lungs during transplant surgery.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Diamond JM, Christie JD (2010) The contribution of airway and lung tissue ischemia to primary graft dysfunction. Curr Opin Organ Transplant 15(5):552–557

    Article  PubMed  Google Scholar 

  2. Christie JD et al (2009) The registry of the international society for heart and lung transplantation: twenty-sixth official adult lung and heart-lung transplantation report-2009. J Heart Lung Transplant 28(10):1031–1049

    Article  PubMed  Google Scholar 

  3. Taylor DO et al (2009) Registry of the international society for heart and lung transplantation: twenty-sixth official adult heart transplant report-2009. J Heart Lung Transplant 28(10):1007–1022

    Article  PubMed  Google Scholar 

  4. Mailey B et al (2009) A disease-based comparison of liver transplantation outcomes. Am Surg 75(10):901–908

    PubMed  Google Scholar 

  5. Linfert D, Chowdhry T, Rabb H (2009) Lymphocytes and ischemia-reperfusion injury. Transplant Rev (Orlando) 23(1):1–10

    Article  Google Scholar 

  6. Raichlin E et al (2009) Acute cellular rejection and the subsequent development of allograft vasculopathy after cardiac transplantation. J Heart Lung Transplant 28(4):320–327

    Article  PubMed  Google Scholar 

  7. Fischer S et al (2000) Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation. Ann Surg 231(3):424–431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. de Perrot M et al (2003) Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 167(4):490–511

    Article  PubMed  Google Scholar 

  9. Liu L et al (2009) Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat. Arch Biochem Biophys 481(1):131–136

    Article  CAS  PubMed  Google Scholar 

  10. Bullock GR et al (2001) Distribution of type-1 and type-2 angiotensin receptors in the normal human lung and in lungs from patients with chronic obstructive pulmonary disease. Histochem Cell Biol 115(2):117–124

    Article  CAS  PubMed  Google Scholar 

  11. Antus B et al (2006) Effects of blockade of the renin-angiotensin and endothelin systems on experimental bronchiolitis obliterans. J Heart Lung Transplant 25(11):1324–1329

    Article  PubMed  Google Scholar 

  12. Chen FP et al (2007) Early lung injury contributes to lung fibrosis via AT1 receptor in rats. Acta Pharmacol Sin 28(2):227–237

    Article  PubMed  Google Scholar 

  13. Ferri C et al (1999) Angiotensin II increases the release of endothelin-1 from human cultured endothelial cells but does not regulate its circulating levels. Clin Sci (Lond) 96(3):261–270

    CAS  Google Scholar 

  14. Adams J et al (2002) Combination treatment with an ET(A)-receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant nephropathy in a ‘Fisher-to-Lewis’ rat model. Nephrol Dial Transplant 17(5):780–787

    Article  CAS  PubMed  Google Scholar 

  15. Soccal PM et al (2004) Matrix metalloproteinase inhibition decreases ischemia-reperfusion injury after lung transplantation. Am J Transplant 4(1):41–50

    Article  CAS  PubMed  Google Scholar 

  16. Chua CC, Hamdy RC, Chua BH (1996) Angiotensin II induces TIMP-1 production in rat heart endothelial cells. Biochim Biophys Acta 1311(3):175–180

    Article  PubMed  Google Scholar 

  17. Yoshiji H et al (2003) Angiotensin-II induces the tissue inhibitor of metalloproteinases-1 through the protein kinase-C signaling pathway in rat liver fibrosis development. Hepatol Res 27(1):51–56

    Article  CAS  PubMed  Google Scholar 

  18. Kurisu S et al (2003) Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension 41(1):99–107

    Article  CAS  PubMed  Google Scholar 

  19. Waseda Y et al (2008) Angiotensin II type 2 receptor antagonist reduces bleomycin-induced pulmonary fibrosis in mice. Respir Res 9:43

    Article  PubMed Central  PubMed  Google Scholar 

  20. Konigshoff M et al (2007) The angiotensin II receptor 2 is expressed and mediates angiotensin II signaling in lung fibrosis. Am J Respir Cell Mol Biol 37(6):640–650

    Article  PubMed  Google Scholar 

  21. Christie JD et al (2005) Report of the ishlt working group on primary lung graft dysfunction part ii: definition. a consensus statement of the international society for heart and lung transplantation. J Heart Lung Transplant 24(10):1454–1459

    Article  PubMed  Google Scholar 

  22. van der Kaaij NP et al (2008) Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study. Respir Res 9:28

    Article  PubMed Central  PubMed  Google Scholar 

  23. Skjot-Arkil H et al (2012) Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation. BMC Pulm Med 12:34

    Article  PubMed Central  PubMed  Google Scholar 

  24. Keck T et al (2002) Matrix metalloproteinase-9 promotes neutrophil migration and alveolar capillary leakage in pancreatitis-associated lung injury in the rat. Gastroenterology 122(1):188–201

    Article  CAS  PubMed  Google Scholar 

  25. Shimoyama T et al (2006) Matrix metalloproteinase inhibitor (ONO-4817) attenuates ischemia-reperfusion injury in rat lung. Med Sci Monit 12(2):BR51–BR56

    CAS  PubMed  Google Scholar 

  26. Jing T et al (2009) Conditional expression of type 2 angiotensin II receptor in rat vascular smooth muscle cells reveals the interplay of the angiotensin system in matrix metalloproteinase 2 expression and vascular remodeling. Int J Mol Med 24(1):103–110

    CAS  PubMed  Google Scholar 

  27. Boulday G et al (2004) Exogenous tissue inhibitor of metalloproteinase-1 promotes endothelial cell survival through activation of the phosphatidylinositol 3-kinase/Akt pathway. Ann N Y Acad Sci 1030:28–36

    Article  CAS  PubMed  Google Scholar 

  28. Chen P et al (2008) Tissue inhibitor of metalloproteinase-1 moderates airway re-epithelialization by regulating matrilysin activity. Am J Pathol 172(5):1256–1270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Hubner RH et al (2005) Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation. Eur Respir J 25(3):494–501

    Article  CAS  PubMed  Google Scholar 

  30. Kastelijn EA et al (2013) YKL-40 and matrix metalloproteinases as potential biomarkers of inflammation and fibrosis in the development of bronchiolitis obliterans syndrome. Sarcoidosis Vasc Diffus Lung Dis 30(1):28–35

    CAS  Google Scholar 

  31. Taghavi S et al (2005) Broncho-alveolar lavage matrix metalloproteases as a sensitive measure of bronchiolitis obliterans. Am J Transplant 5(6):1548–1552

    Article  PubMed  Google Scholar 

  32. Kurihara T et al (2012) Neutrophil-derived matrix metalloproteinase 9 triggers acute aortic dissection. Circulation 126(25):3070–3080

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the surgeons and lung transplant physicians at the Prince Charles Hospital: Dr. Bruce Thomson, Dr. Graeme Hart, Dr. Peter Hopkins, Dr. Daniel Chambers, and Dr. Fiona Kermeen who performed the surgery and bronchoscopies and provided the samples for this study. The authors also thank Dr. Edwina Duhig and Mr. David Butler for providing the facilities to process histology samples in the Department of Anatomical Pathology at the Prince Charles Hospital, Brisbane, Australia. Professor Fraser acknowledges the support of the Office of Health and Medical Research Fellowship.

Conflict of interest

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maria Nataatmadja.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nataatmadja, M., Passmore, M., Russell, F.D. et al. Angiotensin Receptors as Sensitive Markers of Acute Bronchiole Injury After Lung Transplantation. Lung 192, 563–569 (2014). https://doi.org/10.1007/s00408-014-9588-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-014-9588-3

Keywords

Navigation