Skip to main content

Advertisement

Log in

A neutrophil elastase inhibitor improves lung function during ex vivo lung perfusion

  • Original Article
  • Published:
General Thoracic and Cardiovascular Surgery Aims and scope Submit manuscript

Abstract

Objective

Ex vivo lung perfusion (EVLP) has been used not only for graft evaluation but also for graft reconditioning prior to lung transplantation. Inflammatory cells such as neutrophils may cause additional graft injury during EVLP. Neutrophil elastase inhibitors protect lungs against neutrophil-induced lung injury, such as acute respiratory distress syndrome. This study aimed to investigate the effect of a neutrophil elastase inhibitor during EVLP.

Methods

EVLP was performed for 4 h in bilateral pig lungs that had previously experienced warm ischemia for 2 h with or without a neutrophil elastase inhibitor (treated and control groups, respectively; n = 6). Following EVLP, the left lung was transplanted into a recipient pig, and this was followed by observation for 4 h. Pulmonary functions were observed both during EVLP and during the early post-transplant stage.

Results

During EVLP, decreases in neutrophil elastase levels (P < 0.001), the wet–dry weight ratio (P < 0.05), and pulmonary vascular resistance (P < 0.01) and increases in the PaO2/FiO2 ratio (P < 0.01) and pulmonary compliance (P < 0.05) were observed in the treated group. After transplantation, decreased pulmonary vascular resistance (P < 0.05) was observed in the treated group.

Conclusions

A neutrophil elastase inhibitor attenuated the inflammatory response during EVLP and may decrease the incidence of lung reperfusion injury after transplantation.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Oto T, Okada Y, Bando T, Minami M, Shiraishi T, Nagayasu T, et al. Registry of the Japanese Society of Lung and Heart-Lung Transplantation: the official Japanese lung transplantation report 2012. Gen Thorac Cardiovasc Surg. 2013;61:208–11.

    Article  PubMed  Google Scholar 

  2. Kakishita T, Oto T, Hori S, Miyoshi K, Otani S, Yamamoto S, et al. Suppression of inflammatory cytokines during ex vivo lung perfusion with an adsorbent membrane. Ann Thorac Surg. 2010;89:1773–9.

    Article  PubMed  Google Scholar 

  3. Otani S, Oto T, Kakishita T, Miyoshi K, Hori S, Yamane M, et al. Early effects of the ex vivo evaluation system on graft function after swine lung transplantation. Eur J Cardiothorac Surg. 2011;40:956–61.

    PubMed  Google Scholar 

  4. Sadaria MR, Smith PD, Fullerton DA, Justison GA, Lee JH, Puskas F, et al. Cytokine expression profile in human lungs undergoing normothermic ex vivo lung perfusion. Ann Thorac Surg. 2011;92:478–84.

    Article  PubMed  Google Scholar 

  5. Barletta KE, Cagnina RE, Wallace KL, Ramos SI, Mehrad B, Linden J. Leukocyte compartments in the mouse lung: distinguishing between marginated, interstitial, and alveolar cells in response to injury. J Immunol Methods. 2012;375:100–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Zeiher BG, Matsuoka S, Kawabata K, Repine JE. Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics. Crit Care Med. 2002;30:S281–7.

    Article  CAS  PubMed  Google Scholar 

  7. Hayakawa M, Katabami K, Wada T, Minami Y, Sugano M, Shimojima H, et al. Sivelestat (selective neutrophil elastase inhibitor) improves the mortality rate of sepsis associated with both acute respiratory distress syndrome and disseminated intravascular coagulation patients. Shock. 2010;33:14–8.

    Article  CAS  PubMed  Google Scholar 

  8. Fujino N, Kubo H, Suzuki T, He M, Suzuki T, Yamada M, et al. Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice. Exp Lung Res. 2012;38:28–36.

    Article  CAS  PubMed  Google Scholar 

  9. Hagio T, Nakao S, Matsuoka H, Matsumoto S, Kawabata K, Ohno H, et al. Inhibition of neutrophil elastase activity attenuates complement-mediated lung injury in the hamster. Eur J Pharmacol. 2001;426:131–8.

    Article  CAS  PubMed  Google Scholar 

  10. Steen S, Sjoberg T, Pierre L, Liao Q, Eriksson L, Algotsson L, et al. Transplantation of lungs from a non-heart-beating donor. Lancet. 2001;357:825–9.

    Article  CAS  PubMed  Google Scholar 

  11. Steen S, Liao Q, Wierup PN, Bolys R, Pierre L, Sjoberg T. Transplantation of lungs from non–heart-beating donors after functional assessment ex vivo. Ann Thorac Surg. 2003;76:244–52.

    Article  PubMed  Google Scholar 

  12. Cypel M, Yeung JC, Keshavjee S. Novel approaches to expanding the lung donor pool: donation after cardiac death and ex vivo conditioning. Clin Chest Med. 2011;32:233–44.

    Article  PubMed  Google Scholar 

  13. Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364:1431–40.

    Article  CAS  PubMed  Google Scholar 

  14. Erasmus ME, Fernhout MH, Elstrodt JM, Rakhorst G. Normothermic ex vivo lung perfusion of non-heart-beating donor lungs in pigs: from pretransplant function analysis towards a 6-h machine preservation. Transpl Int. 2006;19:589–93.

    Article  PubMed  Google Scholar 

  15. Cypel M, Yeung JC, Hirayama S, Rubacha M, Fischer S, Anraku M, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008;27:1319–25.

    Article  PubMed  Google Scholar 

  16. Aoki T, Tsuchida M, Takekubo M, Saito M, Sato K, Hayashi J. Neutrophil elastase inhibitor ameliorates reperfusion injury in a canine model of lung transplantation. Eur Surg Res. 2005;37:274–80.

    Article  CAS  PubMed  Google Scholar 

  17. Eppinger MJ, Deeb GM, Bolling SF, Ward PA. Mediators of ischemia-reperfusion injury of rat lung. Am J Pathol. 1997;150:1773–84.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Fiser SM, Tribble CG, Long SM, Kaza AK, Cope JT, Laubach VE, et al. Lung transplant reperfusion injury involves pulmonary macrophages and circulating leukocytes in a biphasic response. J Thorac Cardiovasc Surg. 2001;121:1069–75.

    Article  CAS  PubMed  Google Scholar 

  19. Lee WL, Downey GP. Leukocyte elastase: physiological functions and role in acute lung injury. Am J Respir Crit Care Med. 2001;164:896–904.

    Article  CAS  PubMed  Google Scholar 

  20. Kawabata K, Hagio T, Matsuoka S. The role of neutrophil elastase in acute lung injury. Eur J Pharmacol. 2002;451:1–10.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully thank Mr. Tetsuo Kawakami for his technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masaaki Harada.

Ethics declarations

Conflict of interest

Masaaki Harada and other co-authors have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Harada, M., Oto, T., Otani, S. et al. A neutrophil elastase inhibitor improves lung function during ex vivo lung perfusion. Gen Thorac Cardiovasc Surg 63, 645–651 (2015). https://doi.org/10.1007/s11748-015-0585-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11748-015-0585-0

Keywords

Navigation