Experimental study on the method of establishing a pig left lung orthotopic transplantation model_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHAO Heng ¹ , FENG Jinteng ¹ , GAO Shan ¹ , ZHAO Rui ¹ , WANG Hongyi ¹ , SUN Ye ² , LI Yixing ¹ , BAI Haotian ¹ , TAO Runyi ¹ , HE Bin ¹ , WANG Zhiyu ¹ , ZHANG Yanpeng ¹ , SUN Borui ² , LI Shuo ¹ ,  ZHANG Guangjian ¹

1. Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China;
2. Department of Anaesthesia and Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China;

Corresponding author：

ZHANG Guangjian, Email: michael8039@xjtu.edu.cn

Keywords：

Lung transplantation; pig; donor lung procurement; transplantation protocol

DOI：

10.7507/1007-4848.202408044

Video：

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Objective To explore the method for establishing a pig left lung orthotopic transplantation model. Methods Detailed surgical procedures, including animal anesthesia, tracheal intubation, donor lung retrieval, and recipient transplantation, were thoroughly reported. By examining the histological morphology and blood gas analysis of the transplanted lung 2 hours after reperfusion, the histological changes and function of the transplanted lung were assessed. Results This method was applied to four male Yorkshire pigs with an average weight of (40.0 ±2.5) kg for left lung in situ transplantation, effectively simulating conditions relevant to human lung transplantation. Two hours after the transplantation, arterial blood gas analysis showed PaO₂ was 155.4-178.6 mm Hg, PaCO₂ was 53.1-62.4 mm Hg, and the oxygenation index was 310.8-357.2 mm Hg. Hematoxylin and eosin staining indicated a low degree of pulmonary edema and minimal cellular infiltration. Conclusion The pig left lung orthotopic transplantation model possesses strong operability and stability. Researchers can replicate this model according to the described methods and further conduct basic research and explore clinical translational applications.

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5.	Chacon-Alberty L, Fernandez R, Jindra P, et al. Primary graft dysfunction in lung transplantation: A review of mechanisms and future applications. Transplantation, 2023, 107(8): 1687-1697.
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8.	Chiu S, Bharat A. Role of monocytes and macrophages in regulating immune response following lung transplantation. Curr Opin Organ Transplant, 2016, 21(3): 239-245.
9.	Bharat A, Kuo E, Steward N, et al. Immunological link between primary graft dysfunction and chronic lung allograft rejection. Ann Thorac Surg, 2008, 86(1): 189-195.
10.	Bharat A, Narayanan K, Street T, et al. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation, 2007, 83(2): 150-158.
11.	Li W, Terada Y, Tyurina YY, et al. Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury. Proc Natl Acad Sci U S A, 2022, 119(10): e2111537119.
12.	Zhao J, Li J, Wei D, et al. Liproxstatin-1 alleviates lung transplantation-induced cold ischemia-reperfusion injury by inhibiting ferroptosis. Transplantation, 2023, 107(10): 2190-2202.
13.	Akimova T, Zhang T, Christensen LM, et al. Obesity-related IL-18 impairs T-regulatory cell function and promotes lung ischemia-reperfusion injury. Am J Respir Crit Care Med, 2021, 204(9): 1060-1074.
14.	Calabrese DR, Aminian E, Mallavia B, et al. Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury. J Clin Invest, 2021, 131(3): e137047.
15.	Kaes J, Pollenus E, Hooft C, et al. The immunopathology of pulmonary rejection after murine lung transplantation. Cells, 2024, 13(3): 241.
16.	Nayak DK, Zhou F, Xu M, et al. Zbtb7a induction in alveolar macrophages is implicated in anti-HLA-mediated lung allograft rejection. Sci Transl Med, 2017, 9(398): eaal1243.
17.	Tian D, Shiiya H, Sato M, et al. Rat lung transplantation model: Modifications of the cuff technique. Ann Transl Med, 2020, 8(6): 407.
18.	Gracon AS, Wilkes DS. Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance. Hum Immunol, 2014, 75(8): 887-894.
19.	Martins MA, Watkins DI. What is the predictive value of animal models for vaccine efficacy in humans? Rigorous simian immunodeficiency virus vaccine trials can be instructive. Cold Spring Harb Perspect Biol, 2018, 10(4): a029504.
20.	Whiteside GT, Adedoyin A, Leventhal L. Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology, 2008, 54(5): 767-775.
21.	Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: Advantages and disadvantages. Pharmacol Ther, 2014, 141(3): 235-249.
22.	Ghaidan H, Stenlo M, Niroomand A, et al. Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation. Nat Commun, 2022, 13(1): 4173.
23.	Ali A, Nykanen AI, Beroncal E, et al. Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy. EBioMedicine, 2022, 83: 104210.
24.	Cypel M, Yeung JC, Hirayama S, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant, 2008, 27(12): 1319-1325.
25.	Gade J, Nørgaard MA, Andersen CB, et al. The porcine bronchial artery. Anastomoses with oesophageal, coronary and intercostal arteries. J Anat, 1999, 195 ( Pt 1): 65-73.
26.	Hurst DJ, Padilla LA, Cooper DKC, et al. Factors influencing attitudes toward xenotransplantation clinical trials: A report of focus group studies. Xenotransplantation, 2021, 28(4): e12684.
27.	Sundaresan S, Trachiotis GD, Aoe M, et al. Donor lung procurement: Assessment and operative technique. Ann Thorac Surg, 1993, 56(6): 1409-1413.
28.	Veith F J, Sinha S B, Graves J S, et al. Ischemic tolerance of the lung. The effect of ventilation and inflation. J Thorac Cardiovasc Surg, 1971, 61(5): 804-810.
29.	Date H, Matsumura A, Manchester J K, et al. Changes in alveolar oxygen and carbon dioxide concentration and oxygen consumption during lung preservation. The maintenance of aerobic metabolism during lung preservation. J Thorac Cardiovasc Surg, 1993, 105(3): 492-501.
30.	Mariscal A, Caldarone L, Tikkanen J, et al. Pig lung transplant survival model. Nat Protoc, 2018, 13(8): 1814-1828.
31.	冯冬杰, 许林, 蒋峰, 等. 猪自体肺移植模型的建立. 南京医科大学学报(自然科学版), 2010, 30(1): 46-49,76.Feng DJ, Xu L, Jiang F, et al. Establishment of a swine model of lung auto-transplantation. J Nanjing Med Univ (Nat Sci), 2010, 30(1): 46-49,76.
32.	Ali A, Wang A, Ribeiro RVP, et al. Static lung storage at 10℃ maintains mitochondrial health and preserves donor organ function. Sci Transl Med, 2021, 13(611): eabf7601.

1. van der Mark SC, Hoek RAS, Hellemons ME. Developments in lung transplantation over the past decade. Eur Respir Rev, 2020, 29(157): 190132.
2. Wadowski B, Chang SH, Carillo J, et al. Assessing donor organ quality according to recipient characteristics in lung transplantation. J Thorac Cardiovasc Surg, 2023, 165(2): 532-543.
3. Heiden BT, Yang Z, Bai YZ, et al. Development and validation of the lung donor (LUNDON) acceptability score for pulmonary transplantation. Am J Transplant, 2023, 23(4): 540-548.
4. Raskin J, Vanstapel A, Verbeken EK, et al. Mortality after lung transplantation: A single-centre cohort analysis. Transpl Int, 2020, 33(2): 130-141.
5. Chacon-Alberty L, Fernandez R, Jindra P, et al. Primary graft dysfunction in lung transplantation: A review of mechanisms and future applications. Transplantation, 2023, 107(8): 1687-1697.
6. Diamond JM, Lee JC, Kawut SM, et al. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med, 2013, 187(5): 527-534.
7. Snell GI, Yusen RD, Weill D, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, partⅠ: Definition and grading—A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant, 2017, 36(10): 1097-1103.
8. Chiu S, Bharat A. Role of monocytes and macrophages in regulating immune response following lung transplantation. Curr Opin Organ Transplant, 2016, 21(3): 239-245.
9. Bharat A, Kuo E, Steward N, et al. Immunological link between primary graft dysfunction and chronic lung allograft rejection. Ann Thorac Surg, 2008, 86(1): 189-195.
10. Bharat A, Narayanan K, Street T, et al. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation, 2007, 83(2): 150-158.
11. Li W, Terada Y, Tyurina YY, et al. Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury. Proc Natl Acad Sci U S A, 2022, 119(10): e2111537119.
12. Zhao J, Li J, Wei D, et al. Liproxstatin-1 alleviates lung transplantation-induced cold ischemia-reperfusion injury by inhibiting ferroptosis. Transplantation, 2023, 107(10): 2190-2202.
13. Akimova T, Zhang T, Christensen LM, et al. Obesity-related IL-18 impairs T-regulatory cell function and promotes lung ischemia-reperfusion injury. Am J Respir Crit Care Med, 2021, 204(9): 1060-1074.
14. Calabrese DR, Aminian E, Mallavia B, et al. Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury. J Clin Invest, 2021, 131(3): e137047.
15. Kaes J, Pollenus E, Hooft C, et al. The immunopathology of pulmonary rejection after murine lung transplantation. Cells, 2024, 13(3): 241.
16. Nayak DK, Zhou F, Xu M, et al. Zbtb7a induction in alveolar macrophages is implicated in anti-HLA-mediated lung allograft rejection. Sci Transl Med, 2017, 9(398): eaal1243.
17. Tian D, Shiiya H, Sato M, et al. Rat lung transplantation model: Modifications of the cuff technique. Ann Transl Med, 2020, 8(6): 407.
18. Gracon AS, Wilkes DS. Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance. Hum Immunol, 2014, 75(8): 887-894.
19. Martins MA, Watkins DI. What is the predictive value of animal models for vaccine efficacy in humans? Rigorous simian immunodeficiency virus vaccine trials can be instructive. Cold Spring Harb Perspect Biol, 2018, 10(4): a029504.
20. Whiteside GT, Adedoyin A, Leventhal L. Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology, 2008, 54(5): 767-775.
21. Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: Advantages and disadvantages. Pharmacol Ther, 2014, 141(3): 235-249.
22. Ghaidan H, Stenlo M, Niroomand A, et al. Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation. Nat Commun, 2022, 13(1): 4173.
23. Ali A, Nykanen AI, Beroncal E, et al. Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy. EBioMedicine, 2022, 83: 104210.
24. Cypel M, Yeung JC, Hirayama S, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant, 2008, 27(12): 1319-1325.
25. Gade J, Nørgaard MA, Andersen CB, et al. The porcine bronchial artery. Anastomoses with oesophageal, coronary and intercostal arteries. J Anat, 1999, 195 ( Pt 1): 65-73.
26. Hurst DJ, Padilla LA, Cooper DKC, et al. Factors influencing attitudes toward xenotransplantation clinical trials: A report of focus group studies. Xenotransplantation, 2021, 28(4): e12684.
27. Sundaresan S, Trachiotis GD, Aoe M, et al. Donor lung procurement: Assessment and operative technique. Ann Thorac Surg, 1993, 56(6): 1409-1413.
28. Veith F J, Sinha S B, Graves J S, et al. Ischemic tolerance of the lung. The effect of ventilation and inflation. J Thorac Cardiovasc Surg, 1971, 61(5): 804-810.
29. Date H, Matsumura A, Manchester J K, et al. Changes in alveolar oxygen and carbon dioxide concentration and oxygen consumption during lung preservation. The maintenance of aerobic metabolism during lung preservation. J Thorac Cardiovasc Surg, 1993, 105(3): 492-501.
30. Mariscal A, Caldarone L, Tikkanen J, et al. Pig lung transplant survival model. Nat Protoc, 2018, 13(8): 1814-1828.
31. 冯冬杰, 许林, 蒋峰, 等. 猪自体肺移植模型的建立. 南京医科大学学报(自然科学版), 2010, 30(1): 46-49,76.Feng DJ, Xu L, Jiang F, et al. Establishment of a swine model of lung auto-transplantation. J Nanjing Med Univ (Nat Sci), 2010, 30(1): 46-49,76.
32. Ali A, Wang A, Ribeiro RVP, et al. Static lung storage at 10℃ maintains mitochondrial health and preserves donor organ function. Sci Transl Med, 2021, 13(611): eabf7601.

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