Lung transplantation models for preclinical trial (literature review)

Lung transplantation (LT) is the only treatment for many end-stage lung diseases. Despite significant progress in transplantology and surgery, LT remains a high-tech surgical procedure performed at select research centers. Primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction are serious problems that can worsen lung transplant outcomes significantly. Using animal models in experimental studies to investigate these pathologic conditions is one of the more rational approaches. A literature review was conducted in order to select a suitable model that reproduces pathologic processes developing after LT. The literature was searched and ana- lyzed in MEDLINE and Elibrary databases, and the US National Institute of Health guidelines for the period up to December 2023 were reviewed. It was found that the most frequently used models are small laboratory animal models (without LT) and large animal models (with LT).

1. Akopov AL, Ilin AA, Sidelnikova EV. Tracheal transplantation and reconstruction: state of the problem. Regional blood circulation and microcirculation. 2022; 21 (1): 87–94. [In Russ, English abstract]. doi: 10.24884/1682-6655-2022-21-1-87-94.

2. Bilodeaux J, Farooqi H, Osovskaya M, Sosa A, Wallbank A, Knudsen L et al. Differential effects of two-hit models of acute and ventilator-induced lung injury on lung structure, function, and inflammation. Front Physiol. 2023; 14: 1217183.

3. Boehler A, Chamberlain D, Kesten S, Slutsky AS, Liu M, Keshavjee S. Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans. Transplantation. 1997; 64 (2): 311–317.

4. Bribriesco AC, Li W, Nava RG, Spahn JH, Kreisel D. Experimental models of lung transplantation. Front Biosci (Elite Ed). 2013; 5 (1): 266–272.

5. Burkhanova U, Harris A, Leir SH. Enhancement of airway epithelial cell differentiation by pulmonary endothelial cell co-culture. Stem Cell Res. 2022; 65: 102967.

6. Calabrese DR, Tsao T, Magnen M, Valet C, Gao Y, Mallavia B et al. NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes. JCI Insight. 2022; 7 (24): e164603. doi: 10.1172/jci.insight.164603. PMID: 36346670; PMCID: PMC9869973.

7. Chang SH, Chan J, Patterson GA. History of Lung Transplantation. Clin Chest Med. 2023; 44 (1): 1–13.

8. Cheon IS, Son YM, Sun J. Tissue-resident memory T cells and lung immunopathology. Immunol Rev. 2023; 316 (1): 63–83.

9. Danielson A, Liu L, Shontz KM, Syed H, Dharmadhikari S, Reynolds SD et al. Spatial and Temporal Analysis of Host Cells in Tracheal Graft Implantation. Laryngoscope. 2021; 131 (2): E340–E345.

10. Dasgupta S, Dayagi DY, Haimovich G, Wyler E, Olender T, Singer RH et al. Global analysis of contact-dependent human-to-mouse intercellular mRNA and lncRNA transfer in cell culture. Elife. 2023; 12: e83584.

11. Den Hondt M, Vanaudenaerde B, Verbeken E, Vranckx JJ. Requirements for Successful Trachea Transplantation: A Study in the Rabbit Model. Plast Reconstr Surg. 2018; 141 (6): 845e–856e.

12. Diamond JM, Cantu E, Porteous MK, Suzuki Y, Meyer KC, Lederer DJ et al. Clinical Trials in Organ Transplantation I. Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation. Am J Transplant. 2017; 17 (7): 1770– 1777.

13. Diel R, Simon S, Gottlieb J. Chronic Lung Allograft Dysfunction Is Associated with Significant Disability after Lung Transplantation – A Burden of Disease Analysis in 1025 Cases. Adv Respir Med. 2023; 91 (5): 432–444.

14. Esipova OYu, Bogdanov VK, Esipov AS, Kuleshov AP, Buchnev AS, Volkova EA et al. Development of a new lowvolume oxygenator and creation of a hydrodynamic test bench for ex vivo lung perfusion in small animals. Russian Journal of Transplantology and Artificial Organs. 2023; 25 (3): 106–112. [In Russ, English abstract]. doi: 10.15825/1995-1191-2023-3-106-112.

15. Fan K, Qiao XW, Nie J, Yuan L, Guo HZ, Zheng ZK et al. Orthotopic and heterotopic tracheal transplantation model in studying obliterative bronchiolitis. Transpl Immunol. 2013; 28 (4): 170–175.

16. Galagudza MM, Blokhin IO, Shmonin AA, Mischenko KA. Reduction of myocardial ischemia-reperfusion injury with pre- and postconditioning: molecular mechanisms and therapeutic targets. Cardiovasc Hematol Disord Drug Targets. 2008; 8 (1): 47–65. doi: 10.2174/187152908783884966. PMID: 18336253.

17. Gautier SV, Khomyakov SM. Organ donation and transplantation in the Russian Federation in 2022. 15th Report from the Registry of the Russian Transplant Society. Russian Journal of Transplantology and Artificial Organs. 2023; 25 (3): 8–30. doi: 10.15825/1995-1191-2023-3-8-30.

18. Gautier SV, Tsirulnikova OM, Pashkov IV, Grudinin NV, Oleshkevich DO, Bondarenko DM et al. Evaluation of the efficacy of a novel perfusion solution for normothermic ex vivo lung perfusion compared with Steen solution™ (animal experimental study). Russian Journal of Transplantology and Artificial Organs. 2021; 23 (3): 82–89. doi: 10.15825/1995-1191-2021-3-82-89.

19. Gautier SV, Tsirulnikova OM, Pashkov IV, Oleshkevich DO, Filatov IA, Bogdanov VK et al. Normothermic ex vivo perfusion of isolated lungs in an experiment using a russian-made perfusion system. Russian Journal of Transplantology and Artificial Organs. 2022; 24 (2): 94–101. doi: 10.15825/1995-1191-2022-2-94-101.

20. Giannou AD, Ohm B, Zazara DE, Lucke J, Zhang T, Sabihi M et al. Protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. STAR Protoc. 2023; 4 (4): 102701.

21. Habert P, Chetrit E, Coiffard B, Bregeon F, Thomas P., Loundou A et al. Early chest CT abnormalities to predict the subsequent occurrence of chronic lung allograft dysfunction. Insights Imaging. 2023; 14 (1): 154. doi: 10.1186/s13244-023-01509-3. PMID: 37741923; PMCID: PMC10517910.

22. Halverson LP, Hachem RR. Antibody-Mediated Rejection: Diagnosis and Treatment. Clin Chest Med. 2023; 44 (1): 95–103.

23. Jin X, Kaes J, Van Slambrouck J, Inci I, Arni S, Geudens V et al. Comprehensive Review on the Surgical Aspect of Lung Transplant Models in Mice and Rats. Cells. 2022; 11 (3): 480. doi: 10.3390/cells11030480. PMID: 35159289; PMCID: PMC8833959.

24. Jungraithmayr WM, Korom S, Hillinger S, Weder W. A mouse model of orthotopic, single-lung transplantation. J Thorac Cardiovasc Surg. 2009; 137 (2): 486–491.

25. Kanou T, Ohsumi A, Kim H, Chen M, Bai X, Guan Z et al. Inhibition of regulated necrosis attenuates receptor-interacting protein kinase 1-mediated ischemia-reperfusion injury after lung transplantation. J Heart Lung Transplant. 2018; 37 (10): 1261–1270.

26. Karpov AA, Vachrushev NS, Shilenko LA, Smirnov SS, Bunenkov NS, Butskih MG et al. Sympathetic Denervation and Pharmacological Stimulation of Parasympathetic Nervous System Prevent Pulmonary Vascular Bed Remodeling in Rat Model of Chronic Thromboembolic Pulmonary Hypertension. J Cardiovasc Dev Dis. 2023; 10 (2): 40. doi: 10.1016/j.heliyon.2022.e09014. PMID: 35295664; PMCID: PMC8919224.

27. Karpov AA, Vaulina DD, Smirnov SS, Moiseeva OM, Galagudza MM. Rodent models of pulmonary embolism and chronic thromboembolic pulmonary hypertension. Heliyon. 2022; 8 (3): e09014. doi: 10.1016/j.heliyon.2022.e09014. PMID: 35295664; PMCID: PMC8919224.

28. Krupnick AS, Lin X, Li W, Okazaki M, Lai J, Sugimoto S et al. Orthotopic mouse lung transplantation as experimental methodology to study transplant and tumor biology. Nat Protoc. 2009; 4 (1): 86–93. doi: 10.1038/nprot.2008.218. PMID: 19131960; PMCID: PMC3848695.

29. Kulkarni HS, Lee JS, Bastarache JA, Kuebler WM, Downey GP, Albaiceta G et al. Update on the Features and Measurements of Experimental Acute Lung Injury in Animals: An Official American Thoracic Society Workshop Report. Am J Respir Cell Mol Biol. 2022; 66 (2): e1–e14. doi: 10.1165/rcmb.2021-0531ST. PMID: 35103557; PMCID: PMC8845128.

30. Lama VN, Belperio JA, Christie JD, El-Chemaly S, Fishbein MC, Gelman AE et al. Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop. JCI Insight. 2017; 2 (9): e93121. doi: 10.1172/jci.insight.93121. PMID: 28469087; PMCID: PMC5414568.

31. Li B, Hartwig MG, Appel JZ, Bush EL, Balsara KR, Holzknecht ZE et al. Chronic aspiration of gastric fluid induces the development of obliterative bronchiolitis in rat lung transplants. Am J Transplant. 2008; 8 (8): 1614– 1621.

32. Li X, Wu J, Zhu S, Wei Q, Wang L, Chen J. Intragraft immune cells: accomplices or antagonists of recipientderived macrophages in allograft fibrosis? Cell Mol Life Sci. 2023; 80 (7): 195.

33. Li X, Zhao Y, Sun W, Zhang C, Yu Y, Du B et al. Neutrophil depletion attenuates antibody-mediated rejection in a renal transplantation mouse model. Clin Exp Immunol. 2024; 216 (2): 211–219. doi: 10.1093/cei/uxad128. Epub ahead of print. PMID: 38150328.

34. Liao M, Wang C, Zhang M, Qiao K. Insight on immune cells in rejection and infection postlung transplant. Immun Inflamm Dis. 2023; 11 (7): e868.

35. Looby N, Roszkowska A, Yu M, Rios-Gomez G, Pipkin M, Bojko B et al. In vivo solid phase microextraction for therapeutic monitoring and pharmacometabolomic fingerprinting of lung during in vivo lung perfusion of FOLFOX. J Pharm Anal. 2023; 13 (10): 1195–1204.

36. Lunardi F, Vedovelli L, Pezzuto F, Le Pavec J, Dorfmuller P, Ivanovic M et al. Assessing the Role of Phosphorylated S6 Ribosomal Protein in the Pathological Diagnosis of Pulmonary Antibody-Mediated Rejection. J Heart Lung Transplant. 2024; 43 (3): 403–413. doi: 10.1016/j.healun.2023.10.002. Epub 2023 Oct 6. PMID: 37806601.

37. Minasian SM, Galagudza MM, Dmitriev YV, Karpov AA, Vlasov TD. Preservation of the donor heart: from basic science to clinical studies. Interact Cardiovasc Thorac Surg. 2015; 20 (4): 510–519.

38. Gautier SV, Pashkov IV, Bogdanov VK, Oleshkevich DO, Bondarenko DM, Mozheiko NP et al. Normothermic ex vivo lung perfusion using a developed solution followed by orthotopic left lung transplantation (experimental study). Russian Journal of Transplantology and Artificial Organs. 2023; 25 (2): 158–166. doi: 10.15825/1995- 1191-2023-2-158-166.

39. Rizo-Tellez SA, Sekheri M, Filep JG. Myeloperoxidase: Regulation of Neutrophil Function and Target for Therapy. Antioxidants (Basel). 2022; 11 (11): 2302. doi: 10.3390/antiox11112302. PMID: 36421487; PMCID: PMC9687284.

40. Sato M, Keshavjee S, Liu M. Translational research: animal models of obliterative bronchiolitis after lung transplantation. Am J Transplant. 2009; 9 (9): 1981–1987.

41. Shah DD, Raghani NR, Chorawala MR, Singh S, Prajapati BG. Harnessing three-dimensional (3D) cell culture models for pulmonary infections: State of the art and future directions. Naunyn Schmiedebergs Arch Pharmacol. 2023; 396 (11): 2861–2880.

42. Shen Z, Xia T, Zhao J, Pan S. Current status and future trends of reconstructing a vascularized tissue-engineered trachea. Connect Tissue Res. 2023; 64 (5): 428–444.

43. Smith P, Jeffers LA, Koval M. Measurement of Lung Vessel and Epithelial Permeability in vivo with Evans Blue. Methods Mol Biol. 2021; 2367: 137–148.

44. Stocco E, Barbon S, Mammana M, Zambello G, Contran M, Parnigotto PP et al. Preclinical and clinical orthotopic transplantation of decellularized/engineered tracheal scaffolds: A systematic literature review. J Tissue Eng. 2023; 14: 20417314231151826.

45. Sun B, Lei M, Zhang J, Kang H, Liu H, Zhou F. Acute lung injury caused by sepsis: how does it happen? Front Med (Lausanne). 2023; 10: 1289194.

46. Sun F, Shen Z, Zhang B, Lu Y, Shan Y, Wu Q et al. Biomimetic in situ tracheal microvascularization for segmental tracheal reconstruction in one-step. Bioeng Transl Med. 2023; 8 (4): e10534.

47. Tian D, Shiiya H, Sato M, Nakajima J. Rat lung transplantation model: modifications of the cuff technique. Ann Transl Med. 2020; 8 (6): 407.

48. Traxler D, Schweiger T, Schwarz S, Schuster MM, Jaksch P, Lang G et al. The Lymphatic Phenotype of Lung Allografts in Patients With Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome. Transplantation. 2017; 101 (2): 310–315.

49. Tseng HT, Lin YW, Huang CY, Shih CM, Tsai YT, Liu CW et al. Animal Models for Heart Transplantation Focusing on the Pathological Conditions. Biomedicines. 2023; 11 (5): 1414. doi: 10.3390/biomedicines11051414. PMID: 37239085; PMCID: PMC10216327.

50. Wong A, Liu M. Inflammatory responses in lungs from donation after brain death: Mechanisms and potential therapeutic targets. J Heart Lung Transplant. 2021; 40 (9): 890–896.

51. Zhao Y, Main K, Aujla T, Keshavjee S, Liu M. Necroptosis in Organ Transplantation: Mechanisms and Potential Therapeutic Targets. Cells. 2023; 12 (18): 2296. doi: 10.3390/cells12182296.