Commentary: Back(ward) to the future—novel technique of inverted left lung–right chest lung transplant in rats

Central MessageA novel technique of “inverted” rat lung transplant with left donor lung rotated 180° and implanted to recipient contralateral/right chest provides a promising model for future experiments.See Article page 429.Animal models have been a cornerstone in the development of lung transplantation. The first long-term clinical successes with heart–lung transplant at Stanford in 1981 and isolated lung transplantation by the Toronto group in 1983 were built on preceding decades of animal model research.1Venuta F. Van Raemdonck D. History of lung transplantation.J Thorac Dis. 2017; 9: 5458-5471Crossref PubMed Scopus (31) Google Scholar,2Bribriesco A.C. Li W. Nava R.G. Spahn J.H. Kreisel D. Experimental models of lung transplantation.Front Biosci (Elite Ed). 2013; 5: 266-272Crossref PubMed Google ScholarEarly animal experiments were aimed at developing surgical techniques, such as en bloc double-lung transplantation in canine models.3Dark J.H. Patterson G.A. Al-Jilaihawi A.N. Hsu H. Egan T. Cooper J.D. Experimental en bloc double-lung transplantation.Ann Thorac Surg. 1986; 42: 394-398Abstract Full Text PDF PubMed Scopus (36) Google Scholar Presently, more cost-effective and reproducible rodent models are the predominant platform for mechanistic experiments in exploring critical items such as primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction. Compared with other lung transplant models such as hilar occlusion or tracheal transplant, orthotopic left lung transplantation (OLLT) is a robust and versatile experimental technique that most closely simulates the human situation.4Lama V.N. Belperio J.A. Christie J.D. El-Chemaly S. Fishbein M.C. Gelman A.E. et al.Models of lung transplant research: a consensus statement from the National Heart, Lung, and Blood Institute workshop.JCI Insight. 2017; 2: e93121Crossref PubMed Scopus (37) Google Scholar, 5Okazaki M. Krupnick A.S. Kornfeld C.G. Lai J.M. Ritter J.H. Richardson S.B. et al.A mouse model of orthotopic vascularized aerated lung transplantation.Am J Transplant. 2007; 7: 1672-1679Crossref PubMed Scopus (126) Google Scholar, 6Lin X. Li W. Lai J. Okazaki M. Sugimoto S. Yamamoto S. et al.Five-year update on the mouse model of orthotopic lung transplantation: scientific uses, tricks of the trade, and tips for success.J Thorac Dis. 2012; 4: 247-258PubMed Google Scholar However, there are notable limitations to the OLLT model. Anatomically, the rodent left lung consists of only 1 lobe compared with the 5 lobes of the right such that the contribution from the transplanted left lung can be completely masked by the native right lung. This negates the important experimental end point of animal survival as a marker of allograft status. Orthotopic right lung transplant has been described but is technically more challenging, thereby hindering widespread adoption.7Li W. Sugimoto S. Lai J. Patterson G.A. Gelman A.E. Krupnick A.S. et al.Orthotopic vascularized right lung transplantation in the mouse.J Thorac Cardiovasc Surg. 2010; 139: 1637-1643Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar To date, orthotopic bilateral lung transplant (either en bloc or sequential) in the rodent has not been achieved.In this issue of JTCVS Open, Huang and colleagues8Huang H. Yan H.-J. Zheng X.-Y. Wang J.J. Tang H.T. Li C.H. et al.Right lung transplantation with a left-to-right inverted anastomosis in a rat model.J Thorac Cardiovasc Surg Open. 2022; 10: 429-439Scopus (1) Google Scholar turn the tables of the animal model-to-human paradigm with a technical report of a novel “inverted” rat single-lung transplant procedure inspired by the Kyoto group's successful human lobar lung transplantation of a right lower lobe implanted into the left chest.9Chen F. Miyamoto E. Takemoto M. Minakata K. Yamada T. Sato M. et al.Right and left inverted lobar lung transplantation.Am J Transplant. 2015; 15: 1716-1721Crossref PubMed Scopus (22) Google Scholar Elegantly described and depicted in the accompanying video, a rat donor left lung is rotated 180° and transplanted to the recipient's right chest using a standard 3-cuff anastomotic technique (inverted left-right transplant, IL-RT). This innovative model leverages the anatomic size discrepancy between the smaller left lung versus larger right chest cavity, allowing for a technically simpler and reproducible procedure compared with other techniques of right lung transplant.In 10 IL-RT procedures, the authors report 100% intraoperative technical success with 90% survival to the planned end point of 7 days. Total procedure time was comparable between IL-RT and 10 standard/control OLLT animals (58.2 vs 56.6 minutes, P = not significant). Important experimental details to note were the differences in cold and warm ischemic times between the IL-RT and OLLT groups. When compared with the OLLT, the IL-RT group had shorter cold ischemia time (14 minutes vs 25.5 minutes, P < .001) but longer warm ischemia time (19.8 vs 13.7 minutes, P < .001). It is unclear whether these small absolute differences in ischemic times will have meaningful biologic effect, but these and other facets of the IL-RT model will likely be explored and potentially gainfully used in forthcoming experiments.The authors are to be commended for their impressive technical achievement. As with all animal models, there are limitations to be addressed but, overall, this innovative procedure represents an exciting new tool for future research in lung transplantation. A novel technique of “inverted” rat lung transplant with left donor lung rotated 180° and implanted to recipient contralateral/right chest provides a promising model for future experiments. A novel technique of “inverted” rat lung transplant with left donor lung rotated 180° and implanted to recipient contralateral/right chest provides a promising model for future experiments. See Article page 429. See Article page 429. Animal models have been a cornerstone in the development of lung transplantation. The first long-term clinical successes with heart–lung transplant at Stanford in 1981 and isolated lung transplantation by the Toronto group in 1983 were built on preceding decades of animal model research.1Venuta F. Van Raemdonck D. History of lung transplantation.J Thorac Dis. 2017; 9: 5458-5471Crossref PubMed Scopus (31) Google Scholar,2Bribriesco A.C. Li W. Nava R.G. Spahn J.H. Kreisel D. Experimental models of lung transplantation.Front Biosci (Elite Ed). 2013; 5: 266-272Crossref PubMed Google Scholar Early animal experiments were aimed at developing surgical techniques, such as en bloc double-lung transplantation in canine models.3Dark J.H. Patterson G.A. Al-Jilaihawi A.N. Hsu H. Egan T. Cooper J.D. Experimental en bloc double-lung transplantation.Ann Thorac Surg. 1986; 42: 394-398Abstract Full Text PDF PubMed Scopus (36) Google Scholar Presently, more cost-effective and reproducible rodent models are the predominant platform for mechanistic experiments in exploring critical items such as primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction. Compared with other lung transplant models such as hilar occlusion or tracheal transplant, orthotopic left lung transplantation (OLLT) is a robust and versatile experimental technique that most closely simulates the human situation.4Lama V.N. Belperio J.A. Christie J.D. El-Chemaly S. Fishbein M.C. Gelman A.E. et al.Models of lung transplant research: a consensus statement from the National Heart, Lung, and Blood Institute workshop.JCI Insight. 2017; 2: e93121Crossref PubMed Scopus (37) Google Scholar, 5Okazaki M. Krupnick A.S. Kornfeld C.G. Lai J.M. Ritter J.H. Richardson S.B. et al.A mouse model of orthotopic vascularized aerated lung transplantation.Am J Transplant. 2007; 7: 1672-1679Crossref PubMed Scopus (126) Google Scholar, 6Lin X. Li W. Lai J. Okazaki M. Sugimoto S. Yamamoto S. et al.Five-year update on the mouse model of orthotopic lung transplantation: scientific uses, tricks of the trade, and tips for success.J Thorac Dis. 2012; 4: 247-258PubMed Google Scholar However, there are notable limitations to the OLLT model. Anatomically, the rodent left lung consists of only 1 lobe compared with the 5 lobes of the right such that the contribution from the transplanted left lung can be completely masked by the native right lung. This negates the important experimental end point of animal survival as a marker of allograft status. Orthotopic right lung transplant has been described but is technically more challenging, thereby hindering widespread adoption.7Li W. Sugimoto S. Lai J. Patterson G.A. Gelman A.E. Krupnick A.S. et al.Orthotopic vascularized right lung transplantation in the mouse.J Thorac Cardiovasc Surg. 2010; 139: 1637-1643Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar To date, orthotopic bilateral lung transplant (either en bloc or sequential) in the rodent has not been achieved. In this issue of JTCVS Open, Huang and colleagues8Huang H. Yan H.-J. Zheng X.-Y. Wang J.J. Tang H.T. Li C.H. et al.Right lung transplantation with a left-to-right inverted anastomosis in a rat model.J Thorac Cardiovasc Surg Open. 2022; 10: 429-439Scopus (1) Google Scholar turn the tables of the animal model-to-human paradigm with a technical report of a novel “inverted” rat single-lung transplant procedure inspired by the Kyoto group's successful human lobar lung transplantation of a right lower lobe implanted into the left chest.9Chen F. Miyamoto E. Takemoto M. Minakata K. Yamada T. Sato M. et al.Right and left inverted lobar lung transplantation.Am J Transplant. 2015; 15: 1716-1721Crossref PubMed Scopus (22) Google Scholar Elegantly described and depicted in the accompanying video, a rat donor left lung is rotated 180° and transplanted to the recipient's right chest using a standard 3-cuff anastomotic technique (inverted left-right transplant, IL-RT). This innovative model leverages the anatomic size discrepancy between the smaller left lung versus larger right chest cavity, allowing for a technically simpler and reproducible procedure compared with other techniques of right lung transplant. In 10 IL-RT procedures, the authors report 100% intraoperative technical success with 90% survival to the planned end point of 7 days. Total procedure time was comparable between IL-RT and 10 standard/control OLLT animals (58.2 vs 56.6 minutes, P = not significant). Important experimental details to note were the differences in cold and warm ischemic times between the IL-RT and OLLT groups. When compared with the OLLT, the IL-RT group had shorter cold ischemia time (14 minutes vs 25.5 minutes, P < .001) but longer warm ischemia time (19.8 vs 13.7 minutes, P < .001). It is unclear whether these small absolute differences in ischemic times will have meaningful biologic effect, but these and other facets of the IL-RT model will likely be explored and potentially gainfully used in forthcoming experiments. The authors are to be commended for their impressive technical achievement. As with all animal models, there are limitations to be addressed but, overall, this innovative procedure represents an exciting new tool for future research in lung transplantation. Right lung transplantation with a left-to-right inverted anastomosis in a rat modelJTCVS OpenVol. 10PreviewRight lung transplantation in rats has been attempted occasionally, but the technical complexity makes it challenging to apply routinely. Additionally, basic research on inverted lobar lung transplantation is scarce because of the lack of a cost-effective experimental model. We first reported right lung transplantation in a rat model using left-to-right inverted anastomosis to imitate the principle of clinically inverted lung transplantation. Full-Text PDF Open Access

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