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Tracheal Transplantation
antithrombotic treatment for atrial fibrillation. BMJ 1999; 318:1324 –1327 24 Lane D, Lip GY. Anti-thrombotic therapy for atrial fibrillation and patients’ preferences for treatment. Age Ageing 2005; 34:1–3 25 Lip GY, Kamath S, Jafri M, et al. Ethnic differences in patient perceptions of atrial fibrillation and anticoagulation therapy: the West Birmingham atrial fibrillation project. Stroke 2002; 33:238 –242 26 Lane DA, Ponsford J, Shelley A, et al. Patient knowledge and perceptions of atrial fibrillation and anticoagulant therapy: effects of an educational intervention programme; The West Birmingham Atrial Fibrillation Project. Int J Cardiol 2006; 110:354 –358
Tracheal Transplantation Are We Any Closer to the Holy Grail of Airway Management? of tracheal disease is one of the T hemostmanagement challenging problems facing chest physi-
cians. Fortunately, in experienced hands, the majority of abnormalities respond either to advanced endoscopic techniques1 or to definitive primary resection.2 Depending on individual anatomic and physiologic factors, up to 50% of the human trachea can be resected and primarily re-anastomosed, obviating the need for tracheal substitutes. However, two groups of patients would greatly benefit from tracheal replacement: a small group of patients who have extensive primary tracheal neoplasms, such as adenoid cystic carcinoma, for which only palliative treatments are currently available; and a larger group who have long-segment inflammatory lesions or chronic systemic conditions that involve the central airways. Although this latter group is often effectively managed with tracheal T-tubes, quality of life can be adversely affected by the required maintenance and possible complications. Given that the largest group who could benefit from tracheal replacement has benign disease for which other treatments are reasonably effective, a clinically relevant tracheal substitute must be readily available, durable, and foremost safe. Unfortunately, such a substitute has remained elusive.3 In this issue of CHEST (see page 1397), Jaillard and colleagues4 report on their experiments in tracheal replacement using allogenic minipig aortas. The experimental design is based on the work of Martinod et al5,6 in a sheep model, and the aim of the study was to confirm their results in a different animal model. A segment of trachea in 21 male minipigs was replaced with a section of thoracic aorta freshly harvested from female minipigs. Endoluminal silicone stents placed across the graft provided immewww.chestjournal.org
diate structural support to prevent airway collapse. No immunosuppressive agents were administered. The animals were killed and specimens were harvested at 3-month intervals. Specimens were assessed for epithelial ingrowth, neocartilage formation, type-II collagen production, and the presence of the SRY gene in the neocartilage. The 21 pigs were placed into three groups of 7 animals each. The first group of seven pigs had 12 to 14 rings of their cervical trachea replaced. To replace larger, more clinically relevant tracheal sections, the next group of seven pigs underwent a partial sternotomy with resection of 18 to 20 rings. The final group of seven pigs underwent sternotomies with replacement of 12 rings of intrathoracic trachea to assess the feasibility of the technique in the intrathoracic environment. Technically, this operation required a right pneumonectomy. Refinements in the final few animals allowed the same length of intrathoracic trachea to be resected while removing only the right upper lobe. Harvests were scheduled for 3, 6, and 12 months. However, a number of perioperative deaths and multiple stent complications resulted in only two animals surviving to their targeted time points. Of the 21 grafts, 10 matured to at least 3 months, and 4 matured to at least 9 months. In these 14 grafts, there was no evidence of necrosis, but some had contracted longitudinally up to 50% and graft epithelialization was present but incomplete. The presence of type II collagen was confirmed, but no C-shaped or ring-like cartilage structures were seen. Some nests of cartilage showed osteoblastic activity and osseous proliferation. From a practical perspective, this study has relevance. Human allogenic aortic tissue is tubular in shape, similar in diameter to the trachea, impermeable to air and fluids, pliable, strong, holds sutures well, and is readily available. These properties are ideal, but aortic tissue lacks the structural supporting elements necessary to prevent collapse, and an epithelial lining is necessary to prevent stenosis from what is, in essence, an open wound. In this study, Jaillard et al4 showed that recipientderived cells repopulate the graft and form nests of cartilage cells capable of producing their own characteristic extracellular matrix of proteoglycans and type II cartilage. This confirms the finding of Martinod et al5,6 in the sheep model, but unlike Martinod’s report of rings of cartilage with a posterior membranous wall, Jaillard et al4 found only scattered islets of cartilage that failed to form structurally important tissue. Similarly, Jaillard et al4 found incomplete epithelial ingrowth in the pig model. This finding also differs from that of Martinod et al,5,6 who reported CHEST / 130 / 5 / NOVEMBER, 2006
1299
complete epithelialization in sheep. This present study raises concern that the results from the sheep model cannot be expected in other animal models and specifically in humans. However, so few animals lived to the targeted time points that drawing conclusions about the lack of abundant cartilage and epithelial generation is difficult. Scientifically, this trial is important because it supports the concept that allogenic tissue (thoracic aorta in this case) can be placed as long-segment grafts in the trachea and that it can provide a scaffold to support cellular ingrowth of recipient progenitor cells, participating in guided tissue generation. More work is needed to determine whether a more substantial chondrocyte supporting structure can be induced and whether complete epithelialization can be created using tissue engineering techniques. This trial also raises interesting questions about what induces and guides the development of cartilaginous tissue in the walls of the orthotopic aortic graft. It seems unlikely that signaling systems remaining in the chest of an adult animal would be sufficient to initiate and guide the generation of cartilage rings in a piece of aorta transposed to the tracheal position. Aortic allograft calcification is well described in cardiovascular and transplant surgery and often leads to premature graft failure. Calcification has been thought to be the result of a passive process, but recent work suggests a more organized, active process of osteoblastic activity resulting from endochondral ossification. Mathieu et al7 found that transplanted fresh allogenic rat abdominal aortic grafts developed a cartilaginous metaplasia followed by endochondral ossification, whereas transplanted homografts did not. The authors7 suggested that inflammatory cells, through the expression of transforming growth factor 1, induced the ␣-smooth muscle, actin-positive cells in the aortic graft to transform into cartilage and then to undergo further endochondral ossification. The major shortcomings of this trial are the high premature death rate, which is probably related to technical issues specific to the pig model, and the use of multiple different surgeries in a small population of animals. Together, these shortcomings resulted in too few specimens of sufficient maturity for defini-
1300
tive analysis. Thus, despite the interesting aspects of the trial, conclusions about the feasibility (either supportive or otherwise) of this technique in animal models other than sheep cannot yet be made. We consider the results interesting enough, however, to warrant further testing of this approach to long-segment tracheal replacement. Additionally, for the results to be applicable to surgery in humans, similar changes would have to be documented in preserved aortic specimens. Do we have the Holy Grail in our hands? The answer is still no, but Martinod and Jaillard have shown us a way that may (or may not) eventually lead us there. Armin Ernst, MD, FCCP Simon Ashiku, MD, FCCP Boston, MA Dr. Ernst is Instructor in Surgery, and Dr. Ashiku is Associate Professor of Surgery, Harvard Medical School. Dr. Ernst and Dr. Ashiku have no conflicts of interest related to the subject. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Armin Ernst, MD, FCCP, Complex Airway Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA. DOI: 10.1378/chest.130.5.1299
References 1 Ernst A, Feller-Kopman D, Becker H. et al. Central airway obstruction: state of the art. Am J Respir Crit Care Med 2004; 169:1278 –1297 2 Mulliken J, Grillo HC. The limits of tracheal resection with primary anastomosis: further anatomical studies in man. J Thorac Cardiovasc Surg 1968; 55:418 – 421 3 Grillo HC. Tracheal replacement: a critical review. Ann Thorac Surg 2002; 73:1995–2004 4 Jaillard S, Holder-Espinasse M, Hubert T, et al. Tracheal replacement by allogenic aorta in the pig. Chest 2006; 130:1397–1404 5 Martinod E, Seguin A, Holder-Espinasse M. Tracheal regeneration following tracheal replacement with an allogenic aorta. Ann Thorac Surg 2005; 79:942–949 6 Azorin JF, Bertin F, Martinod E. Tracheal replacement with an aortic autograft. Eur J Card Thorac Surg 2006; 29:261–263 7 Mathieu P, Roussel JC, Dagenais F. Cartilaginous metaplasia and calcification in aortic allograft is associated with transforming growth factor. J Thor Cardiovasc Surg 2003; 26: 1449 –1454
Editorials
Tracheal Transplantation Are We Any Closer to the Holy Grail of Airway Management? of tracheal disease is one of the T hemostmanagement challenging problems facing chest physi-
cians. Fortunately, in experienced hands, the majority of abnormalities respond either to advanced endoscopic techniques1 or to definitive primary resection.2 Depending on individual anatomic and physiologic factors, up to 50% of the human trachea can be resected and primarily re-anastomosed, obviating the need for tracheal substitutes. However, two groups of patients would greatly benefit from tracheal replacement: a small group of patients who have extensive primary tracheal neoplasms, such as adenoid cystic carcinoma, for which only palliative treatments are currently available; and a larger group who have long-segment inflammatory lesions or chronic systemic conditions that involve the central airways. Although this latter group is often effectively managed with tracheal T-tubes, quality of life can be adversely affected by the required maintenance and possible complications. Given that the largest group who could benefit from tracheal replacement has benign disease for which other treatments are reasonably effective, a clinically relevant tracheal substitute must be readily available, durable, and foremost safe. Unfortunately, such a substitute has remained elusive.3 In this issue of CHEST (see page 1397), Jaillard and colleagues4 report on their experiments in tracheal replacement using allogenic minipig aortas. The experimental design is based on the work of Martinod et al5,6 in a sheep model, and the aim of the study was to confirm their results in a different animal model. A segment of trachea in 21 male minipigs was replaced with a section of thoracic aorta freshly harvested from female minipigs. Endoluminal silicone stents placed across the graft provided immewww.chestjournal.org
diate structural support to prevent airway collapse. No immunosuppressive agents were administered. The animals were killed and specimens were harvested at 3-month intervals. Specimens were assessed for epithelial ingrowth, neocartilage formation, type-II collagen production, and the presence of the SRY gene in the neocartilage. The 21 pigs were placed into three groups of 7 animals each. The first group of seven pigs had 12 to 14 rings of their cervical trachea replaced. To replace larger, more clinically relevant tracheal sections, the next group of seven pigs underwent a partial sternotomy with resection of 18 to 20 rings. The final group of seven pigs underwent sternotomies with replacement of 12 rings of intrathoracic trachea to assess the feasibility of the technique in the intrathoracic environment. Technically, this operation required a right pneumonectomy. Refinements in the final few animals allowed the same length of intrathoracic trachea to be resected while removing only the right upper lobe. Harvests were scheduled for 3, 6, and 12 months. However, a number of perioperative deaths and multiple stent complications resulted in only two animals surviving to their targeted time points. Of the 21 grafts, 10 matured to at least 3 months, and 4 matured to at least 9 months. In these 14 grafts, there was no evidence of necrosis, but some had contracted longitudinally up to 50% and graft epithelialization was present but incomplete. The presence of type II collagen was confirmed, but no C-shaped or ring-like cartilage structures were seen. Some nests of cartilage showed osteoblastic activity and osseous proliferation. From a practical perspective, this study has relevance. Human allogenic aortic tissue is tubular in shape, similar in diameter to the trachea, impermeable to air and fluids, pliable, strong, holds sutures well, and is readily available. These properties are ideal, but aortic tissue lacks the structural supporting elements necessary to prevent collapse, and an epithelial lining is necessary to prevent stenosis from what is, in essence, an open wound. In this study, Jaillard et al4 showed that recipientderived cells repopulate the graft and form nests of cartilage cells capable of producing their own characteristic extracellular matrix of proteoglycans and type II cartilage. This confirms the finding of Martinod et al5,6 in the sheep model, but unlike Martinod’s report of rings of cartilage with a posterior membranous wall, Jaillard et al4 found only scattered islets of cartilage that failed to form structurally important tissue. Similarly, Jaillard et al4 found incomplete epithelial ingrowth in the pig model. This finding also differs from that of Martinod et al,5,6 who reported CHEST / 130 / 5 / NOVEMBER, 2006
1299
complete epithelialization in sheep. This present study raises concern that the results from the sheep model cannot be expected in other animal models and specifically in humans. However, so few animals lived to the targeted time points that drawing conclusions about the lack of abundant cartilage and epithelial generation is difficult. Scientifically, this trial is important because it supports the concept that allogenic tissue (thoracic aorta in this case) can be placed as long-segment grafts in the trachea and that it can provide a scaffold to support cellular ingrowth of recipient progenitor cells, participating in guided tissue generation. More work is needed to determine whether a more substantial chondrocyte supporting structure can be induced and whether complete epithelialization can be created using tissue engineering techniques. This trial also raises interesting questions about what induces and guides the development of cartilaginous tissue in the walls of the orthotopic aortic graft. It seems unlikely that signaling systems remaining in the chest of an adult animal would be sufficient to initiate and guide the generation of cartilage rings in a piece of aorta transposed to the tracheal position. Aortic allograft calcification is well described in cardiovascular and transplant surgery and often leads to premature graft failure. Calcification has been thought to be the result of a passive process, but recent work suggests a more organized, active process of osteoblastic activity resulting from endochondral ossification. Mathieu et al7 found that transplanted fresh allogenic rat abdominal aortic grafts developed a cartilaginous metaplasia followed by endochondral ossification, whereas transplanted homografts did not. The authors7 suggested that inflammatory cells, through the expression of transforming growth factor 1, induced the ␣-smooth muscle, actin-positive cells in the aortic graft to transform into cartilage and then to undergo further endochondral ossification. The major shortcomings of this trial are the high premature death rate, which is probably related to technical issues specific to the pig model, and the use of multiple different surgeries in a small population of animals. Together, these shortcomings resulted in too few specimens of sufficient maturity for defini-
1300
tive analysis. Thus, despite the interesting aspects of the trial, conclusions about the feasibility (either supportive or otherwise) of this technique in animal models other than sheep cannot yet be made. We consider the results interesting enough, however, to warrant further testing of this approach to long-segment tracheal replacement. Additionally, for the results to be applicable to surgery in humans, similar changes would have to be documented in preserved aortic specimens. Do we have the Holy Grail in our hands? The answer is still no, but Martinod and Jaillard have shown us a way that may (or may not) eventually lead us there. Armin Ernst, MD, FCCP Simon Ashiku, MD, FCCP Boston, MA Dr. Ernst is Instructor in Surgery, and Dr. Ashiku is Associate Professor of Surgery, Harvard Medical School. Dr. Ernst and Dr. Ashiku have no conflicts of interest related to the subject. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Armin Ernst, MD, FCCP, Complex Airway Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA. DOI: 10.1378/chest.130.5.1299
References 1 Ernst A, Feller-Kopman D, Becker H. et al. Central airway obstruction: state of the art. Am J Respir Crit Care Med 2004; 169:1278 –1297 2 Mulliken J, Grillo HC. The limits of tracheal resection with primary anastomosis: further anatomical studies in man. J Thorac Cardiovasc Surg 1968; 55:418 – 421 3 Grillo HC. Tracheal replacement: a critical review. Ann Thorac Surg 2002; 73:1995–2004 4 Jaillard S, Holder-Espinasse M, Hubert T, et al. Tracheal replacement by allogenic aorta in the pig. Chest 2006; 130:1397–1404 5 Martinod E, Seguin A, Holder-Espinasse M. Tracheal regeneration following tracheal replacement with an allogenic aorta. Ann Thorac Surg 2005; 79:942–949 6 Azorin JF, Bertin F, Martinod E. Tracheal replacement with an aortic autograft. Eur J Card Thorac Surg 2006; 29:261–263 7 Mathieu P, Roussel JC, Dagenais F. Cartilaginous metaplasia and calcification in aortic allograft is associated with transforming growth factor. J Thor Cardiovasc Surg 2003; 26: 1449 –1454
Editorials