Kuo Elbert, Bharat Ankit, Shih Jennifer, Street Tyler, Norris Jenyi, Liu Wei, Parks William, Walter Michael, Patterson G Alexander, Mohanakumar T
Department of Surgery, Washington University, St. Louis, Missouri 63110, USA.
Ann Thorac Surg. 2006 Oct;82(4):1226-33. doi: 10.1016/j.athoracsur.2006.03.122.
Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection.
Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts.
Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio.
Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.
小鼠气管移植是用于研究闭塞性细支气管炎综合征的一种模型，该综合征是肺移植后发病和死亡的主要原因。与小鼠异位气管移植不同，尽管主要组织相容性抗原不匹配，但原位移植不会导致管腔闭塞。受体来源的上皮细胞重新填充气管同种异体移植物可防止管腔闭塞。本研究的目的是确定：（1）原位气管移植是否显示同种异体移植排斥反应的迹象；（2）气道上皮细胞损伤是否促进原位气管同种异体移植排斥反应。
进行了40例同基因（C57BL/6至C57BL/6）和40例异基因（BALB/c至C57BL/6）原位气管移植。通过仙台病毒（SdV）感染以及将气管移植到不能重新上皮化的基质金属蛋白酶-7基因敲除（MMP7-KO）受体小鼠中诱导气道上皮细胞损伤。在收获的同种异体移植物上借助计算机计算纤维化百分比和固有层与软骨的比例。
与同基因移植相比，移植后30、60和180天时，同种异体移植物显示出明显更多的壁内纤维化，且无管腔闭塞。与未感染的对照组相比，感染SdV的气管同种异体移植物的纤维化和固有层与软骨的比例增加。从MMP7-KO受体获得的同种异体移植物的纤维化和固有层与软骨的比例也显著增加。
尽管原位气管移植不会导致管腔闭塞，但会导致同种异体移植物纤维化增加。如在MMP7-KO受体小鼠中所见，病毒感染或移植后上皮重新形成缺陷对呼吸道上皮造成的损伤会导致与慢性同种异体移植排斥反应一致的变化，提示上皮损伤在闭塞性细支气管炎综合征发展中起作用。
