Complement-Mediated Microvascular Injury Leads to Chronic Rejection
Complement-Mediated Microvascular Injury Leads to Chronic Rejection
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DOI：
10.1007/978-1-4614-4118-2_16
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发表时间：
2013-01-01
期刊：
影响因子：
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通讯作者：
Nicolls, Mark R.
中科院分区：
文献类型：
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作者：
Khan, Mohammad A.;Nicolls, Mark R.
微血管损失可能是所有实体器官移植慢性排斥反应的一个未被认识的根本原因。作为唯一一种在手术时不进行原发性全身动脉血运重建的实体器官移植，肺移植依赖于微循环的建立，特别容易受到微血管损失的影响。微血管病及其伴随的局部缺血可导致组织梗死和气道纤维化。在肺移植物中维持健康的脉管系统对于预防终末气道纤维化（也称为闭塞性细支气管炎综合征（BOS））可能是至关重要的。BOS是肺移植成功的主要障碍，影响高达60%的存活5年的患者。补体在排斥反应中引起急性微血管损失和缺血的作用最近已经使用小鼠原位气管移植进行了研究，这是一个理想的模型，用于解析气道脉管系统在排斥反应中的作用。在排斥性气管同种异体移植物中发生气道纤维化之前，C3沉积在血管内皮上，就像首次检测到组织缺氧一样。随着血管的最终破坏，流向移植物的微血管血液完全停止了几天。补体缺乏和补体抑制导致移植物中组织氧合显著改善，气道重塑减少，血管修复加速。在急性排斥反应中，CD4（+）T细胞和抗体依赖性补体活性独立地介导血管破坏和持续的组织缺血。因此，在急性排斥发作期间，除了针对CD4（+）T细胞的标准免疫抑制外，还可以通过连续治疗来干预补体介导的微血管损伤，这可能有助于预防随后发生的慢性排斥。
Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant ischemia, can lead to tissue infarction and airway fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). BOS is the major obstacle to lung transplant success and affects up to 60% of patients surviving 5 years. The role of complement in causing acute microvascular loss and ischemia during rejection has recently been examined using the mouse orthotopic tracheal transplantation; this is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway fibrosis in rejecting tracheal allografts, C3 deposits on the vascular endothelium just as tissue hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days. Complement deficiency and complement inhibition lead to markedly improved tissue oxygenation in transplants, diminished airway remodeling, and accelerated vascular repair. CD4(+) T cells and antibody-dependent complement activity independently mediate vascular destruction and sustained tissue ischemia during acute rejection. Consequently, interceding against complement-mediated microvascular injury with adjunctive therapy during acute rejection episodes, in addition to standard immunosuppression which targets CD4(+) T cells, may help prevent the subsequent development of chronic rejection.