Although chronic lung allograft dysfunction (CLAD) remains the major life‐limiting factor following lung transplantation, much of its pathophysiology remains unknown. The discovery that CLAD can manifest both clinically and morphologically in vastly different ways led to the definition of distinct subtypes of CLAD. In this review, recent advances in our understanding of the pathophysiological mechanisms of the different phenotypes of CLAD will be discussed with a particular focus on tissue‐based and molecular studies. An overview of the current knowledge on the mechanisms of the airway‐centered bronchiolitis obliterans syndrome, as well as the airway and alveolar injuries in the restrictive allograft syndrome and also the vascular compartment in chronic antibody‐mediated rejection is provided. Specific attention is also given to morphological and molecular markers for early CLAD diagnosis or histological changes associated with subsequent CLAD development. Evidence for a possible overlap between different forms of CLAD is presented and discussed. In the end, “tissue remains the (main) issue,” as we are still limited in our knowledge about the actual triggers and specific mechanisms of all late forms of posttransplant graft failure, a shortcoming that needs to be addressed in order to further improve the outcome of lung transplant recipients.

中文翻译：

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当组织成为问题时：慢性肺同种异体移植物功能障碍的组织学回顾。

尽管慢性肺同种异体移植物功能障碍 (CLAD) 仍然是肺移植后的主要生命限制因素，但其病理生理学的大部分仍然未知。CLAD 可以以截然不同的方式在临床和形态学上表现的发现导致了 CLAD 不同亚型的定义。在这篇综述中，我们将讨论我们对 CLAD 不同表型的病理生理机制的理解的最新进展，特别关注基于组织和分子的研究。提供了关于以气道为中心的闭塞性细支气管炎综合征机制的当前知识的概述，以及限制性同种异体移植综合征中的气道和肺泡损伤以及慢性抗体介导的排斥反应中的血管隔室。还特别关注用于早期 CLAD 诊断或与随后的 CLAD 发展相关的组织学变化的形态学和分子标记。提出并讨论了不同形式的 CLAD 之间可能重叠的证据。最后，“组织仍然是（主要）问题”，因为我们对所有晚期形式的移植后移植物失败的实际触发因素和具体机制的了解仍然有限，这一缺点需要解决以进一步改进肺移植受者的结果。