Immunoferroptosis: a novel mechanism and promising therapeutic strategy in lung transplantation.

免疫铁死亡：肺移植中的一种新机制和有前途的治疗策略。

• 批准号: 505756743
• 负责人: Privatdozent Dr. Alexey Dashkevich, Ph.D.
• 金额: --
• 依托单位: Institute of Lung Health and Immunity (LHI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505756743?language=en
• 关键词: Immunoferroptosis; novel; mechanism; promising; therapeutic

Lung transplantation is the last resort for patients with end-stage lung diseases. The lung transplant recipients benefit from this procedure with health improvement. Unfortunately, lung transplantation displays the worst long-term survival in all solid organ transplantation. Although surgical technique, donor selection, lung preservation, and immunosuppressive therapies have been advanced, the median survival after lung transplantation has increased only slightly, to just 6.7 years in adults. The greatest threat to long-term survival for lung recipients who have survived more than one year post-transplantation is the onset and progression of chronic lung allograft dysfunction (CLAD), which includes three phenotypes: bronchiolitis obliterans syndrome (BOS), neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome, and each of them is characterized either by airway obstruction or restriction, and is largely unresponsive to immunosuppression.Among various cell death pathways described, ferroptosis is a ROS-dependent form of cell death associated with two main biochemical characteristics, namely iron accumulation and lipid peroxidation, leading to caspase- and necrosome-independent cell death. Ischemia-reperfusion injury (IRI) is one of the risk factors for developing chronic lung allograft rejection and recent publications are linking the severity of IRI with the phenomenon of ferroptosis. However, the molecular mechanisms underlying the induction of ferroptotic cell death in the chronically rejecting lung and its contribution to BOS development remains unknown along with its potential as a much-needed therapeutic target. Here, we aim to elucidate the contribution of specific mechanisms of immunoferroptotis as the primary cell death in orchestrating CLAD and BOS development in the chronically rejecting lung allografts and to delineate their potential as BOS biomarkers in patient to improve an early diagnosis.The mutual application of Dr. Alexey Dashkevich as a clinician and Dr. Ali Önder Yildirim as a basic researcher should enforce the implication of the bench findings to the clinically relevant questions.

肺移植是终末期肺部疾病患者的最后手段。肺移植受者受益于此过程与健康改善。不幸的是，肺移植在所有实体器官移植中显示出最差的长期存活率。尽管手术技术、供体选择、肺保存和免疫抑制治疗已经取得了进展，但肺移植后的中位生存期仅略有增加，成人仅为6.7年。对于移植后存活超过一年的肺移植受者来说，长期生存的最大威胁是慢性肺移植物功能障碍（CLAD）的发生和进展，其中包括三种表型：闭塞性细支气管炎综合征（BOS）、嗜酸性可逆性同种异体移植物功能障碍和限制性同种异体移植物综合征，并且它们中的每一个的特征在于气道阻塞或限制，在所描述的各种细胞死亡途径中，铁凋亡是与两个主要生物化学特征（即铁积累和脂质过氧化）相关的ROS依赖性形式的细胞死亡，导致半胱天冬酶和坏死体非依赖性细胞死亡。缺血再灌注损伤（IRI）是发生慢性肺移植排斥反应的危险因素之一，最近的出版物将IRI的严重程度与铁凋亡现象联系起来。然而，诱导慢性排斥肺中铁凋亡细胞死亡的分子机制及其对BOS发展的贡献仍然是未知的，沿着其作为急需的治疗靶点的潜力。在这里，我们的目标是阐明免疫铁蛋白作为主要细胞死亡在慢性排斥性肺移植物中协调CLAD和BOS发展的特定机制的作用，并描述它们作为患者BOS生物标志物的潜力，以提高早期诊断。Alexey Dashkevich博士作为临床医生和Ali Önder Yildirim博士作为基础研究人员的共同应用应加强实验室研究结果的意义临床相关问题的答案