NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.
NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.
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NKG2D受体激活会导致移植物功能障碍、严重程度和不良的肺移植结果。
DOI：
10.1172/jci.insight.164603
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发表时间：
2022-12-22
期刊：
影响因子：
8
通讯作者：
Looney, Mark R.
中科院分区：
文献类型：
--
作者：
Calabrese, Daniel R.;Tsao, Tasha;Magnen, Melia;Valet, Colin;Gao, Ying;Mallavia, Benat;Tian, Jennifer J.;Aminian, Emily A.;Wang, Kristin M.;Shemesh, Avishai;Punzalan, Elman B.;Sarma, Aartik;Calfee, Carolyn S.;Christenson, Stephanie A.;Langelier, Charles R.;Hays, Steven R.;Golden, Jeffrey A.;Leard, Lorriana E.;Kleinhenz, Mary Ellen;Kolaitis, Nicholas A.;Shah, Rupal;Venado, Aida;Lanier, Lewis L.;Greenland, John R.;Sayah, David M.;Ardehali, Abbas;Kukreja, Jasleen;Weigt, S. Samuel;Belperio, John A.;Singer, Jonathan P.;Looney, Mark R.
肺移植是终末期肺部疾病患者的一种挽救生命的治疗方法，其临床效果受到原发移植物功能障碍(PGD)的限制。PGD是一种急性肺损伤的早期形式，没有特殊的药物治疗。在这里，我们对移植后第一天收集的血浆和支气管肺泡灌洗(BAL)样本进行了一项大型多中心研究，这是研究与PGD相关的免疫途径的关键时间。我们发现，严重PGD患者的BAL中NKG2D受体的配体增加，且与拔管时间延长、重症监护病房住院时间延长和峰值肺功能不良有关。中性粒细胞胞外陷阱(NETs)在PGD中升高，并与BAL、肿瘤坏死因子-α和干扰素-γ细胞因子相关。从机制上讲，我们发现低氧刺激后呼吸道上皮细胞NKG2D配体增加。阻断NKG2D受体后，NK细胞对低氧呼吸道上皮细胞的杀伤作用被阻断，α和γ可刺激中性粒细胞释放Net。这些数据支持在人类PGD发病机制中存在NK细胞/中性粒细胞轴的异常。压力配体的早期测量和NKG2D受体的阻断为PGD的风险分层和管理提供了希望。
Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.
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影响因子：
30.5
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