School of Biological Sciences and Medical Engineering & Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health & Interdisciplinary Innovation Institute for Medicine and Engineering, Southeast University, Nanjing, China.
The Translational Research Institute for Neurological Disorders & Interdisciplinary Research Center of Neuromedicine and Chemical Biology of Wannan Medical College and Anhui Normal University, Department of Neurosurgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
Theranostics. 2023 Jan 22;13(3):991-1009. doi: 10.7150/thno.82552. eCollection 2023.
Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown. We investigated STIM-activating enhancer-positive ADEs (STIMATE ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATE , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE ADEs supplementation. In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATE mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca responsiveness and long-term Ca signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.
肺泡上皮细胞 (AECs) 的完全破坏是终末期肺部疾病的特征。已经提出了 II 型 AEC (AEC-II) 或 AEC-II 衍生的外泌体 (ADE) 的移植治疗作为修复损伤和预防纤维化的一种手段。然而，ADE 平衡气道免疫并减轻损伤和纤维化的机制尚不清楚。我们研究了 112 例 ALI/ARDS 和 44 例 IPF 患者肺中的 STIM 激活增强子阳性 ADE (STIMATE ADE)，并观察了 STIMATE ADE 与组织驻留肺泡巨噬细胞 (TRAMs) 的亚群比例和代谢状态之间的相关性。我们构建了条件敲除小鼠 STIMATE ，其中 STIMATE 特异性敲除了小鼠 AEC-IIs，并观察了 STIMATE ADE 缺乏对疾病进展、TRAMs 的免疫选择和代谢转换的影响。我们构建了 BLM 诱导的 AEC-II 损伤模型，观察了 STIMATE ADEs 补充对损伤/纤维化进展的挽救治疗作用。在临床分析中，ALI/ARFS 和 IPF 中 AM 的明显代谢表型被 STIMATE ADEs 显著扰乱。STIMATE 小鼠肺中的 TRAMs 的免疫和代谢状态失衡，导致自发性炎症损伤和呼吸障碍。STIMATE ADEs 被组织驻留的肺泡巨噬细胞 TRAMs 摄取，以调节高钙反应性和长期钙信号转导，从而维持 M2 样免疫表型和代谢选择。这涉及钙调神经磷酸酶 (CaN)-PGC-1α 途径介导的线粒体生物发生和 mtDNA 编码。在博来霉素诱导的小鼠纤维化模型中，补充吸入 STIMATE ADEs 可减轻早期急性损伤，预防晚期纤维化，缓解通气障碍并降低死亡率。
