Alveolar Mitochondrial Quality Control During Acute Respiratory Distress Syndrome.
Alveolar Mitochondrial Quality Control During Acute Respiratory Distress Syndrome.
复制标题
急性呼吸窘迫综合征时肺泡线粒体的质量控制
DOI：
10.1016/j.labinv.2023.100197
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发表时间：
2023-09
影响因子：
5
通讯作者：
Suliman, Hagir B.
中科院分区：
文献类型：
--
作者：
Kraft, Bryan D.;Pavlisko, Elizabeth N.;Roggli, Victor L.;Piantadosi, Claude A.;Suliman, Hagir B.
关键词：
急性呼吸窘迫综合征（ARDS）是ICU患者呼吸衰竭和死亡的主要原因。在实验上，急性肺损伤（ALI）的解决取决于通过线粒体质量控制（MQC）途径、线粒体生物发生和线粒体自噬来修复线粒体氧化损伤，但在人类肺中对此一无所知。在一项病例对照尸检研究中，我们比较了死于ARDS的受试者（n=8;病例）和死于非肺部原因的年龄/性别匹配的受试者（n=7;对照）的肺部。通过光学显微镜和免疫荧光共聚焦显微镜检查载玻片，随机探测柠檬酸合酶（CS）与氧化应激、线粒体DNA损伤、线粒体自噬和线粒体生物发生标记物的共定位。ARDS肺表现为弥漫性肺泡损伤，伴有水肿、透明膜和中性粒细胞。与对照组相比，在2型上皮（AT 2）细胞和肺泡巨噬细胞的8-羟基脱氧鸟苷和丙二醛与CS共染色的线粒体氧化损伤程度很高。在ARDS中，抗氧化蛋白血红素氧合酶-1和DNA修复酶N-糖基化酶/DNA裂解酶（Ogg 1）在肺泡巨噬细胞中被发现，而不是AT 2细胞。此外，MAP 1轻链-3（LC 3）和丝氨酸/苏氨酸蛋白激酶（Pink 1）染色在AT 2细胞中不存在，表明线粒体自噬失败。核呼吸因子-1（NRF 1）染色在肺泡区缺失，表明线粒体生物合成受损。在ARDS中广泛的AT 2细胞过度增殖可能提示向1型细胞的分化缺陷。ARDS肺显示大量线粒体氧化剂DNA损伤，但AT 2上皮中几乎没有MQC活性的证据。由于这些途径对ALI的解决很重要，我们的研究结果支持MQC作为ARDS解决的新药理学靶点。
Acute respiratory distress syndrome (ARDS) is a leading cause of respiratory failure and death in ICU patients. Experimentally, acute lung injury (ALI) resolution depends on repair of mitochondrial oxidant damage by the mitochondrial quality control (MQC) pathways, mitochondrial biogenesis and mitophagy, but nothing is known about this in human lung. In a case-control autopsy study, we compared lungs of subjects dying of ARDS (n=8; cases) and age/gender-matched subjects dying of non-pulmonary causes (n=7; controls). Slides were examined by light microscopy and immunofluorescence confocal microscopy, randomly probing for co-localization of citrate synthase (CS) with markers of oxidant stress, mitochondrial DNA damage, mitophagy, and mitochondrial biogenesis. ARDS lungs showed diffuse alveolar damage with edema, hyaline membranes, and neutrophils. Compared with controls, a high degree of mitochondrial oxidant damage was seen in type 2 epithelial (AT2) cells and alveolar macrophages by 8-hydroxydeoxyguanosine and malondialdehyde co-staining with CS. In ARDS, anti-oxidant protein heme oxygenase-1 and DNA repair enzyme N-glycosylase/DNA lyase (Ogg1) were found in alveolar macrophages, but not AT2 cells. Moreover, MAP1 light chain-3 (LC3) and serine/threonine-protein kinase (Pink1) staining were absent in AT2 cells, suggesting mitophagy failure. Nuclear respiratory factor-1 (NRF1) staining was missing in the alveolar region, suggesting impaired mitochondrial biogenesis. Widespread hyper-proliferation of AT2 cells in ARDS could suggest defective differentiation into type 1 cells. ARDS lungs show profuse mitochondrial oxidant DNA damage, but little evidence of MQC activity in AT2 epithelium. Since these pathways are important for ALI resolution, our findings support MQC as a novel pharmacologic target for ARDS resolution.
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DOI：
10.1242/dev.163014
发表时间：
2018-05-11
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Chung MI;Bujnis M;Barkauskas CE;Kobayashi Y;Hogan BLM
通讯作者：
Hogan BLM
DOI：
10.1152/ajplung.00240.2015
发表时间：
2015-10-15
影响因子：
4.9
作者：
Fredenburgh, Laura E.;Kraft, Bryan D.;Piantadosi, Claude A.
通讯作者：
Piantadosi, Claude A.
影响因子：
7.4
作者：
Athale, Janhavi;Ulrich, Allison;MacGarvey, Nancy Chou;Bartz, Raquel R.;Welty-Wolf, Karen E.;Suliman, Hagir B.;Piantadosi, Claude A.
通讯作者：
Piantadosi, Claude A.
影响因子：
9.6
作者：
Cardinal-Fernandez, Pablo;Bajwa, Ednan K.;Thompson, B. Taylor
通讯作者：
Thompson, B. Taylor
影响因子：
8.8
作者：
Kraft, Bryan D.;Chen, Lingye;Welty-Wolf, Karen E.
通讯作者：
Welty-Wolf, Karen E.