Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20251, Germany.
Department of Neuropathology, Charite - Universitätsmedizin Charitéplatz 1 | Virchowweg 15, Berlin 10117, Germany.
Cell Death Dis. 2017 Aug 24;8(8):e3005. doi: 10.1038/cddis.2017.403.
In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (V/V) correlating with mortality. High V/V results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.
成人呼吸窘迫综合征（ARDS）中，肺灌注衰竭会导致生理无效腔（V/V）增加，与死亡率相关。无效腔增加会导致肺泡低碳酸血症，这已被证明会导致水肿形成、肺不张和表面活性剂耗竭，至少部分是通过肺泡上皮细胞（AEC）凋亡引起的。然而，低碳酸血症诱导的 AEC 凋亡的机制尚不清楚。在这里，我们使用培养的 AEC 类型 2 的荧光活细胞成像技术表明，就 CO 感应而言，三羧酸循环酶异柠檬酸脱氢酶（IDH）3 似乎是一个重要的参与者，因为低碳酸血症独立于 pH 导致 IDH3 活性升高，随后 NADH 增加，NADH 是呼吸链的底物。因此，线粒体跨膜电位（ΔΨ）上升导致 Ca 从细胞质转移到线粒体，而 IDH3 敲低抑制了这些反应。此外，低碳酸血症诱导的线粒体 Ca 摄取导致活性氧（ROS）的产生，而线粒体 Ca 摄取和 ROS 产生都诱导了细胞凋亡。因此，我们提供的证据表明，在 AEC 类型 2 中，低碳酸血症诱导 IDH3 活性升高，导致细胞凋亡。这一发现可能为 ARDS 的发病机制提供新的见解，并有助于开发减少 ARDS 组织损伤的新策略。
