Hypoxic Pulmonary Vasoconstriction From Molecular Mechanisms to Medicine
Hypoxic Pulmonary Vasoconstriction From Molecular Mechanisms to Medicine
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DOI：
10.1016/j.chest.2016.09.001
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发表时间：
2017-01-01
期刊：
影响因子：
9.6
通讯作者：
Archer, Stephen L.
中科院分区：
文献类型：
--
作者：
Dunham-Snary, Kimberly J.;Wu, Danchen;Archer, Stephen L.
肺血管收缩功能减退（HPV）是肺血管系统固有的一种自我平衡机制。肺内动脉收缩以应对肺泡缺氧，将血液转移到氧合更好的肺段，从而优化通气/灌注匹配和全身氧气输送。线粒体传感器动态改变肺动脉平滑肌细胞（PASMC）中的活性氧和氧化还原对，以响应肺泡缺氧。这抑制钾通道，使PASMC去极化，激活电压门控钙通道，并增加细胞溶质钙，引起血管收缩。持续缺氧激活rho激酶，加强血管收缩，和缺氧诱导因子（HIF）-1 α，导致不利的肺血管重塑和肺动脉高压（PH）。在不通气的胎肺中，HPV将血液转移到全身血管系统。出生后，HPV通常作为局灶性肺炎或肺不张的局部稳态反应发生，其优化全身PO 2而不改变肺动脉压（PAP）。在单肺麻醉中，HPV减少了流向非通气肺的血流量，从而有利于胸外科手术。在高海拔地区，全身缺氧引起弥漫性HPV，增加PAP，并启动PH。夸大或异质性HPV有助于高海拔肺水肿。相反，受损的HPV，无论是由于疾病（如COPD，败血症）或血管扩张药物，促进全身低氧血症。这种氧敏感通路的遗传和表观遗传异常可触发HIF-1 α的常氧激活，并可促进异常代谢和细胞增殖。由此产生的假性缺氧状态是瓦尔堡代谢转变的基础，并有助于PH的瘤样表型。HPV和氧传感在人类健康和疾病中是重要的。
Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict inresponse toalveolarhypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusionmatching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1 alpha, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic PO2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1 alpha and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.