Hannemann Juliane, Böger Rainer
Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany.
Front Med (Lausanne). 2022 Feb 17;9:835481. doi: 10.3389/fmed.2022.835481. eCollection 2022.
The pulmonary circulation responds to hypoxia with vasoconstriction, a mechanism that helps to adapt to short-lived hypoxic episodes. When sustained, hypoxic pulmonary vasoconstriction (HPV) may become deleterious, causing right ventricular hypertrophy and failure, and contributing to morbidity and mortality in the late stages of several chronic pulmonary diseases. Nitric oxide (NO) is an important endothelial vasodilator. Its release is regulated, amongst other mechanisms, by the presence of endogenous inhibitors like asymmetric dimethylarginine (ADMA). Evidence has accumulated in recent years that elevated ADMA may be implicated in the pathogenesis of HPV and in its clinical sequelae, like pulmonary arterial hypertension (PAH). PAH is one phenotypic trait in experimental models with disrupted ADMA metabolism. In high altitude, elevation of ADMA occurs during long-term exposure to chronic or chronic intermittent hypobaric hypoxia; ADMA is significantly associated with high altitude pulmonary hypertension. High ADMA concentration was also reported in patients with chronic obstructive lung disease, obstructive sleep apnoea syndrome, and overlap syndrome, suggesting a pathophysiological role for ADMA-mediated impairment of endothelium-dependent, NO-mediated pulmonary vasodilation in these clinically relevant conditions. Improved understanding of the molecular (dys-)regulation of pathways controlling ADMA concentration may help to dissect the pathophysiology and find novel therapeutic options for these diseases.
肺循环对缺氧的反应是血管收缩，这是一种有助于适应短暂缺氧发作的机制。当这种情况持续存在时，缺氧性肺血管收缩（HPV）可能会变得有害，导致右心室肥大和衰竭，并在几种慢性肺部疾病的晚期导致发病和死亡。一氧化氮（NO）是一种重要的内皮血管舒张剂。其释放受到多种机制的调节，其中包括内源性抑制剂如不对称二甲基精氨酸（ADMA）的存在。近年来积累的证据表明，ADMA升高可能与HPV的发病机制及其临床后果有关，如肺动脉高压（PAH）。PAH是ADMA代谢紊乱的实验模型中的一种表型特征。在高海拔地区，长期暴露于慢性或慢性间歇性低压缺氧期间会出现ADMA升高；ADMA与高原肺动脉高压显著相关。在慢性阻塞性肺疾病、阻塞性睡眠呼吸暂停综合征和重叠综合征患者中也报告了高ADMA浓度，这表明在这些临床相关情况下，ADMA介导的内皮依赖性、NO介导的肺血管舒张功能受损具有病理生理作用。更好地理解控制ADMA浓度的途径的分子（失调）调节可能有助于剖析这些疾病的病理生理学并找到新的治疗选择。
