Bailey Damian M, Culcasi Marcel, Filipponi Teresa, Brugniaux Julien V, Stacey Benjamin S, Marley Christopher J, Soria Rodrigo, Rimoldi Stefano F, Cerny David, Rexhaj Emrush, Pratali Lorenza, Salmòn Carlos Salinas, Jáuregui Carla Murillo, Villena Mercedes, Villafuerte Francisco, Rockenbauer Antal, Pietri Sylvia, Scherrer Urs, Sartori Claudio
Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Wales, UK.
Aix Marseille Univ, CNRS, ICR, UMR, 7273, Marseille, France.
Free Radic Biol Med. 2022 May 1;184:99-113. doi: 10.1016/j.freeradbiomed.2022.03.028. Epub 2022 Apr 6.
Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = <0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = <0.001 vs. CMS-) subsequent to liberation of free 'catalytic' iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = <0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = <0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = <0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r = -0.692 to 0.595, P = <0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+. TRIAL REGISTRY: ClinicalTrials.gov; No: NCT01182792; URL: www.clinicaltrials.gov.
慢性高原病（CMS）是一种高原适应不良综合征，其特征是由于自由基介导的血管一氧化氮（NO）生物利用度降低，导致全身氧化亚硝化应激（OXNOS）升高。为了更好地确定潜在机制和血管后果，本研究将健康男性低地居民（海拔80米，n = 10）与年龄/性别匹配、在玻利维亚拉巴斯出生并长大的高原居民（海拔3600米）进行了比较，其中有慢性高原病的（CMS+，n = 10）和无慢性高原病的（CMS-，n = 10）。使用电子顺磁共振光谱和基于还原臭氧的化学发光法对头静脉血进行检测。通过饮食回忆评估营养摄入情况。使用双功超声和压平式眼压计，通过血流介导的血管舒张、主动脉脉搏波速度和颈动脉内膜中层厚度评估全身血管功能和结构。高原居民的基础全身OXNOS持续升高（与低地居民相比，P = <0.001），在CMS+中进一步加剧，表现为在游离“催化”铁释放后羟基自由基自旋加合物形成增加（与CMS-相比，P = <0.001），这与芬顿和/或亲核加成机制一致。同时伴有整体蛋白质羰基化升高（与CMS-相比，P = 0.046）和血浆亚硝酸盐相应降低（与低地居民相比，P = <0.001）。高原居民维生素C、维生素E、胡萝卜素、镁和视黄醇的饮食摄入量较低，尤其是CMS+中由于水果和蔬菜消费减少而严重缺乏（与低地居民/CMS-相比，P = <0.001至0.028）。高原居民的全身血管功能和结构也受损（与低地居民相比，P = <0.001至0.040），在CMS+中观察到更明显的功能障碍（与CMS-相比，P = 0.035至0.043），与全身OXNOS成正比（r = -0.692至0.595，P = <0.001至0.045）。总体而言，这些发现表明，终生暴露于铁催化的全身OXNOS，再加上抗氧化微量营养素的饮食缺乏，可能导致CMS+中的全身血管并发症以及发病率/死亡率增加。试验注册：ClinicalTrials.gov；编号：NCT01182792；网址：www.clinicaltrials.gov。
