Nourkami-Tutdibi Nasenien, Küllmer Jennifer, Dietrich Sven, Monz Dominik, Zemlin Michael, Tutdibi Erol
Saarland University Medical Center, Hospital for General Pediatrics and Neonatology, Homburg, Germany.
Front Physiol. 2023 Mar 30;14:1083808. doi: 10.3389/fphys.2023.1083808. eCollection 2023.
Acute mountain sickness (AMS) is the most common disease caused by hypobaric hypoxia (HH) in high-altitude (HA) associated with high mortality when progressing to high-altitude pulmonary edema (HAPE) and/or high-altitude cerebral edema (HACE). There is evidence for a role of pro- and anti-inflammatory cytokines in development of AMS, but biological pathways and molecular mechanisms underlying AMS remain elusive. We aimed to measure changes in blood cytokine levels and their possible association with the development of AMS. 15 healthy mountaineers were included into this prospective clinical trial. All participants underwent baseline normoxic testing with venous EDTA blood sampling at the Bangor University in United Kingdom (69 m). The participants started from Beni at an altitude of 869 m and trekked same routes in four groups the Dhaulagiri circuit in the Nepali Himalaya. Trekking a 14-day route, the mountaineers reached the final HA of 5,050 m at the Hidden Valley Base Camp (HVBC). Venous EDTA blood sampling was performed after active ascent to HA the following morning after arrival at 5,050 m (HVBC). A panel of 21 cytokines, chemokines and growth factors were assessed using Luminex system (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-1ra, sIL-2Rα, IFN-γ, TNF-α, MCP-1, MIP-1α, MIP-1β, IP-10, G-CSF, GM-CSF, EGF, FGF-2, VEGF, and TGF-β1). There was a significant main effect for the gradual ascent from sea-level (SL) to HA on nearly all cytokines. Serum levels for TNF-α, sIL-2Rα, G-CSF, VEGF, EGF, TGF-β1, IL-8, MCP-1, MIP-1β, and IP-10 were significantly increased at HA compared to SL, whereas levels for IFN-γ and MIP-1α were significantly decreased. Serum VEGF was higher in AMS susceptible AMS resistant subjects ( < 0.027, main effect of AMS) and increased after ascent to HA in both AMS groups ( < 0.011, main effect of HA). Serum VEGF increased more from SL values in the AMS susceptible group than in the AMS resistant group ( < 0.049, interaction effect). Cytokine concentrations are significantly altered in HA. Within short interval after ascent, cytokine concentrations in HH normalize to values at SL. VEGF is significantly increased in mountaineers suffering from AMS, indicating its potential role as a biomarker for AMS.
急性高原病（AMS）是高原地区低压缺氧（HH）导致的最常见疾病，若进展为高原肺水肿（HAPE）和/或高原脑水肿（HACE），则死亡率很高。有证据表明促炎和抗炎细胞因子在AMS的发生中起作用，但AMS的生物学途径和分子机制仍不清楚。我们旨在测量血液细胞因子水平的变化及其与AMS发生的可能关联。15名健康登山者被纳入这项前瞻性临床试验。所有参与者在英国班戈大学（海拔69米）进行了基线常氧测试，并采集静脉乙二胺四乙酸（EDTA）血样。参与者从海拔869米的贝尼出发，分四组沿相同路线徒步，即尼泊尔喜马拉雅山的道拉吉里环线。经过14天的徒步，登山者到达了隐谷大本营（HVBC），最终海拔为5050米。到达5050米（HVBC）后的第二天早上，在主动上升到高原后采集静脉EDTA血样。使用Luminex系统评估了一组21种细胞因子、趋化因子和生长因子（白细胞介素-1β、白细胞介素-2、白细胞介素-4、白细胞介素-6、白细胞介素-8、白细胞介素-10、白细胞介素-12p40、白细胞介素-1受体拮抗剂、可溶性白细胞介素-2受体α、干扰素-γ、肿瘤坏死因子-α、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白-1α、巨噬细胞炎性蛋白-1β、干扰素诱导蛋白10、粒细胞集落刺激因子、粒细胞-巨噬细胞集落刺激因子、表皮生长因子、成纤维细胞生长因子-2、血管内皮生长因子和转化生长因子-β1）。从海平面（SL）逐渐上升到高原对几乎所有细胞因子都有显著的主要影响。与海平面相比，高原地区肿瘤坏死因子-α、可溶性白细胞介素-2受体α、粒细胞集落刺激因子、血管内皮生长因子、表皮生长因子、转化生长因子-β1、白细胞介素-8、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白-1β和干扰素诱导蛋白10的血清水平显著升高，而干扰素-γ和巨噬细胞炎性蛋白-1α的水平显著降低。在AMS易感和AMS抗性受试者中，血清血管内皮生长因子较高（P<0.027，AMS的主要影响），并且在两个AMS组中上升到高原后均升高（P<0.011，高原的主要影响）。与AMS抗性组相比，AMS易感组中血清血管内皮生长因子从海平面值升高得更多（P<0.049，交互作用）。高原地区细胞因子浓度显著改变。在上升后的短时间内，HH中的细胞因子浓度恢复到海平面时的值。患有AMS的登山者中血管内皮生长因子显著升高，表明其作为AMS生物标志物的潜在作用。
