Clifton Heather L, Machin Daniel R, Groot H Jonathan, Frech Tracy M, Donato Anthony J, Richardson Russell S, Wray D Walter
Geriatric Research, Education, and Clinical Center, George E. Wahlen VA Medical Center, Salt Lake City, UT, USA.
Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, USA.
Exp Physiol. 2018 Oct;103(10):1412-1424. doi: 10.1113/EP086991. Epub 2018 Aug 18.
What is the central question of this study? Do systemic sclerosis patients exhibit impaired nitric oxide-mediated vascular function of the lower limb and are these decrements correlated with plasma biomarkers for inflammation and oxidative stress? What is the main finding and its importance? Findings indicate impaired nitric oxide-mediated vascular function, linked to the incidence of digital ulcers and a milieu of inflammation and oxidative stress. However, the absence of significant correlations between individual biomarkers and blood flow responses suggests that the vasculopathy observed in systemic sclerosis may not be solely the result of derangements in the redox balance or inflammatory signalling.
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, which may be the consequence of inflammation and oxidative stress that ultimately leads to a reduced nitric oxide (NO) bioavailability. Passive leg movement (PLM) is a novel methodology for assessing lower limb vascular function that is predominantly NO dependent. We combined this vascular assessment with a comprehensive panel of plasma biomarkers to assess the axis of inflammation, oxidative stress and NO in SSc patients (n = 12; 62 ± 11 years of age) compared with healthy control subjects (n = 17; 60 ± 16 years of age). The PLM-induced changes in leg blood flow (LBF; 191 ± 104 versus 327 ± 217 ml min ) and LBF area under the curve (39 ± 104 versus 125 ± 131 ml) were reduced in SSc compared with control subjects. Stratification of patients according to history of digital ulcer (DU) formation revealed a further reduction in LBF area under the curve in DU (-13 ± 83 ml) versus non-DU (91 ± 102 ml) patients. Biomarkers of inflammation (C-reactive protein) and oxidative stress (malondialdehyde and protein carbonyl) were all elevated in SSc (C-reactive protein, 3299 ± 2372 versus 984 ± 565 ng ml ; malondialdehyde, 3.2 ± 1.1 versus 1.1 ± 0.7 μm; and protein carbonyl, 0.15 ± 0.05 versus 0.12 ± 0.03 nmol mg ), and C-reactive protein was further elevated in patients with a history of DU (4551 ± 2752 versus 2047 ± 1019 ng ml ) compared with non-DU, although these were not individually correlated with changes in LBF. These findings of impaired NO-mediated vascular function, linked to DU and a milieu of inflammation and oxidative stress, suggest that redox balance plays an important, but not necessarily deterministic, role in the vascular pathophysiology of SSc.
本研究的核心问题是什么？系统性硬化症患者下肢一氧化氮介导的血管功能是否受损，这些减退与炎症和氧化应激的血浆生物标志物是否相关？主要发现及其重要性是什么？研究结果表明一氧化氮介导的血管功能受损，与指端溃疡的发生率以及炎症和氧化应激环境有关。然而，个体生物标志物与血流反应之间缺乏显著相关性，这表明系统性硬化症中观察到的血管病变可能不仅仅是氧化还原平衡或炎症信号紊乱的结果。
系统性硬化症（SSc）是一种以血管病变为特征的自身免疫性疾病，这可能是炎症和氧化应激的结果，最终导致一氧化氮（NO）生物利用度降低。被动腿部运动（PLM）是一种评估下肢血管功能的新方法，主要依赖于NO。我们将这种血管评估与一组全面的血浆生物标志物相结合，以评估SSc患者（n = 12；62±11岁）与健康对照受试者（n = 17；60±16岁）中炎症、氧化应激和NO轴。与对照受试者相比，SSc患者中PLM诱导的腿部血流（LBF；191±104对327±217 ml/min）和LBF曲线下面积（39±104对125±131 ml）降低。根据指端溃疡（DU）形成病史对患者进行分层显示，DU患者（-13±83 ml）的LBF曲线下面积相对于非DU患者（91±102 ml）进一步降低。炎症生物标志物（C反应蛋白）和氧化应激生物标志物（丙二醛和蛋白质羰基）在SSc患者中均升高（C反应蛋白，3299±2372对984±565 ng/ml；丙二醛，3.2±1.1对1.1±0.7 μmol；蛋白质羰基，0.15±0.05对0.12±0.03 nmol/mg），与非DU患者相比，有DU病史的患者C反应蛋白进一步升高（4551±2752对2047±1019 ng/ml），尽管这些与LBF变化无个体相关性。这些一氧化氮介导的血管功能受损的发现，与DU以及炎症和氧化应激环境有关，表明氧化还原平衡在SSc的血管病理生理学中起重要但不一定是决定性的作用。
