Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency.
Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency.
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DOI：
10.1016/j.chest.2021.06.028
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发表时间：
2021-10
期刊：
影响因子：
9.6
通讯作者：
Zamanian RT
中科院分区：
文献类型：
--
作者：
Sweatt AJ;Miyagawa K;Rhodes CJ;Taylor S;Del Rosario PA;Hsi A;Haddad F;Spiekerkoetter E;Bental-Roof M;Bland RD;Swietlik EM;Gräf S;Wilkins MR;Morrell NW;Nicolls MR;Rabinovitch M;Zamanian RT
临床前证据表明中性粒细胞弹性蛋白酶（NE）参与肺动脉高压（PAH）的发病机制，NE抑制剂elafin正在进行早期治疗研究。PAH患者的循环NE和弹力素水平是否异常，是否与临床严重程度相关？在斯坦福大学PAH观察性队列（n = 249）中，与健康对照参与者（n = 106）相比，测量血浆NE和弹性蛋白水平。然后将NE和弹力素测量值与PAH临床特征和相关辅助生物标志物相关。用三次样条函数拟合考克斯回归模型，以将NE和弹性蛋白酶水平与存活率相关联。为了验证预后关系，我们分析了两个英国队列（n = 75和n = 357）。混合效应模型评价了疾病进展期间NE和弹力素的变化。最后，我们研究了NE-弹力素平衡对PAH患者肺动脉内皮细胞（PAECs）的影响。相对于对照参与者，PAH患者的NE水平升高（205.1 ng/mL [四分位距（IQR），123.6-387.3 ng/mL] vs 97.6 ng/mL [IQR，74.4-126.6 ng/mL]; P < .0001）和弹性蛋白水平降低（32.0 ng/mL [IQR，15.3-59.1 ng/mL] vs 45.5 ng/mL [IQR，28.1-92.8 ng/mL]; P < .0001），与PAH亚型、病程和治疗无关。NE水平升高与症状严重程度加重、6分钟步行距离缩短、N末端脑钠肽前体水平升高、右心室功能障碍加重、血流动力学恶化、循环中性粒细胞水平升高、细胞因子水平升高和血液BMPR 2表达降低相关。在斯坦福大学患者中，NE水平> 168.5 ng/mL预示着在校正已知临床预测因子（风险比[HR]，2.52; CI，1.36-4.65，P = .003）或预后细胞因子（HR，2.63; CI，1.42-4.87; P = .001）后死亡风险增加，NE水平增加了已建立的PAH风险评分的增量值。在验证队列中确定了相似的预后阈值。纵向NE变化与临床趋势和结局一起跟踪。PAH PAEC在暴露于患者血液中观察到的NE水平时表现出凋亡增加和血管生成减弱。Elafin挽救了PAEC的稳态，但所需的剂量超过了患者的水平。NE的血液水平增加，而弹性蛋白水平在PAH亚型中缺乏。较高的NE水平与更差的临床疾病严重程度和结果相关，并且这种靶向特异性生物标志物可以促进弹性蛋白酶的治疗开发。
Preclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation. Are circulating NE and elafin levels abnormal in PAH and are they associated with clinical severity? In an observational Stanford University PAH cohort (n = 249), plasma NE and elafin levels were measured in comparison with those of healthy control participants (n = 106). NE and elafin measurements were then related to PAH clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin levels with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (n = 75 and n = 357). Mixed-effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE-elafin balance on pulmonary artery endothelial cells (PAECs) from patients with PAH. Relative to control participants, patients with PAH were found to have increased NE levels (205.1 ng/mL [interquartile range (IQR), 123.6-387.3 ng/mL] vs 97.6 ng/mL [IQR, 74.4-126.6 ng/mL]; P < .0001) and decreased elafin levels (32.0 ng/mL [IQR, 15.3-59.1 ng/mL] vs 45.5 ng/mL [IQR, 28.1-92.8 ng/mL]; P < .0001) independent of PAH subtype, illness duration, and therapies. Higher NE levels were associated with worse symptom severity, shorter 6-min walk distance, higher N-terminal pro-type brain natriuretic peptide levels, greater right ventricular dysfunction, worse hemodynamics, increased circulating neutrophil levels, elevated cytokine levels, and lower blood BMPR2 expression. In Stanford patients, NE levels of > 168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (hazard ratio [HR], 2.52; CI, 1.36-4.65, P = .003) or prognostic cytokines (HR, 2.63; CI, 1.42-4.87; P = .001), and the NE level added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients’ blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients. Blood levels of NE are increased while elafin levels are deficient across PAH subtypes. Higher NE levels are associated with worse clinical disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin.
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影响因子：
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