Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA; Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA.
Department of Pediatrics-Cardiology, Stanford University, Stanford, CA; Betty Irene Moore Children's Heart Center, Stanford University, Stanford, CA.
Chest. 2021 Oct;160(4):1442-1458. doi: 10.1016/j.chest.2021.06.028. Epub 2021 Jun 26.
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.
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 正处于早期治疗研究中。
PAH 患者的循环 NE 和 Elafin 水平是否异常，它们与临床严重程度是否相关？
在斯坦福大学 PAH 队列的一项观察性研究中（n=249），与健康对照组参与者（n=106）进行比较，测量了血浆 NE 和 Elafin 水平。然后，将 NE 和 Elafin 测量值与 PAH 的临床特征和相关辅助生物标志物相关联。采用三次样条函数拟合 Cox 回归模型，以将 NE 和 Elafin 水平与生存相关联。为了验证预后关系，我们分析了两个英国队列（n=75 和 n=357）。混合效应模型评估了疾病进展过程中 NE 和 Elafin 的变化。最后，我们研究了 NE-Elafin 平衡对 PAH 患者肺动脉内皮细胞（PAEC）的影响。
与对照组参与者相比，PAH 患者的 NE 水平升高（205.1ng/mL [四分位距（IQR），123.6-387.3ng/mL] vs 97.6ng/mL [IQR，74.4-126.6ng/mL]；P<0.0001），Elafin 水平降低（32.0ng/mL [IQR，15.3-59.1ng/mL] vs 45.5ng/mL [IQR，28.1-92.8ng/mL]；P<0.0001），与 PAH 亚型、疾病持续时间和治疗无关。较高的 NE 水平与更严重的症状严重程度、更短的 6 分钟步行距离、更高的 N 末端前脑利钠肽水平、更严重的右心室功能障碍、更差的血液动力学、更高的循环中性粒细胞水平、更高的细胞因子水平和更低的血液 BMPR2 表达相关。在斯坦福大学的患者中，NE 水平 >168.5ng/mL 预示着在调整已知临床预测因子（风险比 [HR]，2.52；95%CI，1.36-4.65，P=0.003）或预后细胞因子（HR，2.63；95%CI，1.42-4.87；P=0.001）后死亡风险增加，并且该 NE 水平增加了既定的 PAH 风险评分的附加值。在验证队列中也发现了类似的预后阈值。NE 的纵向变化与临床趋势和结果相关。当将 NE 暴露于患者血液中观察到的水平时，PAH PAEC 表现出增加的凋亡和减弱的血管生成。Elafin 挽救了 PAEC 稳态，但所需剂量超过了患者中的水平。
无论 PAH 亚型如何，血液中的 NE 水平升高，而 Elafin 水平降低。较高的 NE 水平与更严重的临床疾病严重程度和结局相关，这种靶向特异性生物标志物可以促进 Elafin 的治疗开发。
