Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency

Chest. 2021 Oct;160(4):1442-1458. doi: 10.1016/j.chest.2021.06.028. Epub 2021 Jun 26.


Background: Preclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation.

Research question: Are circulating NE and elafin levels abnormal in PAH and are they associated with clinical severity?

Study design and methods: 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.

Results: 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.

Interpretation: 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.

Keywords: biomarkers; elastase’ inflammation’ pulmonary arterial hypertension.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis / drug effects
  • Elafin / blood*
  • Elafin / pharmacology
  • Endothelial Cells / drug effects
  • Female
  • Humans
  • Leukocyte Elastase / blood*
  • Male
  • Middle Aged
  • Neovascularization, Physiologic / drug effects
  • Pancreatic Elastase / pharmacology
  • Pulmonary Arterial Hypertension / blood*
  • Pulmonary Arterial Hypertension / immunology
  • Pulmonary Arterial Hypertension / physiopathology
  • Pulmonary Artery / cytology
  • Severity of Illness Index
  • Vascular Resistance


  • Elafin
  • PI3 protein, human
  • Pancreatic Elastase
  • ELANE protein, human
  • Leukocyte Elastase