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Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency
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 clini...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American College of Chest Physicians
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546243/ https://www.ncbi.nlm.nih.gov/pubmed/34181952 http://dx.doi.org/10.1016/j.chest.2021.06.028 |
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author | Sweatt, Andrew J. Miyagawa, Kazuya Rhodes, Christopher J. Taylor, Shalina Del Rosario, Patricia A. Hsi, Andrew Haddad, Francois Spiekerkoetter, Edda Bental-Roof, Michal Bland, Richard D. Swietlik, Emilia M. Gräf, Stefan Wilkins, Martin R. Morrell, Nicholas W. Nicolls, Mark R. Rabinovitch, Marlene Zamanian, Roham T. |
author_facet | Sweatt, Andrew J. Miyagawa, Kazuya Rhodes, Christopher J. Taylor, Shalina Del Rosario, Patricia A. Hsi, Andrew Haddad, Francois Spiekerkoetter, Edda Bental-Roof, Michal Bland, Richard D. Swietlik, Emilia M. Gräf, Stefan Wilkins, Martin R. Morrell, Nicholas W. Nicolls, Mark R. Rabinovitch, Marlene Zamanian, Roham T. |
author_sort | Sweatt, Andrew J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8546243 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American College of Chest Physicians |
record_format | MEDLINE/PubMed |
spelling | pubmed-85462432021-11-08 Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency Sweatt, Andrew J. Miyagawa, Kazuya Rhodes, Christopher J. Taylor, Shalina Del Rosario, Patricia A. Hsi, Andrew Haddad, Francois Spiekerkoetter, Edda Bental-Roof, Michal Bland, Richard D. Swietlik, Emilia M. Gräf, Stefan Wilkins, Martin R. Morrell, Nicholas W. Nicolls, Mark R. Rabinovitch, Marlene Zamanian, Roham T. Chest Pulmonary Vascular: Original Research 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. American College of Chest Physicians 2021-10 2021-06-26 /pmc/articles/PMC8546243/ /pubmed/34181952 http://dx.doi.org/10.1016/j.chest.2021.06.028 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Pulmonary Vascular: Original Research Sweatt, Andrew J. Miyagawa, Kazuya Rhodes, Christopher J. Taylor, Shalina Del Rosario, Patricia A. Hsi, Andrew Haddad, Francois Spiekerkoetter, Edda Bental-Roof, Michal Bland, Richard D. Swietlik, Emilia M. Gräf, Stefan Wilkins, Martin R. Morrell, Nicholas W. Nicolls, Mark R. Rabinovitch, Marlene Zamanian, Roham T. Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency |
title | Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency |
title_full | Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency |
title_fullStr | Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency |
title_full_unstemmed | Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency |
title_short | Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency |
title_sort | severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency |
topic | Pulmonary Vascular: Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546243/ https://www.ncbi.nlm.nih.gov/pubmed/34181952 http://dx.doi.org/10.1016/j.chest.2021.06.028 |
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