Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis

AREST-CF and IMPEDE-CF

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

Original languageEnglish
Pages (from-to)873-881
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume199
Issue number7
DOIs
Publication statusPublished - 1 Apr 2019

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Pancreatic Elastase
Exocytosis
Cystic Fibrosis
Neutrophils
Lung
Dimercaprol
Leukocytes
Image Cytometry
Bronchiectasis
Energy Transfer
Protease Inhibitors
Flow Cytometry
Peptide Hydrolases
Anti-Inflammatory Agents
Thorax
Biomarkers
Tomography
Inflammation

Cite this

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title = "Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis",
abstract = "Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and F{\"o}rster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.",
keywords = "Air trapping, Degranulation, Mucus plugging, Proteolysis, Scavenging",
author = "{AREST-CF and IMPEDE-CF} and Camilla Margaroli and Garratt, {Luke W.} and Hamed Horati and Dittrich, {A. Susanne} and Timothy Rosenow and Montgomery, {Samuel T.} and Frey, {Dario L.} and Brown, {Milton R.} and Carsten Schultz and Lokesh Guglani and Anthony Kicic and Limin Peng and Scholte, {Bob J.} and Mall, {Marcus A.} and Janssens, {Hettie M.} and Stick, {Stephen M.} and Rabindra Tirouvanziam",
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language = "English",
volume = "199",
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journal = "American Journal of Respiratory Critical Care Medicine",
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Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis. / AREST-CF and IMPEDE-CF.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 199, No. 7, 01.04.2019, p. 873-881.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis

AU - AREST-CF and IMPEDE-CF

AU - Margaroli, Camilla

AU - Garratt, Luke W.

AU - Horati, Hamed

AU - Dittrich, A. Susanne

AU - Rosenow, Timothy

AU - Montgomery, Samuel T.

AU - Frey, Dario L.

AU - Brown, Milton R.

AU - Schultz, Carsten

AU - Guglani, Lokesh

AU - Kicic, Anthony

AU - Peng, Limin

AU - Scholte, Bob J.

AU - Mall, Marcus A.

AU - Janssens, Hettie M.

AU - Stick, Stephen M.

AU - Tirouvanziam, Rabindra

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

AB - Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

KW - Air trapping

KW - Degranulation

KW - Mucus plugging

KW - Proteolysis

KW - Scavenging

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U2 - 10.1164/rccm.201803-0442OC

DO - 10.1164/rccm.201803-0442OC

M3 - Article

VL - 199

SP - 873

EP - 881

JO - American Journal of Respiratory Critical Care Medicine

JF - American Journal of Respiratory Critical Care Medicine

SN - 1073-449X

IS - 7

ER -