Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis

Dittrich, Anna‐Maria; Kühbandner, Iris; Gehrig, Stefanie; Rickert-Zacharias, Verena; Twigg, Matthew S.; Wege, Sabine; Taggart, Clifford C.; Herth, Felix J.F.; Schultz, Carsten; Mall, Marcus

doi:10.1183/13993003.01910-2017

Cited by 73 publications

(79 citation statements)

References 41 publications

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“…60 While both surface-bound and free elastase correlated with FEV 1 , only surface-bound elastase activity correlated with FRC. 60 Perhaps surface-bound elastase activity could serve as a biomarker for worsening lung hyperinflation. Given the central role of the neutrophil and its products in CF airway pathophysiology, an effective anti-inflammatory drug necessarily will have to address either the neutrophil itself or its products.…”

Section: Neutrophilsmentioning

confidence: 91%

“…In addition to being free in the airway lumen, active neutrophil elastase can also be detected on the surface of neutrophils. Surface‐bound elastase activity was increased on the surface of neutrophils from people with CF compared to healthy volunteers, and it correlated with free elastase activity and concentrations of other inflammatory mediators . While both surface‐bound and free elastase correlated with FEV 1 , only surface‐bound elastase activity correlated with FRC .…”

Section: Cellular Contributions To the Cf Airway Inflammatory Responsementioning

confidence: 99%

“…Surface‐bound elastase activity was increased on the surface of neutrophils from people with CF compared to healthy volunteers, and it correlated with free elastase activity and concentrations of other inflammatory mediators . While both surface‐bound and free elastase correlated with FEV 1 , only surface‐bound elastase activity correlated with FRC . Perhaps surface‐bound elastase activity could serve as a biomarker for worsening lung hyperinflation.…”

Section: Cellular Contributions To the Cf Airway Inflammatory Responsementioning

confidence: 99%

See 2 more Smart Citations

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

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Section: Neutrophilsmentioning

confidence: 91%

Section: Cellular Contributions To the Cf Airway Inflammatory Responsementioning

confidence: 99%

Section: Cellular Contributions To the Cf Airway Inflammatory Responsementioning

confidence: 99%

See 1 more Smart Citation

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

View full text Add to dashboard Cite

show abstract

“…Levels of 20 inflammatory mediators were measured in BALF using a multiplexed high-sensitivity chemiluminescent assay (U-plex; Meso Scale Diagnostics), per the manufacturer's protocol. Free extracellular NE activity was measured using a conventional spectrophotometric assay (28) based on the chromogenic substrate N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (working range, 0.02-12.0 mg/ml), and the FRET-based NEmo-1 probe (Sirius Fine Chemicals SiChem GmbH), as previously described (37)(38)(39). The NEmo-1 probe was also used to assess the potential of native BALF from children with CF to inhibit NE activity, as before (38).…”

Section: Balf Assays For Inflammatory Mediators and Free Extracellulamentioning

confidence: 99%

“…To address this question, we performed phenotyping of airway leukocytes from children with CF using flow and image cytometry (35). Concomitantly, we used chest CT scans scored with the sensitive Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) tool recently developed for early disease monitoring (36), and free extracellular NE activity measurement by a Förster resonance energy transfer (FRET)based method (37)(38)(39). Our findings support the notion that NE exocytosis by airway neutrophils occurs in children with CF, and that its cellular measure correlates with early lung damage.…”

mentioning

confidence: 99%

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

Margaroli

Garratt

Horati

et al. 2019

Am J Respir Crit Care Med

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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.

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Mucus obstruction and inflammation in early cystic fibrosis lung disease: Emerging role of the IL‐1 signaling pathway

Balázs

Mall

2019

Pediatric Pulmonology

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Mucus plugging constitutes a nutrient‐rich nidus for a bacterial infection that has long been recognized as a potent stimulus for neutrophilic airway inflammation driving progressive lung damage in people with cystic fibrosis (CF). However, mucus plugging and neutrophilic inflammation are already present in many infants and young children with CF even in the absence of detectable bacterial infection. A series of observational studies in young children with CF, as well as investigations in animal models with CF‐like lung disease support the concept that mucus plugging per se can trigger inflammation before the onset of airways infection. Here we review emerging evidence suggesting that activation of the interleukin‐1 (IL‐1) signaling pathway by hypoxic epithelial cell necrosis, leading to the release of IL‐1α in mucus‐obstructed airways, may be an important mechanistic link between mucus plugging and sterile airway inflammation in early CF lung disease. Furthermore, we discuss recent data from preclinical studies demonstrating that treatment with the IL‐1 receptor (IL‐1R) antagonist anakinra has anti‐inflammatory as well as mucus modulating effects in mice with CF‐like lung disease and primary cultures of human CF airway epithelia. Collectively, these studies support an important role of the IL‐1 signaling pathway in sterile neutrophilic inflammation and mucus hypersecretion and suggest inhibition of this pathway as a promising anti‐inflammatory strategy in patients with CF and potentially other muco‐obstructive lung diseases.

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Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis

Cited by 73 publications

References 41 publications

Inflammation in cystic fibrosis: An update

Inflammation in cystic fibrosis: An update

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

Mucus obstruction and inflammation in early cystic fibrosis lung disease: Emerging role of the IL‐1 signaling pathway

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