Lack of Neutrophil Elastase Reduces Inflammation, Mucus Hypersecretion, and Emphysema, but Not Mucus Obstruction, in Mice with Cystic Fibrosis–like Lung Disease

Gehrig, Stefanie; Duerr, Julia; Weitnauer, Michael; Wagner, Christina; Graeber, Simon Y.; Schatterny, Jolanthe; Hirtz, Stephanie; Belaaouaj, Abderrazzaq; Dalpke, Alexander H.; Schultz, Carsten; Mall, Marcus

doi:10.1164/rccm.201311-1932oc

Cited by 135 publications

(174 citation statements)

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“…On the other hand, Foucher et al demonstrated that immunization with human MPO and injection of neutrophil lysosomal extract into the lung of a rat resulted in severe pulmonary injuries (41). Because neutrophil elastase has been shown to cause fibrosis (42), emphysema (42,43), and airway inflammation (43), MPO-ANCA-associated activation and degranulation of neutrophils may directly injure these different pulmonary systems, independently of capillaritis.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Responsiveness to Treatment of Lung Abnormalities on Chest Computed Tomography in Patients With Microscopic Polyangiitis: A Multicenter, Longitudinal, Retrospective Study of One Hundred Fifty Consecutive Hospital‐Based Japanese Patients

Yamagata

Ikeda

Tsushima

et al. 2016

Arthritis & Rheumatology

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Objective. To determine the prevalence of lung abnormalities on chest computed tomography (CT) in patients with microscopic polyangiitis (MPA), to assess the responsiveness of such abnormalities to initial treatment, and to assess associations between these abnormalities and patient and disease characteristics and mortality.Methods. We retrospectively identified 167 consecutive hospital-based patients with MPA in 3 hospitals in Japan. We longitudinally collected clinical information for 150 of these patients, for whom CT images obtained before treatment were available. We then determined the presence of 22 imaging components of lung abnormalities in these patients.Results. The vast majority of patients (97%) had at least 1 lung abnormality on chest CT images, including interstitial lung lesions (66%), airway lesions (66%), pleural lesions (53%), and emphysematous lesions (37%). In multivariate analyses, ground-glass opacity was associated with the Birmingham Vasculitis Activity Score, whereas 3 of 4 airway lesions were associated with myeloperoxidase-antineutrophil cytoplasmic antibodies. Latent class analysis identified a distinct group of patients with airwaypredominant lung lesions. Airway lesions such as bronchiolitis and bronchovascular bundle thickening were among the components that showed improvement within 3 months of the initial treatment. An idiopathic pulmonary fibrosis pattern was the only chest CT variable that was independently associated with shorter survival.Conclusion. Abnormalities in a wide range of anatomic areas, including the whole airway, can be identified in the lungs of patients with MPA before treatment. The prevalence, clustering patterns, and responsiveness to treatment of individual lung abnormalities provide groundwork for informing future studies to understand the pathophysiology of MPA.Microscopic polyangiitis (MPA) is a necrotizing systemic vasculitis that affects small to medium-sized vessels. In MPA, immune deposits on the vessel wall are usually absent, and serum antineutrophil cytoplasmic antibodies (ANCAs) are frequently present. MPA shares these

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Section: Discussionmentioning

confidence: 99%

Prevalence and Responsiveness to Treatment of Lung Abnormalities on Chest Computed Tomography in Patients With Microscopic Polyangiitis: A Multicenter, Longitudinal, Retrospective Study of One Hundred Fifty Consecutive Hospital‐Based Japanese Patients

Yamagata

Ikeda

Tsushima

et al. 2016

Arthritis & Rheumatology

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“…We speculate that the persistent airspace enlargement may reflect at least two different scenarios. First, raised neutrophil elastase levels mediated by increased neutrophil numbers may have dominated emphysema pathophysiology, producing the observed worsening rather than amelioration of airspace enlargement (34,35). Second, immature macrophage populations may exhibit protease:antiprotease imbalance with increased protease release (matrix metalloproteinases) or/and decreased antiprotease release (tissue inhibitors of metalloproteinases [TIMPs]) (35,36).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses

Saini

Wilkinson²,

Terrell³

et al. 2016

Am J Respir Cell Mol Biol

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Resident immune cells (e.g., macrophages [MFs]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MF function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated MF depletion was generated, characterized, and crossed with the sodium channel b subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM 1 pulmonary MFs in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM 1 MF depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM 1 MF-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway mucus plugging. Bacterial burden (CFUs) was comparable between Scnn1b-Tg and nonpneumonic LysM 1 MF-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM 1 MF-depleted Scnn1b-Tg mice exhibited increased airway inflammation, the presence of neutrophilic infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid compared with Scnn1b-Tg mice. Collectively, these data identify key MF-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease.

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“…Collectively, these studies demonstrated that this mouse model exhibits many characteristic features of early CF lung disease [27][28][29]. Of note, the lung disease phenotype of older bENaC-Tg mice also shows some differences compared to patients with CF, such as transient eosinophilic inflammation, in addition to chronic airway neutrophilia at juvenile ages, and clearance of spontaneous bacterial airway infection and development of pulmonary emphysema rather than bronchiectasis in adult mice [26,27,[30][31][32][33].…”

Section: Airway Surface Dehydration: a Key Disease Mechanism In Cf Lumentioning

confidence: 96%

“…For example, recent studies showed that neutrophil elastase (NE), a major product released from activated neutrophils that has recently been identified as a key risk factor for the development of bronchiectasis in young children with CF diagnosed by newborn screening [38], is also a potent regulator of CFTR and ENaC. Besides its previously described roles in the modulation of airway inflammation, mucus hypersecretion, bacterial killing, and proteolytic lung and immune cell damage [32,[39][40][41][42], NE can activate ENaC by proteolytic cleavage and removal of ''inhibitory'' segments, probably leading to a conformational change of the channel that improves its conductivity for Na + [43,44]. Interestingly, a recent study showed that wild-type CFTR, but not DF508, interacts with ENaC in the plasma membrane of airway epithelial cells and, thus, may impede the proteolytic stimulation of ENaC by NE and potentially other extracellular proteases released by inflammatory cells [45,46].…”

Section: Airway Proteases Aggravate Basic Cf Ion Transport Defectmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

Self Cite

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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Lack of Neutrophil Elastase Reduces Inflammation, Mucus Hypersecretion, and Emphysema, but Not Mucus Obstruction, in Mice with Cystic Fibrosis–like Lung Disease

Cited by 135 publications

References 55 publications

Prevalence and Responsiveness to Treatment of Lung Abnormalities on Chest Computed Tomography in Patients With Microscopic Polyangiitis: A Multicenter, Longitudinal, Retrospective Study of One Hundred Fifty Consecutive Hospital‐Based Japanese Patients

Prevalence and Responsiveness to Treatment of Lung Abnormalities on Chest Computed Tomography in Patients With Microscopic Polyangiitis: A Multicenter, Longitudinal, Retrospective Study of One Hundred Fifty Consecutive Hospital‐Based Japanese Patients

Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses

CFTR: cystic fibrosis and beyond

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