Proteases and cystic fibrosis

Voynow, Judith A.; Fischer, Bernard M.; Zheng, Shuo

doi:10.1016/j.biocel.2008.03.003

Cited by 173 publications

(168 citation statements)

References 102 publications

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“…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

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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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Section: Airway Proteases Aggravate Basic Cf Ion Transport Defectmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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“…Secreted actively (as a consequence of cell activation) or passively (as a consequence of necrotic cell death), neutrophil serine proteases (NSPs; e.g., neutrophil elastase [NE], cathepsin G [CG], and proteinase 3 [PR3]) are major contributors to neutrophil dysfunction. NE is considered a major contributor to a range of pulmonary pathologies, including cystic fibrosis (CF) (1)(2)(3), and is an important therapeutic target (3). Under well-controlled conditions in otherwise healthy individuals, NSPs contribute to the effective control of infection.…”

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confidence: 99%

Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor

Berg

Tambourgi

Clark

et al. 2014

The Journal of Immunology

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Neutrophil dysfunction, resulting in inefficient bacterial clearance, is a feature of several serious medical conditions, including cystic fibrosis (CF) and sepsis. Poorly controlled neutrophil serine protease (NSP) activity and complement activation have been implicated in this phenomenon. The capacity for excess NSP secretion and complement activation to influence the expression and function of the important neutrophil-activating receptor C5aR was investigated. Purified NSPs cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 cleaved C5aR to a 26- to 27-kDa membrane-bound fragment, thereby inactivating its C5a-induced signaling ability. In a supernatant transfer assay, NSPs released from neutrophils in response to C5a induced the cleavage of the C5aR on unstimulated cells. Stimulation of myeolomonocytic U937 cells and purified neutrophils with C5a resulted in downregulation of the C5aR on these cells, which, in the case of U937 cells, was largely caused by NSP-mediated cleavage of C5aR, but in the case of neutrophils, intracellular degradation was likely the main mediator in addition to a small role for NSPs. CG and NE in bronchoalveolar lavage fluid from CF patients both contributed to C5aR cleavage. We propose two converging models for C5a- and NSP-mediated neutrophil dysfunction whereby C5aR cleavage is induced by NSPs, secreted in response to: 1) excess C5a generation or other stimuli; or 2) necrosis. The consequent impairment of C5aR activity contributes to suboptimal local neutrophil priming and bacterial clearance. NSP inhibitors with specificity for both CG and NE may aid the treatment of pathologies associated with neutrophil dysfunction including sepsis and CF.

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“…This cleavage step releases soluble CXCR1, which stimulates IL-8 production by airway epithelial cells, thereby initiating a feedback circuit that amplifies neutrophil recruitment within the CF airways [46]. Extracellular neutrophil elastase can also [47]:…”

Section: Why Is It Important To Identify Molecular Factor(s) Associatmentioning

confidence: 99%