scholarly journals CFTR: cystic fibrosis and beyond

2014 ◽  
Vol 44 (4) ◽  
pp. 1042-1054 ◽  
Author(s):  
Marcus A. Mall ◽  
Dominik Hartl
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Lessons Learned ◽  
Chronic Obstructive ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Obstructive Pulmonary Disease ◽  
Airway Diseases ◽  
Δf508 Cftr

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 ΔF508-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.

Pulmonary Evaluation

2016 ◽  
pp. 747-766
Author(s):  
Vivek N. Iyer
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cystic Fibrosis ◽  
Lung Disease ◽  
Lung Diseases ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Airway Stenosis ◽  
Obstructive Lung Diseases ◽  
Diffuse Panbronchiolitis ◽  
Antitrypsin Deficiency

Obstructive lung diseases include chronic obstructive pulmonary disease (COPD) (eg, chronic bronchitis and emphysema), asthma, bronchiectasis, cystic fibrosis, obliterative bronchiolitis, and diffuse panbronchiolitis (eg, bullous lung disease, α‎1-antitrypsin deficiency, and airway stenosis). The 2 most prevalent obstructive lung diseases are COPD and asthma.

Respiratory issues in rehabilitation

2019 ◽  
pp. 233-250
Author(s):  
Manoj Sivan ◽  
Margaret Phillips ◽  
Ian Baguley ◽  
Melissa Nott
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cystic Fibrosis ◽  
Lung Disease ◽  
Pulmonary Rehabilitation ◽  
The Other ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Respiratory Impairment ◽  
Neurological Conditions ◽  
Respiratory Conditions

Respiratory aspects of rehabilitation fall into two broad and overlapping categories. One is that of pulmonary rehabilitation which traditionally has focused on exercise, behaviour change, and educational-based intervention for those with chronic lung disease, predominantly chronic obstructive pulmonary disease, but its efficacy has since been proven in other chronic respiratory conditions (e.g. asthma, interstitial lung disease, cystic fibrosis, bronchiectasis, lung transplantation, and pulmonary hypertension). The other is rehabilitation in the context of neurogenic respiratory impairment, which is relevant to persons with both degenerative and monophasic-onset neurological conditions. These categories are overlapping as techniques from one may have relevance to the other. This chapter describes these aspects, investigations, and interventions.

In vivo activation of CFTR-dependent chloride transport in murine airway epithelium by CNP

1997 ◽  
Vol 273 (5) ◽  
pp. L1065-L1072 ◽  
Author(s):  
Thomas J. Kelley ◽  
Calvin U. Cotton ◽  
Mitchell L. Drumm
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Nasal Epithelium ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Cyclic Monophosphate ◽  
Δf508 Cftr ◽  
Membrane Bound

Inhibitors of guanosine 3′,5′-cyclic monophosphate (cGMP)-inhibited phosphodiesterases stimulate Cl− transport across the nasal epithelia of cystic fibrosis mice carrying the ΔF508 mutation [cystic fibrosis transmembrane conductance regulator (CFTR) (ΔF/ΔF)], suggesting a role for cGMP in regulation of epithelial ion transport. Here we show that activation of membrane-bound guanylate cyclases by C-type natriuretic peptide (CNP) stimulates hyperpolarization of nasal epithelium in both wild-type and ΔF508 CFTR mice in vivo but not in nasal epithelium of mice lacking CFTR [CFTR(−/−)]. With the use of a nasal transepithelial potential difference (TEPD) assay, CNP was found to hyperpolarize lumen negative TEPD by 6.1 ± 0.6 mV in mice carrying wild-type CFTR. This value is consistent with that obtained with 8-bromoguanosine 3′,5′-cyclic monophosphate (6.2 ± 0.9 mV). A combination of the adenylate cyclase agonist forskolin and CNP demonstrated a synergistic ability to induce Cl− secretion across the nasal epithelium of CFTR(ΔF/ΔF) mice. No effect on TEPD was seen with this combination when used on CFTR(−/−) mice, implying that the CNP-induced change in TEPD in CFTR(ΔF/ΔF) mice is CFTR dependent.

scholarly journals Cystic Fibrosis Lung Disease in the Aging Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Lisa Künzi ◽  
Molly Easter ◽  
Meghan June Hirsch ◽  
Stefanie Krick
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Chronic Inflammation ◽  
Accelerated Aging ◽  
Aging Population ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Repair Mechanisms ◽  
Inflammatory State

The demographics of the population with cystic fibrosis (CF) is continuously changing, with nowadays adults outnumbering children and a median predicted survival of over 40 years. This leads to the challenge of treating an aging CF population, while previous research has largely focused on pediatric and adolescent patients. Chronic inflammation is not only a hallmark of CF lung disease, but also of the aging process. However, very little is known about the effects of an accelerated aging pathology in CF lungs. Several chronic lung disease pathologies show signs of chronic inflammation with accelerated aging, also termed “inflammaging”; the most notable being chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In these disease entities, accelerated aging has been implicated in the pathogenesis via interference with tissue repair mechanisms, alterations of the immune system leading to impaired defense against pulmonary infections and induction of a chronic pro-inflammatory state. In addition, CF lungs have been shown to exhibit increased expression of senescence markers. Sustained airway inflammation also leads to the degradation and increased turnover of cystic fibrosis transmembrane regulator (CFTR). This further reduces CFTR function and may prevent the novel CFTR modulator therapies from developing their full efficacy. Therefore, novel therapies targeting aging processes in CF lungs could be promising. This review summarizes the current research on CF in an aging population focusing on accelerated aging in the context of chronic airway inflammation and therapy implications.

scholarly journals Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 5018
Author(s):  
Michael C. McKelvey ◽  
Ryan Brown ◽  
Sinéad Ryan ◽  
Marcus A. Mall ◽  
Sinéad Weldon ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Lung Diseases ◽  
Lung Damage ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Obstructive Pulmonary Disease ◽  
Chronic Lung Diseases ◽  
Multifunctional Enzymes ◽  
Disease Experience

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.

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