Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications

Edmondson, C.; Davies, Jane C.

doi:10.1177/2040622316641352

Cited by 46 publications

(36 citation statements)

References 97 publications

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“…Second, practical applications based on purine metabolism did not yield positive results. For instance, the P2Y 2 receptor agonist denufosol failed to show replicable results in phase III clinical trials [52], and to the best of our knowledge, there are, at the moment, no chemical compounds in clinical trials that target purine metabolism. Third, compounds associated with SPLUNC1, while in the early stages of clinical tests, have been producing positive results [27,53,54]; correspondingly, we focused on the relationships between ENaC, ASL, SPLUNC1 and PI(4,5)P 2 .…”

Section: Discussionmentioning

confidence: 99%

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Olivença

Fonseca

Voit

et al. 2019

J. R. Soc. Interface.

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The lung epithelium is lined with a layer of airway surface liquid (ASL) that is crucial for healthy lung function. ASL thickness is controlled by two ion channels: epithelium sodium channel (ENaC) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Here, we present a minimal mathematical model of ENaC, CFTR and ASL regulation that sheds light on the control of ENaC by the short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and by phosphatidylinositol 4,5-biphosphate (PI(4,5)P 2 ). The model, despite its simplicity, yields a good fit to experimental observations and is an effective tool for exploring the interplay between ENaC, CFTR and ASL. Steady-state data and dynamic information constrain the model's parameters without ambiguities. Testing the hypothesis that PI(4,5)P 2 protects ENaC from ubiquitination suggests that this protection does not improve the model results and that the control of the ENaC opening probability by PI(4,5)P 2 is sufficient to explain all available data. The model analysis further demonstrates that ASL at the steady state is sensitive to small changes in PI(4,5)P 2 abundance, particularly in CF conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for CF patients.

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Section: Discussionmentioning

confidence: 99%

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Olivença

Fonseca

Voit

et al. 2019

J. R. Soc. Interface.

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“…Beside amyloid and tau pathology, alternative theories have been proposed for the pathogenesis of AD, such as inflammation, oxidative damage, iron deregulation, and cholesterol metabolism, etc. [ 31 , 32 ].…”

Section: Ad Pathophysiology and Treatment Statusmentioning

confidence: 99%

Calcium Dysregulation in Alzheimer's Disease: A Target for New Drug Development

Wang

Shi

Wei

2017

J Alzheimers Dis Parkinsonism

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia among aged people whose population is rapidly increasing. AD not only seriously affects the patient’s physical health and quality of life, but also adds a heavy burden to the patient’s family and society. It is urgent to understand AD pathogenesis and develop the means of prevention and treatment. AD is a chronic devastating neurodegenerative disease without effective treatment. Current approaches for management focus on helping patients relieve or delay the symptoms of cognitive dysfunction. The calcium ion (Ca2+) is an important second messenger in the function and structure of nerve cell circuits in the brain such as neuronal growth, exocytosis, as well as in synaptic and cognitive function. Increasing numbers of studies suggested that disruption of intracellular Ca2+ homeostasis, especially the abnormal and excessive Ca2+ release from the endoplasmic reticulum (ER) via the ryanodine receptor (RYR), plays important roles in orchestrating the dynamic of the neuropathology of AD and associated memory loss, cognitive dysfunction. Dantrolene, a known antagonist of the RYR and a clinically available drug to treat malignant hyperthermia, can ameliorate the abnormal Ca2+ release from the RYR in AD and the subsequent pathogenesis, such as increased β-secretase and γ-secretase activities, production of Amyloid-β 42 (Aβ 42) and its oligomer, impaired autophagy, synapse dysfunction, and memory loss. However, more studies are needed to confirm the efficacy and safety repurposing dantrolene as a therapeutic drug in AD.

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“… 14 , 20 Standard strategies used in CF treatment, the fluidization of the sputum by a recombinant human deoxyribonuclease (rhDNase) and using antibiotics in high doses in a systemic and aerosolized form can at least partially overcome the inhibiting influence of a polyanionic network. 21 Although the utility of rhDNase significantly improves lung function, not all patients with CF benefit from this treatment. 22 Therefore, there is a continuous need for new effective therapies.…”

Section: Discussionmentioning

confidence: 99%

Targeting polyelectrolyte networks in purulent body fluids to modulate bactericidal properties of some antibiotics

Bucki¹,

Durnaś²,

Wątek³

et al. 2018

IDR

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The response of the human immune system to most bacterial infections results in accumulation of neutrophils at infection sites that release a significant quantity of DNA and F-actin. Both are negatively charged polyelectrolytes that can interact with positively charged host defense molecules such as cathelicidin-delivered LL-37 peptide or other cationic antibiotic agents. Evaluation of the ability of bacterial outgrowth (using luminescence measurements or counting colony-forming units) to form a biofilm (quantified by crystal violet staining) and analysis of the structure of DNA/F-actin network by optical microscopy in human pus samples treated with different antibiotics in combination with plasma gelsolin, DNAse 1, and/or poly-aspartic acid revealed that bactericidal activity of most tested antibacterial agents increases in the presence of DNA/F-actin depolymerizing factors.

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Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications

Cited by 46 publications

References 97 publications

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

Calcium Dysregulation in Alzheimer's Disease: A Target for New Drug Development

Targeting polyelectrolyte networks in purulent body fluids to modulate bactericidal properties of some antibiotics

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