CrossTalk opposing view: mucosal acidification does not drive early progressive lung disease in cystic fibrosis

Stick, Stephen M.; Schultz, André

doi:10.1113/jp275426

Cited by 6 publications

(3 citation statements)

References 23 publications

(50 reference statements)

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“…Stick and Schulz claimed that only a small fraction of infants diagnosed early with CF through the Australian AREST CF early surveillance program, present lower airway infection (Stick and Schultz, 2018). This may support the “inflammation first” concept, proposing that inflammation in CF lungs is present early in life and clearly before airway infection (Khan et al, 1995; Doring and Worlitzsch, 2000).…”

Section: Still Unresolved: the Pathogenesis Of Cfmentioning

confidence: 99%

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

et al. 2019

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The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl− channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl− channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl− conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

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Section: Still Unresolved: the Pathogenesis Of Cfmentioning

confidence: 99%

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

et al. 2019

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“…Examples are the following. Why do manifestations of the disease appear at very different times in different organs, as is the case with the pancreas and the liver? Why does CF disproportionally affect people of Northern European descent? Is the cause an evolutionary benefit in the form of increased tolerance to typhoid fever, cholera, or tuberculosis that outweighs the sequelae of CF (Poolman & Galvani, 2006)? Is the pH of the lungs of pwCF different from normal (Figueira et al, 2018a, 2018b; Stick & Schultz, 2018a, 2018b)? Is CFTR expressed in alpha and beta cells of the endocrine pancreas and does it play a functional role? It is evident that the loss of pancreatic endocrine function becomes worse over time, which can be observed in patients bearing severe CFTR genotypes that lead to loss of exocrine pancreatic function.…”

Section: Discussionmentioning

confidence: 99%

Mathematical models of cystic fibrosis as a systemic disease

Olivença

Davis

Kumbale

et al. 2023

WIREs Mechanisms of Disease

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Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi‐species bacterial communities, called “infection microbiomes,” that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi‐scale modeling framework, known as template‐and‐anchor modeling, that allows the gradual integration of refined sub‐models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases.This article is categorized under: Congenital Diseases > Computational Models

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“…Schultz and Stick () based their arguments on one dataset, which measured airway surface liquid (ASL) pH in cystic fibrosis (CF) children (Schultz et al . 2017).…”

mentioning

confidence: 99%