Asthma and cystic fibrosis: A tangled web

Kent, Brian D.; Lane, Stephen; Beek, Edwin Jacques Rudolph van; Dodd, Jonathan D.; Costello, Richard W.; Tiddens, Harm A.W.M.

doi:10.1002/ppul.22934

Cited by 39 publications

(32 citation statements)

References 84 publications

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“…As there are no clear criteria for establishing the diagnosis of asthma in patients with CF or PCD, we did not formally exclude asthma in patients; however, no patient had concomitant asthma medication, and no patient had a history of airborne allergies, seasonal asthma-like symptoms, or eosinophilia. Nevertheless, we did not systematically test for airborne allergies, and we did not perform spirometry for bronchodilator response or bronchial provocation test because in CF (and supposedly also PCD) these tests do not discriminate asthma from CF [48]. We cannot rule out that in some patients undiagnosed asthma might have influenced the results, but we assume a minimal effect size due to the reasons stated above.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Nocturnal Cough Analysis in Healthy Subjects and in Patients with Cystic Fibrosis and Primary Ciliary Dyskinesia: A Prospective Observational Study

et al. 2018

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Background: Cough is a key symptom in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). Objective: The study objectives were to test whether cough is related to parameters reflecting their disease severity and whether CF and PCD differ in cough frequency. Methods: In this prospective observational study, we used a microphone-based monitoring system (LEOSound® Monitor) to count the coughs in healthy subjects (HS) and in stable patients with CF and PCD (25 subjects per group) on 2 consecutive nights. Results: The median number of coughs/h in the HS, CF, and PCD groups was 0.0, 1.3, and 0.5 on the first night and 0.0, 2.3, and 0.2 on the second night, respectively. Patients with CF and PCD coughed more than HS (p < 0.001 and p = 0.009, respectively) and CF patients coughed more than PCD patients (p = 0.023). A multivariable mixed model analysis revealed forced expiratory volume in 1 s as an independent risk factor for increased cough frequency in patients. The reliability for repeated measurements was higher for cough epochs/h than for coughs/h (intraclass correlation coefficient: 0.75 and 0.49, respectively). Conclusions: Patients with CF cough more than patients with PCD. The cough frequency in CF and PCD is associated with parameters reflecting disease severity. Cough frequency is a possible endpoint in clinical trials and cough epochs/h may be more useful than coughs/h.

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Section: Discussionmentioning

confidence: 99%

Comparison of Nocturnal Cough Analysis in Healthy Subjects and in Patients with Cystic Fibrosis and Primary Ciliary Dyskinesia: A Prospective Observational Study

et al. 2018

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“…Such a role of TMEM16A is particularly evident under inflammatory conditions like asthma, when TMEM16A is strongly upregulated in the ASM. Because asthma appears to be a common problem also in patients with CF [12], therapeutic activation of TMEM16A could trigger bronchoconstriction in CF patients. Activation of TMEM16A could also trigger mucus release and enhance airway mucus plugging [3,5,13,14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Centeio

Cabrita

Benedetto

et al. 2020

IJMS

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TMEM16A is a Ca 2+ activated Cl − channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl − secretion and to enhance airway surface liquid (ASL). This CFTR-agnostic approach is thought to improve mucociliary clearance and lung function in CF. This could indeed improve ASL, however, mucus release and airway contraction may also be induced by activators of TMEM16A, particularly in inflamed airways of patients with asthma, COPD, or CF. Currently, both activators and inhibitors of TMEM16A are developed and examined in different types of tissues. Here we compare activation and inhibition of endogenous and overexpressed TMEM16A and analyze potential off-target effects. The three well-known blockers benzbromarone, niclosamide, and Ani9 inhibited both TMEM16A and ATP-induced Ca 2+ increase by variable degrees, depending on the cell type. Niclosamide, while blocking Ca 2+ activated TMEM16A, also induced a subtle but significant Ca 2+ store release and inhibited store-operated Ca 2+ influx. Niclosamide, benzbromarone and Ani9 also affected TMEM16F whole cell currents, indicating limited specificity for these inhibitors. The compounds Eact, cinnamaldehyde, and melittin, as well as the phosphatidylinositol diC8-PIP 2 are the reported activators of TMEM16A. However, the compounds were unable to activate endogenous TMEM16A in HT 29 colonic epithelial cells. In contrast, TMEM16A overexpressed in HEK293 cells was potently stimulated by these activators. We speculate that overexpressed TMEM16A might have a better accessibility to intracellular Ca 2+ , which causes spontaneous activity even at basal intracellular Ca 2+ concentrations. Small molecules may therefore potentiate pre-stimulated TMEM16A currents, but may otherwise fail to activate silent endogenous TMEM16A.

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“…Airway smooth muscle (ASM) abnormalities have been described in people with CF, including increased smooth muscle mass, bronchodilator responsiveness, and airway hyperreactivity (7–13). However, whether these findings are due to the primary loss of CFTR in ASM or secondary confounding factors is unknown and has been difficult to study in humans.…”

Section: Introductionmentioning

confidence: 99%

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities

Adam¹,

Hisert

Dodd³

et al. 2016

JCI Insight

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Background Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. Methods To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. Results Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. Conclusions Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. Funding This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.

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Asthma and cystic fibrosis: A tangled web

Cited by 39 publications

References 84 publications

Comparison of Nocturnal Cough Analysis in Healthy Subjects and in Patients with Cystic Fibrosis and Primary Ciliary Dyskinesia: A Prospective Observational Study

Comparison of Nocturnal Cough Analysis in Healthy Subjects and in Patients with Cystic Fibrosis and Primary Ciliary Dyskinesia: A Prospective Observational Study

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities

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