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Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease
Raquel Centeio1, Jiraporn Ousingsawat1, Inês Cabrita1
1Physiological Institute, University of Regensburg, Germany University Street 31, D-93053 Regensburg, Germany.
Abstract:
Activation of the Ca2+ activated Cl- channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF.
Insights
Activating the calcium-activated chloride channel TMEM16A in inflammatory airway diseases may worsen mucus production and bronchoconstriction. Inhibiting TMEM16A, however, shows promise in reducing inflammation and mucus, potentially by downregulating SPDEF.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Immunology
Background:
- The calcium-activated chloride channel TMEM16A is a potential therapeutic target for inflammatory airway diseases.
- Its activation is hypothesized to improve airway conditions by promoting electrolyte secretion, reducing mucus, and enhancing mucociliary clearance.
- However, conflicting reports exist regarding TMEM16A's role, with some studies suggesting it increases mucus production and airway contraction.
Purpose of the Study:
- To investigate the role of TMEM16A in inflammatory airway diseases.
- To analyze TMEM16A expression in healthy and inflamed airways.
- To determine the effects of TMEM16A activation and inhibition on mucus production and airway function in asthma models.
Main Methods:
- Analysis of TMEM16A expression in human and mouse airway tissues from healthy and diseased states.
- In vivo and in vitro studies using asthmatic mice and airway epithelial cells.
- Administration of TMEM16A activators (Eact, brevenal) and an inhibitor (niclosamide).
- Assessment of mucus release, bronchoconstriction, and SPDEF expression.
Main Results:
- TMEM16A was upregulated in the lungs of patients with asthma and cystic fibrosis, and in asthmatic mouse airways.
- Activation of TMEM16A led to acute mucus release and bronchoconstriction in mice.
- Inhibition of TMEM16A by niclosamide suppressed mucus production and secretion.
- Niclosamide treatment inhibited the expression of SPDEF, a key factor in Th2 inflammation and goblet cell differentiation.
Conclusions:
- Activation of TMEM16A in inflammatory airway diseases is likely to exacerbate mucus secretion and cause airway constriction.
- Inhibitors of TMEM16A may offer a therapeutic strategy by suppressing pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction.
- Inhibition of SPDEF expression is a potential mechanism underlying the beneficial effects of TMEM16A inhibitors.
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