Niflumic Acid Inhibits Goblet Cell Degranulation in a Guinea Pig Asthma Model

Kondo, Mitsuko; Nakata, Junko; Arai, Naoki; Izumo, Takehiro; Tagaya, Etsuko; Takamatsu, Kiyoshi; Tamaoki, Jun; Nagai, Atsushi

doi:10.2332/allergolint.11-oa-0307

Cited by 21 publications

(19 citation statements)

References 29 publications

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“…Consistent with a previous report (6), we did not detect TMEM16A in association with mucins in secretory vesicles. A recent study showed that the nonspecific chloride channel blocker NFA inhibits the secretion of mucus granules in guinea pig asthma models, further supporting our hypothesis that CaCC may be associated with goblet cell degranulation, and CaCC inhibitors may be useful for the treatment of hypersecretion in asthma (55). In addition to the respiratory epithelium, we detected TMEM16A expression in ASM.…”

Section: Discussionsupporting

confidence: 68%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

310

342

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Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calciumactivated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.A sthma is a significant cause of morbidity and mortality worldwide, and the prevalence of this disease is increasing among all age, sex, and racial groups. Characteristic features of asthma include inflammation, subepithelial fibrosis, hyperplasia of mucus-producing cells, accumulation of mucus within airway lumens, hyperplasia of airway smooth muscle (ASM), and ASM hyperresponsiveness. Together, these symptoms impair lung function by limiting the flow of gases to and from the alveoli in the distal lung.The current standard of care for asthma involves inhaled corticosteroids for the management of inflammation combined with long-acting agonists of β2-adrenergic receptors. Despite this treatment, lung function is not improved in 30-45% of asthmatic patients, and exacerbations continue to be a major problem (reviewed in ref. 1). Asthma can be divided into at least two distinct molecular phenotypes defined by the degree of Th2 inflammation (2, 3). Cytokines, including IL-4 and IL-13, promote airway epithelial mucous cell metaplasia, subepithelial fibrosis, and hyperplasia of smooth muscle in Th2-high asthmatics, and these patients generally show improved lung function with inhaled corticosteroid therapy. A greater understanding of this heterogeneity and the molecular and physiological events that lead to airway remodeling might lead to improved diagnosis and treatment.Calcium-activated chloride channels (CaCCs) have been ascribed numerous cellular functions (reviewed in refs. 4 and 5), among these are epithelial fluid secretion and smooth muscle contraction, both of which contribute to the progression and severity of asthma. Moreover, calcium-activated chloride currents in the airway epithelium are enhanced by the Th2 cytokines IL-4 and IL-13, as well as IFN-γ (6). For these reasons, CaCC is an attractive potential therapeutic target for asthma (7). However, the study of CaCC was impeded by lack of information about the gene(s) encoding this channel. It was only relatively recently that TMEM16A (transmembrane p...

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Section: Discussionsupporting

confidence: 68%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

310

342

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“…Those genes (particularly Ear11 and Clca3) that were regulated by both MWCNT and αST2-blocking Ab experimental conditions were considered of particular interest. Indeed, although the exact mechanisms remain unknown, Ear11 and Clca3 have previously been implicated in asthma pathology (Di Valentin et al 2009; Zhou et al 2001; Kondo et al 2012) and may represent suitable therapeutic targets to mediate Th2-associated inflammation. Experiments are currently underway in our laboratories to better understand the contributions of Ear11 and Clca3 expression to the IL-33/ST2 signaling axis and their importance to the establishment of Th2-associated inflammation following MWCNT exposure.…”

Section: Discussionmentioning

confidence: 99%

IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung

et al. 2012

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Allergic asthma is a chronic inflammatory disorder of the airway associated with bronchial obstruction, airway hyper-reactivity (AHR), and mucus production. The epithelium may direct and propagate asthmatic-like responses. Central to this theory is the observation that viruses, air pollution, and allergens promote epithelial damage and trigger the generation of IL-25, IL-33, and TSLP via innate pathways such as TLRs and purinergic receptors. Similarly, engineered nanomaterials promote a Th2-associated pathophysiology. In this study, we tested the hypothesis that instillation of multi-walled carbon nanotubes (MWCNT) impair pulmonary function in C57Bl/6 mice due to the development of IL-33-dependent Th2-associated inflammation. MWCNT exposure resulted in elevated levels of IL-33 in the lavage fluid (likely originating from airway epithelial cells), enhanced AHR, eosinophil recruitment, and production of Th2-associated cytokines and chemokines. Moreover, these events were dependent on IL-13 signaling and the IL-33/ST2 axis, but independent of T and B cells. Finally, MWCNT exposure resulted in the recruitment of innate lymphoid cells. Collectively, our data suggest that MWCNT induce epithelial damage that results in release of IL-33, which in turn promotes innate lymphoid cell recruitment and the development of IL-13-dependent inflammatory response.

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“…Moreover, niflumic acid (0.64 mg/kg) significantly inhibited the Mch-induced decrease in C dyn (P , 0.0005, OVA-sensitized mice with and without niflumic acid). Because niflumic acid was administered 5 minutes before Mch application, it is unlikely that the effect of niflumic acid on lung function resulted from its influence on cytokine production, mucin synthesis, or goblet cell degranulation (9)(10)(11). To validate this, we examined the effect of niflumic acid on IL-17, a cytokine critical to the pathogenesis of asthma in this mouse model (30).…”

Section: Resultsmentioning

confidence: 99%

The Transmembrane Protein 16A Ca²⁺-activated Cl⁻ Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

Zhang

Li²,

Zhao

et al. 2013

Am J Respir Crit Care Med

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Rationale: Asthma is a chronic inflammatory disorder with a characteristic of airway hyperresponsiveness (AHR). Ca 21 -activated Cl 2 [Cl (Ca) ] channels are inferred to be involved in AHR, yet their molecular nature and the cell type they act within to mediate this response remain unknown. Objectives: Transmembrane protein 16A (TMEM16A) and TMEM16B are Cl (Ca) channels, and activation of Cl (Ca) channels in airway smooth muscle (ASM) contributes to agonist-induced airway contraction. We hypothesized that Tmem16a and/or Tmem16b encode Cl (Ca) channels in ASM and mediate AHR. Methods:We assessed the expression of the TMEM16 family, and the effects of niflumic acid and benzbromarone on AHR and airway contraction, in an ovalbumin-sensitized mouse model of chronic asthma. We also cloned TMEM16A from ASM and examined the Cl 2 currents it produced in HEK293 cells. We further studied the impacts of TMEM16A deletion on Ca 21 agonist-induced cell shortening, and on Cl (Ca) (Ca) currents, and weakens caffeine-and methacholineinduced cell shortening. Conclusions: Tmem16a encodes Cl (Ca) channels in ASM and contributes to Ca 21 agonist-induced contraction. In addition, up-regulation of TMEM16A and its augmented activation contribute to AHR in an ovalbumin-sensitized mouse model of chronic asthma. TMEM16A may represent a potential therapeutic target for asthma.Keywords: TMEM16A; airway smooth muscle; airway hyperresponsiveness Asthma, affecting 300 million people worldwide, is characterized by chronic inflammation, mucus overproduction, reversible airway obstruction, and airway hyperresponsiveness (AHR). AHR is a heightened tendency to airway narrowing in response to nonspecific contractile agents, and underlies much of the pathology of asthmatic symptoms. Although intensively studied, the cellular and molecular mechanisms underlying AHR remain only partially understood and controversial. A number of studies have implied that Ca 21 -activated Cl 2 [Cl (Ca) ] channels are involved in AHR. Gene expression profile studies have consistently revealed that type 3 Cl (Ca) channels (mCLCA3) are highly upregulated in mouse models of asthma (1-6), and hCLCA1, the human counterpart of mCLCA3, is significantly more abundant in the airway epithelium of patients with asthma (4, 7, 8). Moreover, suppressing the expression of mCLCA3 or hCLCA1 by antisense or its function by niflumic acid, a relatively selective inhibitor of Cl (Ca) channels, prevents allergen-or helper T-cell type 2 (Th2) cytokine (e.g., IL-13)-induced mucus overproduction and AHR (5, 9-11). Not surprisingly, mCLCA3/hCLCA1 Supported by the National Natural Science Foundation of China (grant 31272311) (to M.-S.Z.) and the Natural Science Foundation of Zhejiang Province (Y2100346) (to H.L.), and by U.S. National Heart, Lung, and Blood Institute grant HL73875 (to R.Z.G.).Author Contributions: C.-H.Z., Y.L., W.Z., and H.L. performed research; B.D.H. provided TMEM16A null mice; L.M.L. performed data analysis and edited the paper; M.-S.Z. designed and supervised the stu...

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Niflumic Acid Inhibits Goblet Cell Degranulation in a Guinea Pig Asthma Model

Abstract: NFA inhibited the secretory response of mucus granules in an asthma model, suggesting that CLCA may be associated with goblet cell degranulation and that CLCA inhibitors may be useful for the treatment of hypersecretion in asthma.

Cited by 21 publications

References 29 publications

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung

The Transmembrane Protein 16A Ca²⁺-activated Cl⁻ Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

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Niflumic Acid Inhibits Goblet Cell Degranulation in a Guinea Pig Asthma Model

Abstract: NFA inhibited the secretory response of mucus granules in an asthma model, suggesting that CLCA may be associated with goblet cell degranulation and that CLCA inhibitors may be useful for the treatment of hypersecretion in asthma.

Cited by 21 publications

References 29 publications

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung

The Transmembrane Protein 16A Ca2+-activated Cl− Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

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The Transmembrane Protein 16A Ca²⁺-activated Cl⁻ Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness