Niflumic acid and MSI-2216 reduce TNF-α–induced mucin expression in human airway mucosa

Hauber, Hans Peter; Daigneault, Patrick; Frenkiel, Saul; Lavigne, François; Hung, Hsiao Ling; Levitt, Roy C.; Hamid, Qutayba

doi:10.1016/j.jaci.2004.09.039

Cited by 37 publications

(51 citation statements)

References 20 publications

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“…In particular, CLCA1 has been associated with the hypersecretion of mucin 5AC (MUC5AC), as both genes are induced in upper airway mucosal explant tissue upon stimulation with TNF-␣ (21,22,36). In these studies, treatment of bronchial epithelial cells with the chloride channel blocker, NFA, resulted in decreased MUC5AC mRNA expression; however, the mechanism by which CLCA1 regulates MUC5AC has yet to be elucidated (21,36). We have previously reported an increased expression of MUC5AC during ovarian cancer-peritoneal interaction (37).…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)

Musrap

Tuccitto

Karagiannis

et al. 2015

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)

Musrap

Tuccitto

Karagiannis

et al. 2015

Journal of Biological Chemistry

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“…Chloride channel blockers, such as niflumic acid (NFA) and its derivatives, reduce mucin secretion and improve airway function in asthma models (28)(29)(30)(31)(32)(33)(34)(35)(36); however, further drug development has been hampered by several factors, including a lack of knowledge about the molecular identity of CaCC (37)(38)(39). Our findings that TMEM16A-CaCC is up-regulated in the airway epithelium of asthmatics and preferentially in secretory cells in several asthma models support the relevance of this molecule as a target for the treatment of this disease.…”

Section: Tmem16a Is Preferentially Expressed In Secretory Cells In Asmentioning

confidence: 99%

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.

295

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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“…LCM was conducted as described previously (17,18). Frozen tissue sections placed onto glass slides were completely air dried and desiccated to prevent the activation of endogenous RNase in the tissues.…”

Section: Laser Capture Microdissection (Lcm) Of Asmc Bundlesmentioning

confidence: 99%

Increased Expression of IL-33 in Severe Asthma: Evidence of Expression by Airway Smooth Muscle Cells

Préfontaine

Lajoie-Kadoch

Foley

et al. 2009

The Journal of Immunology

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476

382

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IL-33, a new member of the IL-1 cytokine family, promotes Th2 inflammation, but evidence on the implications of this cytokine in asthma is lacking. IL-33 would be mainly expressed by structural cells, but whether proinflammatory cytokines modulate its expression in airway smooth muscle cells (ASMC) is unknown. Endobronchial biopsies were obtained from adults with mild (n = 8), moderate (n = 8), severe (n = 9), asthma and from control subjects (n = 5). Immunocytochemistry, laser-capture microdissection, reverse transcriptase, and real-time quantitative PCR were used for determining IL-33 expression in the lung tissues. ASMC isolated from resected lung specimens were cultured with proinflammatory cytokines and with dexamethasone. IL-33 expression by ASMC was determined by PCR, ELISA, and Western blotting. Higher levels of IL-33 transcripts are detected in biopsies from asthmatic compared with control subjects, and especially in subjects with severe asthma. ASMC show IL-33 expression at both protein and mRNA levels. IL-33 and TNF-α transcript levels correlate in the lung tissues, and TNF-α up-regulates IL-33 expression by cultured ASMC in a time- and dose-dependent manner. IFN-γ also increases IL-33 expression and shows synergistic effect with TNF-α. Dexamethasone fails to abolish TNF-α-induced IL-33 up-regulation. IL-33 expression increases in bronchial biopsies from subjects with asthma compared with controls, as well as subjects with asthma severity. ASMC are a source of the IL-33 cytokine. Our data propose IL-33 as a novel inflammatory marker of severe and refractory asthma.

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Niflumic acid and MSI-2216 reduce TNF-α–induced mucin expression in human airway mucosa

Cited by 37 publications

References 20 publications

Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)

Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)

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

Increased Expression of IL-33 in Severe Asthma: Evidence of Expression by Airway Smooth Muscle Cells

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