A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma

Singer, Monique; Martin, Linda D.; Vargaftig, B. Boris; Park, Joungjoa; Gruber, Achim D.; Li, Yuehua; Adler, Kenneth B.

doi:10.1038/nm983

Cited by 158 publications

(171 citation statements)

References 18 publications

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“…4 A and B, benzbromarone (10 μM) applied on the apical side of IL-13-treated NHBE cells effectively blocked the ATP (100 μM)-induced CaCC current in Ussing chamber recordings (1.137 ± 0.1301 vs. 3.099 ± 0.4721, n = 4, P = 0.0071). Similar to previous studies (45,46), we observed a depletion of the mucin stores in mucous cells after exposing the apical side of NHBE cells to ATP for 30 min (Fig. 4 C and E).…”

Section: Tmem16a Is Preferentially Expressed In Secretory Cells In Assupporting

confidence: 91%

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: Tmem16a Is Preferentially Expressed In Secretory Cells In Assupporting

confidence: 91%

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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“…Indeed, it is possible that mucin hypersecretion per se is beneficial to the host, increasing the capacity to trap and clear inhaled foreign materials. Animal models of mucin hypersecretion, e.g., ovalbumin-sensitized mice (13) and the βENaC transgenic (14) mouse models, exhibit muco-obstructive airway disease associated with inflammatory cell infiltrates but these models have not permitted dissection of the relative roles for mucin hypersecretion vs. inflammation in disease pathogenesis. The increasing interest in mucin hypersecretion as a therapeutic target argues for studies designed to understand the role of mucin hypersecretion in disease pathogenesis.…”

mentioning

confidence: 99%

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Ehré

Worthington

Liesman

et al. 2012

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

172

178

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MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an “expanded” rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection.

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“…7A) and is supported by inhibited apoE secretion by the peptide inhibitor, BIO-11000. MARCKS regulates the hypersecretion of mucus in respiratory diseases, such as asthma and cystic fibrosis (70,81). Phosphorylation of MARCKS allows movement to the cytoplasm, binding to chaperone HSP70, which engages the cysteine string protein located on the surface of the secretory vesicles containing mucin (69,82).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Controls Vesicular Transport and Secretion of Apolipoprotein E from Primary Human Macrophages

Karunakaran

Kockx

Owen

et al. 2013

Journal of Biological Chemistry

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A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma

Cited by 158 publications

References 18 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

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Protein Kinase C Controls Vesicular Transport and Secretion of Apolipoprotein E from Primary Human Macrophages

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