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

Abstract

Mucus hypersecretion is a crucial feature of pulmonary diseases such as asthma, chronic bronchitis and cystic fibrosis. Despite much research, there is still no effective therapy for this condition. Recently, we showed that the myristoylated, alanine-rich C-kinase substrate (MARCKS) protein is required for mucus secretion by human bronchial epithelial cells in culture1. Having synthesized a peptide corresponding to the N-terminal domain of MARCKS, we now show that the intratracheal instillation of this peptide blocks mucus hypersecretion in a mouse model of asthma. A missense peptide with the same amino acid composition has no effect. Based on quantitative histochemical analysis of the mouse airways, the peptide seems to act by blocking mucus release from goblet cells, possibly by inhibiting the attachment of MARCKS to membranes of intracellular mucin granules. These results support a pivotal role for MARCKS protein, specifically its N-terminal region, in modulating this secretory process in mammalian airways. Intratracheal administration of this MARCKS-related peptide could therapeutically reduce mucus secretion in the airways of human patients with asthma, chronic bronchitis and cystic fibrosis.

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Figure 1: Effects of peptides on mucin secretion in mouse airways.
Figure 2: Representative PAS- and hematoxylin-stained sections of bronchi from sensitized and challenged BALB/c mice.
Figure 3: The association of MARCKS with mucin granule membranes is inhibited by MANS peptide.

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Acknowledgements

This study was supported by grant RO1-HL36982 from the National Institutes of Health (to K.B.A.). The authors thank P. Blackshear (National Institute of Environmental Health Sciences) for providing invaluable assistance and reagents, and S. Ho (University of Minnesota) for generously providing antibodies.

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Correspondence to Kenneth B Adler.

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L.D.M., Y.L. and K.B.A. are listed on a patent filed by North Carolina State University, describing the effects of the peptides used in these studies. The licensed technology is held by a startup company.

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Singer, M., Martin, L., Vargaftig, B. et al. A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat Med 10, 193–196 (2004). https://doi.org/10.1038/nm983

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