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1 Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, United States; Molecular Immunogenetics Laboratory, Institute of Genomic and Integrative Biology, Delhi, India; Department of Physiology, Vallabhbhai Patel Chest Institute, Delhi, India
2 Molecular Immunogenetics Laboratory, Institute of Genomic and Integrative Biology, Delhi, India
3 Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina, United States
4 Department of Physiology, Vallabhbhai Patel Chest Institute, Delhi, India
5 Department of Pulmonary Medicine, MD Anderson Cancer Center, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: aagrawal{at}bcm.tmc.edu.
Allergic asthma is associated with airway epithelial cell mucous metaplasia and mucin hypersecretion, but the consequences of mucin hypersecretion on airway function are unclear. Recently, a peptide derived from the MARCKS protein N-terminal sequence (MANS) was shown to inhibit methacholine (MCh) induced mucin secretion from airway mucous cells by more than 90%. We studied the effect of intranasal pre-treatment with this peptide on specific airway conductance (SGaw) during challenge with MCh in mice with allergen-induced mucous metaplasia. SGaw was non-invasively measured in spontaneously breathing restrained mice, using a double chamber plethysmograph. Pre-treatment with MANS peptide, but not a control peptide (RNS), resulted in partial inhibition of the fall in SGaw induced by 60 mM MCh (mean ± SE; baseline 1.15±0.06; MANS/MCh 0.82±0.05; RNS/MCh 0.55±0.05 (cm H2O.s)-1). The protective effect of MANS was also seen in mice challenged with allergen for 3 consecutive days to increase airway hyperresponsiveness (AHR), though the degree of protection was less (baseline 1.1± 0.08; MANS/MCh, 0.65±0.06; RNS/MCh 0.47±0.03). Since routine SGaw measurement in mice includes nasal airways, the effectiveness of MANS was also confirmed in mice breathing through their mouths after nasal occlusion (baseline 0.92±0.05; MANS/MCh 0.83±0.06; RNS/MCh 0.61±0.03). In all instances, SGaw in the MANS-pretreated group was about 35% higher than in RNS treated controls, and mucous obstruction accounted for about 50% of the MCh-induced fall in SGaw. In summary, mucin secretion has a significant role in airway obstruction in a mouse model of allergic asthma, and strategies to inhibit mucin secretion merit further investigation.
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