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TRANSLATIONAL PHYSIOLOGY

Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma

¹Department of Medicine, Baylor College of Medicine, Houston, Texas; ²Department of Physiology, Vallabhbhai Patel Chest Institute, Delhi, India; ³Molecular Immunogenetics Laboratory, Institute of Genomic and Integrative Biology, Delhi, India; ⁴Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; and ⁵Department of Pulmonary Medicine, MD Anderson Cancer Center, Houston, Texas

Submitted 6 June 2006 ; accepted in final form 18 August 2006

ABSTRACT

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 myristoylated alanine-rich C kinase substrate protein NH₂-terminal sequence (MANS) was shown to inhibit methacholine (MCh)-induced mucin secretion from airway mucous cells by >90%. We studied the effect of intranasal pretreatment with this peptide on specific airway conductance (sGaw) during challenge with MCh in mice with allergen-induced mucous cell metaplasia. sGaw was noninvasively measured in spontaneously breathing restrained mice, using a double-chamber plethysmograph. Pretreatment with MANS peptide, but not a control peptide [random NH₂-terminal sequence (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 cmH₂O/s). The protective effect of MANS was also seen in mice challenged with allergen for 3 consecutive days to increase airway hyperresponsiveness, although the degree of protection was less (baseline 1.1 ± 0.08; MANS/MCh, 0.65 ± 0.06; RNS/MCh 0.47 ± 0.03 cmH₂O/s). Because 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 cmH₂O/s). In all instances, sGaw in the MANS-pretreated group was 35% higher than in RNS-treated controls, and mucous obstruction accounted for 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.

myristoylated alanine-rich C kinase substrate NH₂-terminus sequence; specific airway conductance; goblet cells

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