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

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 NH(2)-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 NH(2)-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 cmH(2)O/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 cmH(2)O/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 cmH(2)O/s). In all instances, sGaw in the MANS-pretreated group was approximately 35% higher than in RNS-treated controls, and mucous obstruction accounted for approximately 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.

• Authors: A Agrawal, S Rengarajan, K B Adler, A Ram, B Ghosh, M Fahim, B F Dickey
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 102 Issue 1 Pg. 399-405 (Jan 2007) ISSN: 8750-7587 [Print] United States
• PMID: 16946028 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bronchoconstrictor Agents
• MARCKS-related peptide
• Mucins
• Peptide Fragments
• Methacholine Chloride

Topics

• Airway Obstruction (drug therapy, metabolism, physiopathology)
• Animals
• Asthma (drug therapy, metabolism, physiopathology)
• Bronchoconstriction (drug effects, physiology)
• Bronchoconstrictor Agents (administration & dosage)
• Disease Models, Animal
• Methacholine Chloride (administration & dosage)
• Mice
• Mice, Inbred BALB C
• Mucins (metabolism)
• Peptide Fragments (adverse effects, pharmacology, therapeutic use)