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

J Appl Physiol (1985). 2007 Jan;102(1):399-405. doi: 10.1152/japplphysiol.00630.2006. Epub 2006 Aug 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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