Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma.
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.
Agrawal
A
A
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. aagrawal@bcm.tmc.edu
Rengarajan
S
S
Adler
K B
KB
Ram
A
A
Ghosh
B
B
Fahim
M
M
Dickey
B F
BF
D000402:Airway Obstruction / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000378:metabolism*; D010446:Peptide Fragments / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D016085:Bronchoconstrictor Agents; C483227:MARCKS-related peptide; D009077:Mucins; D010446:Peptide Fragments; D016210:Methacholine Chloride