In a mouse model of
neutrophil elastase-induced
bronchitis that exhibits goblet cell
metaplasia and
inflammation, we investigated the effects of intratracheal instillation of the
MANS peptide, a
peptide identical to the NH(2) terminus of the
myristoylated alanine-rich C kinase substrate (MARCKS) on
mucin protein airway secretion,
inflammation, and airway reactivity. To induce mucus cell
metaplasia in the airways, male BALB/c mice were treated repetitively with the
serine protease,
neutrophil elastase, on days 1, 4, and 7. On day 11, when goblet cell
metaplasia was fully developed and profiles of proinflammatory
cytokines were maximal, the animals were exposed to aerosolized
methacholine after intratracheal instillation of MANS or a missense control
peptide (RNS). MANS, but not RNS, attenuated the
methacholine-stimulated secretion of the major respiratory
mucin protein, Muc5ac (50% reduction). Concurrently,
elastase-induced proinflammatory
cytokines typically recovered in bronchoalveolar lavage (BAL), including KC, IL-1beta,
IL-6, MCP-1, and
TNFalpha, were reduced by the
MANS peptide (mean levels decreased 50-60%). Secondary to the effects of MANS on
mucin secretion and
inflammation, mechanical lung function by forced oscillation technique was characterized with respect to airway reactivity in response to cumulative
aerosol stimulation with
serotonin. The
MANS peptide was also found to effectively attenuate
airway hyperresponsiveness to
serotonin in this airway hypersecretory model. Collectively, these findings support the concept that even in airway epithelia remodeled with goblet cell
metaplasia and in a state of
mucin hypersecretion, exogenous attenuation of function of
MARCKS protein via the
MANS peptide decreases airway
mucin secretion,
inflammation, and hyperreactivity.