MARCKS-related peptide modulates in vivo the secretion of airway Muc5ac.
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.
Foster
W Michael
WM
Division of Pulmonary, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. foste028@mc.duke.edu
Adler
Kenneth B
KB
Crews
Anne L
AL
Potts
Erin N
EN
Fischer
Bernard M
BM
Voynow
Judith A
JA
D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D019272:Leukocyte Elastase / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008679:Metaplasia / Q000139:chemically induced; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010446:Peptide Fragments / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000503:physiopathology; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism*; D012701:Serotonin
D000336:Aerosols; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C483227:MARCKS-related peptide; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D010446:Peptide Fragments; D016210:Methacholine Chloride; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D012701:Serotonin; D019272:Leukocyte Elastase