PURPOSE: This study will determine whether inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) decreases ozone-induced airway inflammation. Ozone exposure commonly exacerbates chronic obstructive lung disease (COPD and asthma). The precise mechanisms by which ozone induces airway inflammation and worsens airway obstruction remain unclear. Evidence suggests that MARCKS protein is required for mucus secretion and release of inflammatory mediators from lung epithelial cells.
METHODS: BALB/c mice were exposed to ozone (100 parts per billion) for 4 hours after intratracheal injection of saline or myristoylated amino-terminal sequence (MANS) peptide, an inhibitor of MARCKS. Airway inflammation was then characterized by cell differential counts, cytokine and chemokine secretion in the bronchoalveolar lavage.
RESULTS: Ozone significantly increased neutrophil cell number, IL-6 and KC (murine IL-8 analog) levels in the bronchoalveolar lavage. In comparison to saline intratracheal injection, MANS peptide markedly inhibited neutrophil cell numbers in the bronchoalveolar lavage fluid after ozone exposure (85% ± 5%, MANS vs. saline control, p < 0.01). In parallel, MANS peptide also markedly diminished KC (95% ± 2%, MANS vs. saline control, p < 0.01) and IL-6 levels (82% ± 8%, MANS vs. saline control, p < 0.05) after ozone exposure but had little effect on interferon gamma levels.
CONCLUSION: Collectively, these data suggest that inhibition of MARCKS protein markedly diminishes ozone-induced neutrophil migration into the airways as well as decreases selective chemokine and cytokine expression.
CLINICAL IMPLICATIONS: Given these data, MARCKS protein inhibition may offer a new therapeutic target in the management of ozone-induced exacerbations of COPD and asthma.
DISCLOSURE: Reynold Panettieri, Jr, No Financial Disclosure Information; No Product/Research Disclosure Information