Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation

Gautam Damera, William F. Jester, Meiqi Jiang, Hengjiang Zhao, Homer W. Fogle, Michael Mittelman, Angela Franciska Haczku, Edwin Murphy, Indu Parikh, Reynold A. Panettieri

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Evidence suggests inhibition of leukocyte trafficking mitigates, in part, ozone-induced inflammation. In the present study, the authors postulated that inhibition of myristoylated alanine-rich C kinase substrate (MARCKS), an 82-kDa protein with multiple biological roles, could inhibit ozone-induced leukocyte trafficking and cytokine secretions. BALB/c mice (n=5/cohort) were exposed to ozone (100 ppb) or forced air (FA) for 4 hours. MARCKS-inhibiting peptides, MANS, BIO-11000, BIO-11006, or scrambled control peptide RNS, were intratracheally administered prior to ozone exposure. Ozone selectively enhanced bronchoalveolar lavage (BAL) levels of killer cells (KCs; 6 ± 0.9-fold), interleukin-6 (IL-6; 12.7 ± 1.9-fold), and tumor necrosis factor (TNF; 2.1 ± 0.5-fold) as compared to cohorts exposed to FA. Additionally, ozone increased BAL neutrophils by 21 ± 2% with no significant (P > .05) changes in other cell types. MANS, BIO-11000, and BIO-11006 significantly reduced ozone-induced KC secretion by 66% ± 14%, 47% ± 15%, and 71.1% ± 14%, and IL-6 secretion by 69% ± 12%, 40% ± 7%, and 86.1% ± 11%, respectively. Ozone-mediated increases in BAL neutrophils were reduced by MANS (86% ± 7%) and BIO-11006 (84% ± 2.5%), but not BIO-11000. These studies identify for the first time the novel potential of MARCKS protein inhibitors in abrogating ozone-induced increases in neutrophils, cytokines, and chemokines in BAL fluid. BIO-11006 is being developed as a treatment for chronic obstructive pulmonary disorder (COPD) and is currently being evaluated in a phase 2 clinical study.

Original languageEnglish (US)
Pages (from-to)75-84
Number of pages10
JournalExperimental Lung Research
Volume36
Issue number2
DOIs
StatePublished - 2010
Externally publishedYes

Keywords

  • Asthma
  • BIO-11006
  • COPD
  • Cytokines
  • Inflammation
  • MANS peptide

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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  • Cite this

    Damera, G., Jester, W. F., Jiang, M., Zhao, H., Fogle, H. W., Mittelman, M., Haczku, A. F., Murphy, E., Parikh, I., & Panettieri, R. A. (2010). Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation. Experimental Lung Research, 36(2), 75-84. https://doi.org/10.3109/01902140903131200