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

15 Citations (Scopus)

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

Fingerprint

Ozone
Inflammation
Proteins
Bronchoalveolar Lavage
Interleukin-6
Neutrophils
Leukocytes
Air
Cytokines
myristoylated alanine-rich C kinase substrate
Bronchoalveolar Lavage Fluid
Chemokines
Tumor Necrosis Factor-alpha
Lung
Peptides
Fluids

Keywords

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

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation. / Damera, Gautam; Jester, William F.; Jiang, Meiqi; Zhao, Hengjiang; Fogle, Homer W.; Mittelman, Michael; Haczku, Angela Franciska; Murphy, Edwin; Parikh, Indu; Panettieri, Reynold A.

In: Experimental Lung Research, Vol. 36, No. 2, 2010, p. 75-84.

Research output: Contribution to journalArticle

Damera, G, Jester, WF, Jiang, M, Zhao, H, Fogle, HW, Mittelman, M, Haczku, AF, Murphy, E, Parikh, I & Panettieri, RA 2010, 'Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation', Experimental Lung Research, vol. 36, no. 2, pp. 75-84. https://doi.org/10.3109/01902140903131200
Damera, Gautam ; Jester, William F. ; Jiang, Meiqi ; Zhao, Hengjiang ; Fogle, Homer W. ; Mittelman, Michael ; Haczku, Angela Franciska ; Murphy, Edwin ; Parikh, Indu ; Panettieri, Reynold A. / Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation. In: Experimental Lung Research. 2010 ; Vol. 36, No. 2. pp. 75-84.
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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.",
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