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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

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

Published In Exp Lung Res, (2010 Mar)

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.

PubMed ID: 20205598 Exiting the NIEHS site

MeSH Terms: Animals; Bronchitis/chemically induced; Bronchitis/drug therapy*; Bronchitis/immunology; Bronchoalveolar Lavage Fluid/cytology; Bronchoalveolar Lavage Fluid/immunology; Cytokines/secretion; Drug Evaluation, Preclinical; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors*; Membrane Proteins/antagonists & inhibitors*; Mice; Mice, Inbred BALB C; Myristoylated Alanine-Rich C Kinase Substrate; Neutrophil Infiltration/drug effects*; Peptides/pharmacology; Peptides/therapeutic use*

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