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Neutralizing Granulocyte/Macrophage Colony–Stimulating Factor Inhibits Cigarette Smoke–induced Lung Inflammation

¹ Department of Pharmacology, and ³ Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia; and ² Lung Immunology Group, Department of Internal Medicine/Respiratory Medicine and Allergology, Institute of Medicine, Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden

Correspondence and requests for reprints should be addressed to Ross Vlahos, Ph.D., Department of Pharmacology, The University of Melbourne, VIC 3010 Australia. E-mail: rossv{at}unimelb.edu.au

Rationale: Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), and there is currently no satisfactory therapy to treat people with COPD. We have previously shown that granulocyte/macrophage colony–stimulating factor (GM-CSF) regulates lung innate immunity to LPS through Akt/Erk activation of nuclear factor-B and activator protein (AP)-1.

Objectives: The aim of this study was to determine whether neutralization of GM-CSF can inhibit cigarette smoke–induced lung inflammation in vivo.

Methods: Male BALB/c mice were exposed to cigarette smoke generated from 9 cigarettes per day for 4 days. Mice were treated intranasally with 100 µg 22E9 (anti–GM-CSF mAb) and isotype control antibody on Days 2 and 4, 1 hour before cigarette smoke or sham exposure. On the fifth day mice were killed, and the lungs were lavaged with PBS and then harvested for genomic and proteomic analysis.

Measurements and Main Results: Cigarette smoke–exposed mice treated with anti–GM-CSF mAb had significantly less BALF macrophages and neutrophils, whole lung TNF-, macrophage inflammatory protein (MIP)-2, and matrix metalloproteinase (MMP)-12 mRNA expression and lost less weight compared with smoke-exposed mice treated with isotype control. In contrast, smoke-induced increases in MMP-9 and net gelatinase activity were unaffected by treatment with anti–GM-CSF. In addition, neutralization of GM-CSF did not affect the phagocytic function of alveolar macrophages.

Conclusions: GM-CSF is a key mediator in smoke-induced airways inflammation, and its neutralization may have therapeutic implications in diseases such as COPD.

Key Words: leukocyte • innate immunity • macrophage growth factors

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Elevated levels of granulocyte/macrophage colony–stimulating factor (GM-CSF) have been observed in a variety of human inflammatory lung diseases. Previously, GM-CSF has been considered a homeostatic mediator in lung macrophages, epithelial innate immunity, and leukocyte survival. We have shown that antibody neutralization of GM-CSF markedly reduces smoke-induced lung inflammation and sequelae. What This Study Adds to the Field Antibody neutralization of GM-CSF may represent a novel means of controlling inflammatory lung disease.

 

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