Neutralizing granulocyte/macrophage colony-stimulating factor inhibits cigarette smoke-induced lung inflammation.
BACKGROUND
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-kappaB and activator protein (AP)-1.


OBJECTIVE
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 microg 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.


RESULTS
Cigarette smoke-exposed mice treated with anti-GM-CSF mAb had significantly less BALF macrophages and neutrophils, whole lung TNF-alpha, 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.
Vlahos
Ross
R
Department of Pharmacology, The University of Melbourne, VIC 3010, Australia. rossv@unimelb.edu.au
Bozinovski
Steven
S
Chan
Sheau Pyng Jamie
SP
Ivanov
Stefan
S
Lindén
Anders
A
Hamilton
John A
JA
Anderson
Gary P
GP
D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000276:immunology / Q000517:prevention & control*; D012907:Smoking / Q000276:immunology*
D057134:Antibodies, Neutralizing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor