Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung disease as a major regulator governing the functions of granulocyte and macrophage lineage populations. Chronic obstructive pulmonary disease (COPD) is a disease characterized by lung inflammation with accumulation of neutrophils and increased levels of pro-inflammatory cytokines including GM-CSF in the patient's lungs. We used intranasal administration of lipopolysaccharide (LPS) to mice to induce a disease that resembles COPD with pulmonary inflammation, neutrophil recruitment and release of pro-inflammatory mediators in the bronchoalveolar lavage fluid of the diseased mice. 2 h prior to LPS administration, mice were systemically treated with the murine GM-CSF neutralizing antibody mAb 22E9 per intraperitoneal injection. Intranasal challenge with LPS-induced an increase of total cell number and of neutrophils in the bronchoalveolar lavage fluid. Elevated levels of tumor necrosis factor alpha (TNF-alpha), keratinocyte cytokine and macrophage inflammatory protein-2 (MIP-2) were also observed at this time point. GM-CSF was no longer detectable in bronchoalveolar lavage fluid at 24 h due to its early expression with a peak reached 6 h after LPS challenge. Pretreatment of mice with GM-CSF neutralizing antibody dose-dependently inhibited the accumulation of neutrophils and reduced TNF-alpha and MIP-2 protein levels in bronchoalveolar lavage fluid. These data suggest that neutralization of GM-CSF may represent a novel treatment modality for lung inflammation and in particular for COPD.
Puljic
Ruzica
R
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany.
Benediktus
Ewald
E
Plater-Zyberk
Christine
C
Baeuerle
Patrick A
PA
Szelenyi
Stefan
S
Brune
Kay
K
Pahl
Andreas
A
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor