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.

Smoke induced changes in epithelial cell gene expression: development of an in vitro model for COPD.

Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis, which are characterised by a progressive airflow limitation and chronic inflammation. The pathogenesis of COPD involves different cells, mainly epithelial cells, macrophages, neutrophils, and CD8 lymphocytes. Bronchial epithelium lines the mucosal surface of the airways, forming a mechanical barrier that separates the external environment from the internal milieu. Recently, substantial evidence has emerged indicating that airway epithelial cells are able to liberate a number of chemokines fundamental to both inflammatory and immune responses. Therefore, we established an in vitro model by showing that cigarette smoke is able to induce the release of chemokines by lung epithelial cells. Furthermore, we show that cigarette smoke induced chemokine expression is resistant to dexamethasone, mimicking the clinical situation. In contrast, pyrrolidinedithiocarbamic acid, an experimental antioxidant compound, inhibited smoke induced chemokine expression. These results suggest that this epithelial cell culture model may allow the evaluation of novel anti-inflammatory compounds for the treatment of COPD directly on the relevant target cells in vitro. This approach may result in the replacement of animal experimentation in screening of new therapeutics for COPD.