Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARβ/δ ligand GW0742

Objective: To define the anti-inflammatory effects of PPAR beta/8 delta activation by use of the selective PPAR beta/delta ligand (GW0742) in a model of lipopolysaccharide (LPS)-induced pulmonary inflammation. Methods: Male BALB/c mice were pretreated for three days with the PPAR beta/delta agonist, GW0742, prior to induction of LPS-mediated pulmonary inflammation. Bronchial alveolar lavage fluid (BALF) was analyzed for inflammatory cell influx and for levels of pro-inflammatory mediators. BALF derived inflammatory cells were also collected for mRNA analysis. Results: Pretreatment with GW0742 resulted in a significant decrease in leukocyte recruitment into the pulmonary space. Protein and mRNA levels of the pro-inflammatory cytokines IL-6, IL-1 beta and TNF alpha in BALF were found to be significantly decreased in GW0742-treated animals (30mg/kg). A significant decrease in granulocyte macrophage-colony stimulating factor (GM-CSF), a major regulator of neutrophil chemotaxis (via its downstream actions on TNF alpha and other cytokines/chemokines), activation and survival, was also noted in the BALF levels of GW0742-treated animals. Conclusions: The present study demonstrates that activation of PPAR beta/delta attenuates the degree of inflammation in a model of LPS-induced pulmonary inflammation and may therefore represent a novel therapeutic approach for the treatment of inflammation-mediated pathologies.