Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARβ/δ ligand GW0742
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Male BALB/c mice were pretreated for three days with the PPARβ/δ 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.
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-1β and TNFα in BALF were found to be significantly decreased in GW0742-treated animals (30 mg/kg). A significant decrease in granulocyte macrophage-colony stimulating factor (GM-CSF), a major regulator of neutrophil chemotaxis (via its downstream actions on TNFα and other cytokines/chemokines), activation and survival, was also noted in the BALF levels of GW0742-treated animals.
The present study demonstrates that activation of PPARβ/δ 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.
- Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARβ/δ ligand GW0742
Volume 57, Issue 7 , pp 314-321
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- SP Birkhäuser Verlag Basel
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- PPARβ/δ agonism
- PPARβ/δ activators
- Lipopolysaccharide-induced inflammation
- Pulmonary injury
- Industry Sectors
- Author Affiliations
- 1. Biopharmaceutical Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA, USA
- 2. Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA
- 3. Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC, USA
- 4. Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Collegeville, PA, USA
- 5. ImmunoInflammation Center for Excellence in Drug Discovery, GlaxoSmithKline, 1250 Collegeville Rd., Collegeville, PA, 19426, USA