Peroxisome proliferator-activated receptor-γ (PPARγ) ligands supply a protective effect in respiratory syncytial virus (RSV)-infected human lung epithelial cells

Background: Respiratory syncytial virus (RSV) is worldwide the leading cause for severe lower respiratory tract infection (LRTI) in infants requiring hospitalization. Evidence accumulated that RSV-induced LRTI leads to bronchiolitis, pneumonia, and airway hyperresponsiveness. Persistent lung function abnormalities were even observed 20 years following RSV infection. Currently, there exists neither an active vaccine nor a promising antiviral or antiinflammatory therapy. During the onset of RSV infection the viral lytic replication process, the fulminant cytopathic effect mediated by the viral fusion protein (F protein), and the intense RSV-induced inflammatory lung response are considered to be responsible for the epithelial cell damage.

Methods and Results: Our data show that the addition of specific peroxisome proliferator-activated receptor-γ (PPARγ) agonists (15d-PGJ₂, Fmoc-Leu, ciglitazone, and troglitazone) to RSV-infected human lung epithelial cells (A549, NHBE) led to a significantly reduced cell surface expression of ICAM-1- and MHC-I molecules. Furthermore, the release of immunomodulatory (IL-6, GM-CSF) – and proinflammatory cytokines (IL-1α, TNF-α) as well as chemokines (IL-8, RANTES) was significantly reduced. In contrast, the PPARα agonist bezafibrate was without any influence. A down-regulated binding activity of NF-κB (p65/p50) and AP-1 (c-Fos) paralleled these findings suggesting a PPARγ agonist-mediated inhibition of gene expression. Since RSV replication leads to a fulminant activation of NF-κB in epithelial cells, we, therefore, asked whether the replication of RSV might be directly influenced by activation of PPARγ. Our data show that all PPARγ agonists, but not the PPARα agonist bezafibrate, inhibited by nearly 1000fold the replication of RSV in lung epithelial cells. Concomitantly, the expression of the viral G- and F protein was significantly reduced and confluent RSV-infected A549 monolayers were fully protected from cytopathic cell damage.

Conclusion: In summary, PPARγ agonists might be of therapeutical value in the course of RSV infection.