Fisetin Suppresses Pulmonary Inflammatory Responses through Heme Oxygenase-1 Mediated Downregulation of Inducible Nitric Oxide Synthase

The effects of a mixture of fisetin on cytokine-mediated pulmonary damages have not been studied, despite its known antiviral, neuroprotective, and anti-inflammatory activities. Using lipopolysaccharide (LPS)-Activated human pulmonary artery endothelial cells (HPAECs), we determined the effects of fisetin on the induction of heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the lung tissue of LPS-Treated mice, fisetin was also evaluated for its effect on the regulation of iNOS and tumor necrosis factor (TNF)-?. In LPS-Activated HPAECs, fisetin increased nuclear factor erythrocyte 2-related factor 2-Antioxidant response element (Nrf2-ARE) reporter activity through the nuclear translocation of Nrf2, and the expression of HO-1, and decreased IL-1? and iNOS/NO production. In particular, the suppression of iNOS/NO expression by the administration of fisetin was dependent on HO-1. Current findings indicate that the anti-inflammatory activity of fisetin was due to its HO-1 dependent downregulation of p-STAT-1 and nuclear factor kappa B (NF-?B) and the resultant inhibition of iNOS, and also suggest TNF-? as a potential target for HO-1. We propose that administration of fisetin may be a novel approach, ideal for the treatment of inflammatory pulmonary disease.