Diosmetin alleviates benzo[a]pyrene-exacerbated H1N1 influenza virus-induced acute lung injury and dysregulation of inflammation through modulation of the PPAR-γ-NF-κB/P38 MAPK signaling axis

Abstract

The severity of a viral respiratory illness was greatly exacerbated after exposure to a contaminant containing benzo[a]pyrene (B[a]P). Flavonoid-rich fruit intake has gained intense interest due to their health-promoting benefits for viral respiratory diseases, including influenza viruses. In our study, diosmetin (3′,5,7-trihydroxy-4′-methoxyflavone), a naturally occurring hydroxylated methoxyflavone that is abundant in Citrus fruits, was explored for its effects on B[a]P-exacerbated H1N1 influenza virus-mediated inflammation and lung injury. Initially, in vivo results demonstrated that diosmetin protected against H1N1 virus-elicited acute lung injury. Simultaneously, H1N1 virus or B[a]P-stimulated A549 cells treated with diosmetin inhibited NF-κB and P-P38 activation, resulting in suppression of pro-inflammatory cytokines and apoptosis. Interestingly, diosmetin obviously promoted the expression of PPAR-γ as well as nuclear translocation of PPAR-γ, whereas, PPAR-γ inhibition by GW9662 weakened the inhibitory effects of diosmetin on H1N1 virus or B[a]P-mediated activation of NF-κB and P-P38, elevated expression of pro-inflammatory mediators as well as apoptosis. Furthermore, it was surprising to discover that mice exposed to both B[a]P and H1N1 viruses contributed to exacerbated acute lung injury, which were significantly ameliorated by diosmetin administration. In vitro studies showed that A549 cells with the combination of B[a]P and H1N1 virus augmented NF-κB and P-P38 activation, accompanied by higher levels of pro-inflammatory mediators and apoptosis, all of which were also significantly reduced by diosmetin treatment. Repressing PPAR-γ abrogated the inhibitory effects of diosmetin on B[a]P-exacerbated H1N1 virus-mediated NF-κB and P-P38 activation, inflammation, and apoptosis in A549 cells. Our findings suggest that diosmetin protected against B[a]P-exacerbated H1N1 virus-mediated lung injury by suppressing the exacerbation of NF-κB and P38 kinase activation in a PPAR-γ-dependent manner, suggesting potential benefits for B[a]P-exacerbated influenza-related illness therapeutics.