The role of reactive oxygen species as mediators of respiratory syncytial virus induced pulmonary inflammation
Shawn Monique Castro
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Respiratory Syncytial Virus (RSV) is the leading cause of epidemic respiratory tract illness in children worldwide. Although the mechanisms of RSV-induced airway disease are unknown, experimental evidence suggests that early local inflammatory processes serve as major initiating events in the pathogenesis of RSV-induced lung disease. RSV induced inflammation is mediated in part by small inflammatory chemokines. We investigated the mechanism of RSV-induced chemokine RANTES gene expression in epithelial cells and identified reactive oxygen species as critical signaling molecules involved in STAT and IRF transcription factor activation and the IKK-epsilon pathway, two activated pathways involved in the regulation of pro-inflammatory gene expression. We showed that RSV induced oxidative stress in vivo and that antioxidant therapy with butylated hydroxyanisole (BHA) attenuated RSV induced oxidative stress, pulmonary inflammation and airway hyper-responsiveness. The one caveat to anti-inflammatory antioxidant therapy was the slight increase in RSV viral load observed following antioxidant administration. To eliminate the undesired outcome of increased viral load, a combination therapy approach was utilized employing BHA and the potent anti-viral IFN-alpha. Combination therapy yielded similar results of diminishing RSV-induced pulmonary inflammation while also decreasing RSV viral load in the lungs. Another key mediator regulated by oxidative stress and involved in inflammation is Poly (ADP)-Ribose Polymerase (PARP). We demonstrated that RSV is a potent inducer of PARP activity and that pharmacological inhibition of PARP with INO-1001 abolished RSV-induced PARP activity. INO-1001 also significantly reduced RSV-induced release of inflammation and lung pathology. Of environmental significance, cigarette smoke is also a potent oxidant mixture and important risk factor for the severity of RSV-induced disease. The mechanism(s) causing a worsening of RSV-induced lung disease by environmental tobacco exposure are unclear. Therefore, we investigated the effect of co-exposure of airway epithelial cells to cigarette smoke condensate (CSC) and RSV on inflammatory chemokine gene expression. We demonstrated that CSC and RSV synergistically increased MCP-1 and IL-8 chemokine expression through NF-kappaB and IRF transcription activation. Overall, the modulation of RSV-induced oxidative processes, either by dampening ROS production through pharmacological intervention or by heightening it by toxicant exposure, identify ROS as major signaling molecules involved in regulating RSV-induced inflammation.