RESUMO
Yellow fever (YF) presents a wide spectrum of severity, with clinical manifestations in humans ranging from febrile and self-limited to fatal cases. Although YF is an old disease for which an effective and safe vaccine exists, little is known about the viral- and host-specific mechanisms that contribute to liver pathology. Several studies have demonstrated that oxidative stress triggered by viral infections contributes to pathogenesis. We evaluated whether yellow fever virus (YFV), when infecting human hepatocytes cells, could trigger an imbalance in redox homeostasis, culminating in oxidative stress. YFV infection resulted in a significant increase in reactive oxygen species (ROS) levels from 2 to 4 days post infection (dpi). When measuring oxidative parameters at 4 dpi, YFV infection caused oxidative damage to lipids, proteins, and DNA, evidenced by an increase in lipid peroxidation/8-isoprostane, carbonyl protein, and 8-hydroxy-2'-deoxyguanosine, respectively. Furthermore, there was a significant reduction in the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), in addition to a reduction in the ratio of reduced to oxidized glutathione (GSH/GSSG), indicating a pro-oxidant environment. However, no changes were observed in the enzymatic activity of the enzyme catalase (CAT) or in the gene expression of SOD isoforms (1/2/3), CAT, or GPx. Therefore, our results show that YFV infection generates an imbalance in redox homeostasis, with the overproduction of ROS and depletion of antioxidant enzymes, which induces oxidative damage to cellular constituents. Moreover, as it has been demonstrated that oxidative stress is a conspicuous event in YFV infection, therapeutic strategies based on antioxidant biopharmaceuticals may be new targets for the treatment of YF.
Assuntos
Antioxidantes , Febre Amarela , Humanos , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Vírus da Febre Amarela/metabolismo , Glutationa/metabolismo , Estresse Oxidativo , Oxirredução , Catalase/genética , Catalase/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Dissulfeto de Glutationa/metabolismo , Hepatócitos/metabolismo , Peroxidação de Lipídeos , Glutationa Peroxidase/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismoRESUMO
BACKGROUND: The nature of the aging process has been the subject of considerable speculation. It has been reported that in the aging process several components of the signal transduction pathways, including phosphoinositide, protein kinase C, protein kinase A and reactive oxygen intermediate (ROI) generation, are altered. OBJECTIVE: The aim of our study was to evaluate the functional metabolic balance among cAMP, cGMP and ROI generation by human neutrophils in relation to age. METHODS: The age-induced ROI generation was studied in healthy subjects ranging in age from 20 to 80 years old, divided into 6 age groups: 20-29, 30-39, 40-49, 50-59, 60-69 and 70-80 years old. The oxidizing cellular generation was quantified in a luminol-dependent (ROI production) chemiluminescence assay and the results expressed as relative light units per minute. RESULTS: Our results show a differential functional metabolic balance of cAMP and cGMP in relation to age from 50 years on. This phenomenon is reflected by the increase in ROI generation by neutrophil stimulation with cGMP at all ages and a simultaneous lack of effect of cAMP on cGMP from 50 years old. The same results were observed when neutrophil reacted with endogenous contents of cGMP (levamisole, an inhibitor of cGMP phosphodiesterase) or cAMP (aminophylline, an inhibitor of cAMP phosphodiesterase). Our results show that the lack of modulation of the endogenous or exogenous contents of cAMP or cGMP on ROI generation altered the age-related functional metabolic balance. CONCLUSIONS: This altered functional metabolic balance in cAMP, cGMP and ROI generation of neutrophils may certainly have consequences on host defenses, mainly on inflammatory processes, in healthy subjects from 50 years old. However, the exact consequences of this phenomenon on the aging process remain unknown.