Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe Respiratory Syncytial Virus Bronchiolitis

Abstract

Rationale : Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in children, for which no specific treatment or vaccine is currently available. We have previously shown that RSV induces reactive oxygen species in cultured cells and oxidative injury in the lungs of experimentally infected mice. The mechanism(s) of RSV-induced oxidative stress in vivo is not known. Objectives : To measure changes of lung antioxidant enzymes expression/activity and activation of NF-E2-related factor 2 (Nrf2), a transcription factor that regulates detoxifying and antioxidant enzyme gene expression, in mice and in infants with naturally acquired RSV infection. Methods : Superoxide dismutase 1 (SOD 1), SOD 2, SOD 3, catalase, glutathione peroxidase, and glutathione S-transferase, as well as Nrf2 expression, were measured in murine bronchoalveolar lavage, cell extracts of conductive airways, and/or in human nasopharyngeal secretions by Western blot and two-dimensional gel electrophoresis. Antioxidant enzyme activity and markers of oxidative cell injury were measured in either murine bronchoalveolar lavage or nasopharyngeal secretions by colorimetric/immunoassays. Measurements and Main Results : RSV infection induced a significant decrease in the expression and/or activity of SOD, catalase, glutathione S-transferase, and glutathione peroxidase in murine lungs and in the airways of children with severe bronchiolitis. Markers of oxidative damage correlated with severity of clinical illness in RSVinfected infants. Nrf2 expression was also significantly reduced in the lungs of viral-infected mice. Conclusions : RSV infection induces significant down-regulation of the airway antioxidant system in vivo, likely resulting in lung oxidative damage. Modulation of oxidative stress may pave the way toward important advances in the therapeutic approach of RSV-induced acute lung disease.

Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses

“…Microarray analysis of gene expression studies from hMPV infected airway epithelial cells demonstrated progressively decreased levels of SOD 3, catalase, GST and peroxiredoxin gene expression and protein levels, with a concomitant increase in SOD 2 [63], similar to what has been observed with RSV. These changes in AOE expression was also observed in a mouse model of hMPV infection [11]. Such an increase in SOD 2 expression and decreased expression of catalase, as well as decreased GSH/GSSG ratio, has also been reported in influenza infection both in vitro and in vivo [64][65][66].…”

“…As Nrf2 positively regulates its own gene transcription, reduced Nrf2 mRNA levels were observed in airway epithelial cells at late time point of RSV infection [8]. Our recent studies indicate that RSV infection is associated with Nrf2 deacetylation, likely due to RSV-induced upregulation of histone deacetylase was confirmed in vivo, both in a mouse model of RSV infection as well as in children with severe bronchiolitis [11].…”

“…In addition to MDA and HNE, 8-isoprostane are also considered markers of cellular oxidative stress, as they are formed in vivofrom the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase enzymes. The unbalance between ROS formation and antioxidant defenses leads to oxidative stress during the course of RSV infection, as it has been demonstrated by the increased formation of lipid peroxidation products both in vitro and in vivo models of infection [8,61], as well as in patients with primary RSV infection, in which the levels of 8-isoprostane, as well as MDA and HNE present in respiratory secretion correlate with the severity of infection [11].…”

“…Failure to keep the equilibrium between ROS formation and antioxidant defenses leads to oxidative stress. This is characterized by an augmented generation of oxidant species and reduced antioxidant cellular capacity [2,[8][9][10][11]. At molecular level, the oxidative damage to DNA cause polysaccharide ring cleavage, base modification or chain breakage, leading to mutations and altered/ failed gene transcription; damage to proteins can modify functional groups, such as addition of nitro radicals and carbonyl groups, resulting in altered activity, aggregation, fragmentation and/or cleavage; damage to lipids leads to formation of lipid aldehydes, lipid peroxides, causing changes in fluidity and permeability of membranes [6,12,13].…”

Превентивна Та Лікувальна Ефективність Біофлавоноїдів У Дітей З Рекурентними Респіраторними Інфекціями

“…Дані проведених на сьогодні досліджень свід-чать, що імунна система дітей з ГРРІ хоча і не має грубих первинних і набутих дефектів, але характе-ризується крайньою напруженістю процесів імун-ного реагування, порушенням міжклітинної ко-операції та недостатністю резервних можливос-тей, що є результатом тривалого й масивного ан-тигенного впливу на організм дитини [9][10][11].…”