Abstract
Respiratory syncytial virus (RSV) infection in mouse and human lung is associated with oxidative injury and pathogenic inflammation. RSV impairs antioxidant responses by increasing the degradation of transcription factor NRF2, which controls the expression of several antioxidant enzyme (AOE) genes, including catalase. Since catalase is a key enzyme for the dismutation of virus-mediated generation of hydrogen peroxide (H2O2) we developed a model of intranasal supplementation of polyethylene glycol-conjugated catalase (PG-CAT) for RSV-infected mice. The results of our study show that PG-CAT supplementation was able to increase specific enzymatic activity along with reduction in H2O2 in the airways and had a significant protective effect against RSV-induced clinical disease and airway pathology. PG-CAT treated mice showed amelioration in airway obstruction, reduction in neutrophil elastase and inflammation. Improved airway hyperresponsiveness was also observed in mice that received PG-CAT as a treatment post-viral inoculation. In addition, PG-CAT greatly reduced the concentration of inflammatory cytokines and chemokines, including IL-1, TNF-α, IL-9, CXCL1, CCL2, and CCL5 in the bronchoalveolar lavage fluid of RSV-infected mice, without increasing viral replication in the lung. In conclusion, catalase supplementation may represent a novel pharmacologic approach to be explored in human for prevention or treatment of respiratory infections caused by RSV.
Highlights
Respiratory syncytial virus (RSV) bronchiolitis remains one of the most common respiratory infections in infants and young children
We have previously shown that RSV inhibits expression of antioxidant enzyme (AOE) in airway epithelial cells, which are the major site of viral replication[7]
polyethylene glycol-conjugated catalase (PG-CAT) treatment resulted in a reduction in overall levels of H2O2 in BAL fluid (BALF) (Fig. 1C), and in a significant increase of airway antioxidant capacity, compared to infected untreated mice (RSV infection resulted in a ~2 fold reduction in antioxidant capacity compared to PBS) (Fig. 1D)
Summary
Respiratory syncytial virus (RSV) bronchiolitis remains one of the most common respiratory infections in infants and young children. Since underlying genetic factors may contribute to the overall pro-oxidative and anti-oxidative balance and consequent disease severity following RSV infection we conducted a study in a group of 115 infants and young children with RSV positive LRTI (62 categorized as mild, 36 moderate and 17 severe disease) and genotyped them for ten known alleles (SNPs) in six AOE genes and in the Nrf[2] gene From this analysis, we found that one SNP in the antioxidant enzyme catalase, rs1001179, which is mapped to the gene promoter region and has been shown to be functional with higher enzyme expression/activity, had a protective effect on disease severity: while present at the expected population level among patients with mild disease, it had lower frequency in those with moderately severe and was absent in patients with severe disease[17]. Some of the results of this study have previously been presented as an abstract[17]
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