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Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection.

Lee GI, Saravia J, You D, Shrestha B, Jaligama S, Hebert VY, Dugas TR, Cormier SA - Part Fibre Toxicol (2014)

Bottom Line: Increased oxidative stress was also observed in EPFR exposed neonates.Reduction of EPFR-induced oxidative stress attenuated these effects.EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Exposures to elevated levels of particulate matter (PM) enhance severity of influenza virus infection in infants. The biological mechanism responsible for this phenomenon is unknown. The recent identification of environmentally persistent free radicals (EPFRs) associated with PM from a variety of combustion sources suggests its role in the enhancement of influenza disease severity.

Methods: Neonatal mice (< seven days of age) were exposed to DCB230 (combustion derived PM with a chemisorbed EPFR), DCB50 (non-EPFR PM sample), or air for 30 minutes/day for seven consecutive days. Four days post-exposure, neonates were infected with influenza intranasally at 1.25 TCID50/neonate. Neonates were assessed for morbidity (% weight gain, peak pulmonary viral load, and viral clearance) and percent survival. Lungs were isolated and assessed for oxidative stress (8-isoprostanes and glutathione levels), adaptive immune response to influenza, and regulatory T cells (Tregs). The role of the EPFR was also assessed by use of transgenic mice expressing human superoxide dismutase 2.

Results: Neonates exposed to EPFRs had significantly enhanced morbidity and decreased survival following influenza infection. Increased oxidative stress was also observed in EPFR exposed neonates. This correlated with increased pulmonary Tregs and dampened protective T cell responses to influenza infection. Reduction of EPFR-induced oxidative stress attenuated these effects.

Conclusions: Neonatal exposure to EPFR containing PM resulted in pulmonary oxidative stress and enhanced influenza disease severity. EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.

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Effect of EPFR exposure on adaptive immune response (Tc1 and Th1) to influenza infection in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) or sham infected with DPBS (Air). Lung effector T cell profiles were determined by flow cytometry at six dpi. (A) Percentage of CD8+ cells expressing IFNγ (Tc1) with representative flow contour plots demonstrating outliers. N = 3-12/group. (B) Percentage of CD4+ cells expressing IFNγ (Th1) with representative flow contour plots demonstrating outliers. N = 3-12/group. Data plotted as mean ± SEM. *p <0.05 D230F vs AirF, D50F, and D230F(hSOD+); multiple t tests with Holm-Sidak correction for multiple comparisons.
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Fig3: Effect of EPFR exposure on adaptive immune response (Tc1 and Th1) to influenza infection in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) or sham infected with DPBS (Air). Lung effector T cell profiles were determined by flow cytometry at six dpi. (A) Percentage of CD8+ cells expressing IFNγ (Tc1) with representative flow contour plots demonstrating outliers. N = 3-12/group. (B) Percentage of CD4+ cells expressing IFNγ (Th1) with representative flow contour plots demonstrating outliers. N = 3-12/group. Data plotted as mean ± SEM. *p <0.05 D230F vs AirF, D50F, and D230F(hSOD+); multiple t tests with Holm-Sidak correction for multiple comparisons.

Mentions: To determine the effects of EPFR exposure on the adaptive immune response to influenza, lungs were isolated at six dpi and T cell profiles were assessed. T cells expressing IFNγ are critical to control and clear influenza. The percent of CD8+ T cells expressing IFNγ (Tc1) were significantly reduced in D230F neonates (Figure 3A) compared to AirF or D50F. Furthermore, the percent of CD4+ T cells expressing IFNγ (Th1) were significantly lower in D230F neonates (Figure 3B) compared to AirF and D50F. The increased antioxidant capacity afforded to D230F(hSOD+) neonates resulted in significant increases in the percentage of both the Tc1 and Th1 cells compared to D230F. To further confirm whether percent Tc1 and Th1 values show similar trends in terms of total number of lung Tc1 and Th1 cells, the percent data was transformed to and analyzed in terms of total lung Tc1 and Th1 cells. Similar to percent data, the total number of both Tc1 and Th1 cells were significantly reduced in D230F neonates compared to AF or D50F and increased antioxidant capacity in D230F(hSOD+) neonates resulted in a significant increase in total lung Tc1 and Th1 cells compared to D230F (Additional file 4: Figure S4).Figure 3


Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection.

Lee GI, Saravia J, You D, Shrestha B, Jaligama S, Hebert VY, Dugas TR, Cormier SA - Part Fibre Toxicol (2014)

Effect of EPFR exposure on adaptive immune response (Tc1 and Th1) to influenza infection in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) or sham infected with DPBS (Air). Lung effector T cell profiles were determined by flow cytometry at six dpi. (A) Percentage of CD8+ cells expressing IFNγ (Tc1) with representative flow contour plots demonstrating outliers. N = 3-12/group. (B) Percentage of CD4+ cells expressing IFNγ (Th1) with representative flow contour plots demonstrating outliers. N = 3-12/group. Data plotted as mean ± SEM. *p <0.05 D230F vs AirF, D50F, and D230F(hSOD+); multiple t tests with Holm-Sidak correction for multiple comparisons.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4222384&req=5

Fig3: Effect of EPFR exposure on adaptive immune response (Tc1 and Th1) to influenza infection in neonates. Neonatal mice were exposed to air, DCB50, or DCB230 and infected i.n. with influenza (AirF, D50F, D230F, D230F(hSOD+)) or sham infected with DPBS (Air). Lung effector T cell profiles were determined by flow cytometry at six dpi. (A) Percentage of CD8+ cells expressing IFNγ (Tc1) with representative flow contour plots demonstrating outliers. N = 3-12/group. (B) Percentage of CD4+ cells expressing IFNγ (Th1) with representative flow contour plots demonstrating outliers. N = 3-12/group. Data plotted as mean ± SEM. *p <0.05 D230F vs AirF, D50F, and D230F(hSOD+); multiple t tests with Holm-Sidak correction for multiple comparisons.
Mentions: To determine the effects of EPFR exposure on the adaptive immune response to influenza, lungs were isolated at six dpi and T cell profiles were assessed. T cells expressing IFNγ are critical to control and clear influenza. The percent of CD8+ T cells expressing IFNγ (Tc1) were significantly reduced in D230F neonates (Figure 3A) compared to AirF or D50F. Furthermore, the percent of CD4+ T cells expressing IFNγ (Th1) were significantly lower in D230F neonates (Figure 3B) compared to AirF and D50F. The increased antioxidant capacity afforded to D230F(hSOD+) neonates resulted in significant increases in the percentage of both the Tc1 and Th1 cells compared to D230F. To further confirm whether percent Tc1 and Th1 values show similar trends in terms of total number of lung Tc1 and Th1 cells, the percent data was transformed to and analyzed in terms of total lung Tc1 and Th1 cells. Similar to percent data, the total number of both Tc1 and Th1 cells were significantly reduced in D230F neonates compared to AF or D50F and increased antioxidant capacity in D230F(hSOD+) neonates resulted in a significant increase in total lung Tc1 and Th1 cells compared to D230F (Additional file 4: Figure S4).Figure 3

Bottom Line: Increased oxidative stress was also observed in EPFR exposed neonates.Reduction of EPFR-induced oxidative stress attenuated these effects.EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Exposures to elevated levels of particulate matter (PM) enhance severity of influenza virus infection in infants. The biological mechanism responsible for this phenomenon is unknown. The recent identification of environmentally persistent free radicals (EPFRs) associated with PM from a variety of combustion sources suggests its role in the enhancement of influenza disease severity.

Methods: Neonatal mice (< seven days of age) were exposed to DCB230 (combustion derived PM with a chemisorbed EPFR), DCB50 (non-EPFR PM sample), or air for 30 minutes/day for seven consecutive days. Four days post-exposure, neonates were infected with influenza intranasally at 1.25 TCID50/neonate. Neonates were assessed for morbidity (% weight gain, peak pulmonary viral load, and viral clearance) and percent survival. Lungs were isolated and assessed for oxidative stress (8-isoprostanes and glutathione levels), adaptive immune response to influenza, and regulatory T cells (Tregs). The role of the EPFR was also assessed by use of transgenic mice expressing human superoxide dismutase 2.

Results: Neonates exposed to EPFRs had significantly enhanced morbidity and decreased survival following influenza infection. Increased oxidative stress was also observed in EPFR exposed neonates. This correlated with increased pulmonary Tregs and dampened protective T cell responses to influenza infection. Reduction of EPFR-induced oxidative stress attenuated these effects.

Conclusions: Neonatal exposure to EPFR containing PM resulted in pulmonary oxidative stress and enhanced influenza disease severity. EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.

Show MeSH
Related in: MedlinePlus