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Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma.

North ML, Amatullah H, Khanna N, Urch B, Grasemann H, Silverman F, Scott JA - Respir. Res. (2011)

Bottom Line: Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models.Arginase inhibition significantly reduced the CAP+O₃-induced increase in AHR in both models.Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

ABSTRACT

Background: Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR.

Methods: To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O₃), or HEPA-filtered air (FA), for 4 hours. After the CAP+O₃ exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization.

Results: Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O₃-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O₃-induced increase in AHR in both models.

Conclusions: This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes to the pollution-induced exacerbation of airways responsiveness. Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.

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Pulmonary arginase activity and arginase isozyme expression in CAP+O3-exposed mice and filtered air controls. Total arginase activity in FA- and CAP+O3-exposed model OVA/PBS (□) and OVA/OVA (■) mice in the sub-acute (A) and chronic (B) models. Western blotting and quantification of arginase 1 and actin loading controls in the sub-acute (C) and chronic (D) models (*P < 0.05, **P < 0.01, ***P < 0.001, (n)). E) Correlation between levels of arginase 1 expression in the OVA/OVA mice in the sub-acute model and CAP exposure concentration (Spearman ρ = 0.6219; P = 0.013, n = 11 independent exposure dates).
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Figure 2: Pulmonary arginase activity and arginase isozyme expression in CAP+O3-exposed mice and filtered air controls. Total arginase activity in FA- and CAP+O3-exposed model OVA/PBS (□) and OVA/OVA (■) mice in the sub-acute (A) and chronic (B) models. Western blotting and quantification of arginase 1 and actin loading controls in the sub-acute (C) and chronic (D) models (*P < 0.05, **P < 0.01, ***P < 0.001, (n)). E) Correlation between levels of arginase 1 expression in the OVA/OVA mice in the sub-acute model and CAP exposure concentration (Spearman ρ = 0.6219; P = 0.013, n = 11 independent exposure dates).

Mentions: To investigate whether alterations in the arginase pathway were induced by exposure to air pollution we measured total arginase activity in mouse lung homogenates from FA and CAP+O3 exposed mice. FA-exposed OVA/OVA mice from both models exhibited significantly increased pulmonary arginase activity, relative to the FA-exposed OVA/PBS controls (Figure 2A &2B). In both models, OVA/OVA mice exposed to CAP+O3 exhibited further significant increases in pulmonary arginase activity, compared to the FA-exposed OVA/OVA mice (1.7- and 1.6-fold, respectively). CAP+O3 exposure did not affect total pulmonary arginase activity in the OVA/PBS mice.


Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma.

North ML, Amatullah H, Khanna N, Urch B, Grasemann H, Silverman F, Scott JA - Respir. Res. (2011)

Pulmonary arginase activity and arginase isozyme expression in CAP+O3-exposed mice and filtered air controls. Total arginase activity in FA- and CAP+O3-exposed model OVA/PBS (□) and OVA/OVA (■) mice in the sub-acute (A) and chronic (B) models. Western blotting and quantification of arginase 1 and actin loading controls in the sub-acute (C) and chronic (D) models (*P < 0.05, **P < 0.01, ***P < 0.001, (n)). E) Correlation between levels of arginase 1 expression in the OVA/OVA mice in the sub-acute model and CAP exposure concentration (Spearman ρ = 0.6219; P = 0.013, n = 11 independent exposure dates).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037317&req=5

Figure 2: Pulmonary arginase activity and arginase isozyme expression in CAP+O3-exposed mice and filtered air controls. Total arginase activity in FA- and CAP+O3-exposed model OVA/PBS (□) and OVA/OVA (■) mice in the sub-acute (A) and chronic (B) models. Western blotting and quantification of arginase 1 and actin loading controls in the sub-acute (C) and chronic (D) models (*P < 0.05, **P < 0.01, ***P < 0.001, (n)). E) Correlation between levels of arginase 1 expression in the OVA/OVA mice in the sub-acute model and CAP exposure concentration (Spearman ρ = 0.6219; P = 0.013, n = 11 independent exposure dates).
Mentions: To investigate whether alterations in the arginase pathway were induced by exposure to air pollution we measured total arginase activity in mouse lung homogenates from FA and CAP+O3 exposed mice. FA-exposed OVA/OVA mice from both models exhibited significantly increased pulmonary arginase activity, relative to the FA-exposed OVA/PBS controls (Figure 2A &2B). In both models, OVA/OVA mice exposed to CAP+O3 exhibited further significant increases in pulmonary arginase activity, compared to the FA-exposed OVA/OVA mice (1.7- and 1.6-fold, respectively). CAP+O3 exposure did not affect total pulmonary arginase activity in the OVA/PBS mice.

Bottom Line: Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models.Arginase inhibition significantly reduced the CAP+O₃-induced increase in AHR in both models.Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

ABSTRACT

Background: Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR.

Methods: To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O₃), or HEPA-filtered air (FA), for 4 hours. After the CAP+O₃ exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization.

Results: Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O₃-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O₃-induced increase in AHR in both models.

Conclusions: This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes to the pollution-induced exacerbation of airways responsiveness. Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.

Show MeSH
Related in: MedlinePlus