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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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Bronchoalveolar lavage differential cell counts and macrophage expression of arginase 1. A) Differential cell counts from BAL samples in the sub-acute model OVA/PBS (□) and OVA/OVA (■) mice exposed to FA or CAP+O3 (*P < 0.05). (B) Images of arginase 1 immunostained slides of BAL samples and quantification of the percentage of positive macrophages (400× magnification; bar = 100 μm; brown colour indicates positivity; representative images of n = 5-6/group; *P < 0.05, **P < 0.01).
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Figure 3: Bronchoalveolar lavage differential cell counts and macrophage expression of arginase 1. A) Differential cell counts from BAL samples in the sub-acute model OVA/PBS (□) and OVA/OVA (■) mice exposed to FA or CAP+O3 (*P < 0.05). (B) Images of arginase 1 immunostained slides of BAL samples and quantification of the percentage of positive macrophages (400× magnification; bar = 100 μm; brown colour indicates positivity; representative images of n = 5-6/group; *P < 0.05, **P < 0.01).

Mentions: To determine which cell types were responsible for the augmented arginase 1 expression following exposure to CAP+O3, we investigated BAL and lung tissues, using immunohistochemical staining. We first examined the differential cell counts of the BAL samples from the sub-acute model. While there was an overall increase in the numbers of inflammatory cells in the OVA/OVA compared to OVA/PBS mice, there were no significant alterations in the differential cell counts in the CAP+O3 compared with the FA exposure groups (Figure 3A).


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)

Bronchoalveolar lavage differential cell counts and macrophage expression of arginase 1. A) Differential cell counts from BAL samples in the sub-acute model OVA/PBS (□) and OVA/OVA (■) mice exposed to FA or CAP+O3 (*P < 0.05). (B) Images of arginase 1 immunostained slides of BAL samples and quantification of the percentage of positive macrophages (400× magnification; bar = 100 μm; brown colour indicates positivity; representative images of n = 5-6/group; *P < 0.05, **P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Bronchoalveolar lavage differential cell counts and macrophage expression of arginase 1. A) Differential cell counts from BAL samples in the sub-acute model OVA/PBS (□) and OVA/OVA (■) mice exposed to FA or CAP+O3 (*P < 0.05). (B) Images of arginase 1 immunostained slides of BAL samples and quantification of the percentage of positive macrophages (400× magnification; bar = 100 μm; brown colour indicates positivity; representative images of n = 5-6/group; *P < 0.05, **P < 0.01).
Mentions: To determine which cell types were responsible for the augmented arginase 1 expression following exposure to CAP+O3, we investigated BAL and lung tissues, using immunohistochemical staining. We first examined the differential cell counts of the BAL samples from the sub-acute model. While there was an overall increase in the numbers of inflammatory cells in the OVA/OVA compared to OVA/PBS mice, there were no significant alterations in the differential cell counts in the CAP+O3 compared with the FA exposure groups (Figure 3A).

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