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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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Functional effects of CAP+O3 exposure on airways responsiveness to methacholine and attenuation by arginase inhibition. Dose-response relationships for the increase in total lung resistance (R) to methacholine in OVA/PBS (A) and OVA/OVA (B) mice from the sub-acute model exposed to FA or CAP+O3. Effects of treatment with arginase inhibitor (BEC) vs. vehicle control (PBS) on maximum total lung resistance (RMax) in OVA/PBS (□) and OVA/OVA (■) mice following CAP+O3 exposures in the sub-acute (C) and chronic (D) models (*P < 0.05, ** P < 0.01, *** P < 0.001; n = 9-12/group).
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Figure 5: Functional effects of CAP+O3 exposure on airways responsiveness to methacholine and attenuation by arginase inhibition. Dose-response relationships for the increase in total lung resistance (R) to methacholine in OVA/PBS (A) and OVA/OVA (B) mice from the sub-acute model exposed to FA or CAP+O3. Effects of treatment with arginase inhibitor (BEC) vs. vehicle control (PBS) on maximum total lung resistance (RMax) in OVA/PBS (□) and OVA/OVA (■) mice following CAP+O3 exposures in the sub-acute (C) and chronic (D) models (*P < 0.05, ** P < 0.01, *** P < 0.001; n = 9-12/group).

Mentions: After demonstrating augmentation of arginase 1 protein expression in OVA/OVA mice exposed to CAP+O3, we initially examined the functional effects of air pollution exposure on methacholine responsiveness in vivo in the sub-acute model. Total lung resistance (R) to methacholine was not significantly augmented in the OVA/OVA mice compared to OVA/PBS controls under FA conditions (Figure 5A and 5B), making this model suitable to investigate the development of AHR induced specifically by CAP+O3 exposure. Exposure to CAP+O3 did not evoke any significant change in the methacholine responsiveness of the total lung in OVA/PBS mice (Figure 5A). However, significant augmentation of the methacholine dose-response curve was observed in the CAP+O3-exposed OVA/OVA mice, with a two-fold increase in the maximum resistance to methacholine, compared with the FA-exposed OVA/OVA controls (F-test and 2-way ANOVA, P < 0.001, Figure 5B and 5C). In the chronic model, FA-exposed OVA/OVA mice exhibited a moderate 1.5-fold increase in methacholine responsiveness compared with the OVA/PBS, FA-exposed controls (P = 0.0418), which was further augmented by 1.6-fold in CAP+O3-exposed OVA/OVA mice (P = 0.0071)(Figure 5D).


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)

Functional effects of CAP+O3 exposure on airways responsiveness to methacholine and attenuation by arginase inhibition. Dose-response relationships for the increase in total lung resistance (R) to methacholine in OVA/PBS (A) and OVA/OVA (B) mice from the sub-acute model exposed to FA or CAP+O3. Effects of treatment with arginase inhibitor (BEC) vs. vehicle control (PBS) on maximum total lung resistance (RMax) in OVA/PBS (□) and OVA/OVA (■) mice following CAP+O3 exposures in the sub-acute (C) and chronic (D) models (*P < 0.05, ** P < 0.01, *** P < 0.001; n = 9-12/group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Functional effects of CAP+O3 exposure on airways responsiveness to methacholine and attenuation by arginase inhibition. Dose-response relationships for the increase in total lung resistance (R) to methacholine in OVA/PBS (A) and OVA/OVA (B) mice from the sub-acute model exposed to FA or CAP+O3. Effects of treatment with arginase inhibitor (BEC) vs. vehicle control (PBS) on maximum total lung resistance (RMax) in OVA/PBS (□) and OVA/OVA (■) mice following CAP+O3 exposures in the sub-acute (C) and chronic (D) models (*P < 0.05, ** P < 0.01, *** P < 0.001; n = 9-12/group).
Mentions: After demonstrating augmentation of arginase 1 protein expression in OVA/OVA mice exposed to CAP+O3, we initially examined the functional effects of air pollution exposure on methacholine responsiveness in vivo in the sub-acute model. Total lung resistance (R) to methacholine was not significantly augmented in the OVA/OVA mice compared to OVA/PBS controls under FA conditions (Figure 5A and 5B), making this model suitable to investigate the development of AHR induced specifically by CAP+O3 exposure. Exposure to CAP+O3 did not evoke any significant change in the methacholine responsiveness of the total lung in OVA/PBS mice (Figure 5A). However, significant augmentation of the methacholine dose-response curve was observed in the CAP+O3-exposed OVA/OVA mice, with a two-fold increase in the maximum resistance to methacholine, compared with the FA-exposed OVA/OVA controls (F-test and 2-way ANOVA, P < 0.001, Figure 5B and 5C). In the chronic model, FA-exposed OVA/OVA mice exhibited a moderate 1.5-fold increase in methacholine responsiveness compared with the OVA/PBS, FA-exposed controls (P = 0.0418), which was further augmented by 1.6-fold in CAP+O3-exposed OVA/OVA mice (P = 0.0071)(Figure 5D).

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