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Acrolein exposure suppresses antigen-induced pulmonary inflammation.

Spiess PC, Kasahara D, Habibovic A, Hristova M, Randall MJ, Poynter ME, van der Vliet A - Respir. Res. (2013)

Bottom Line: Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein-exposed lungs, associated with increased carbonylation of RelA and JNK.Acrolein inhalation suppresses Th2-driven allergic inflammation in sensitized animals, due to direct protein alkylation resulting in activation of Nrf2 and anti-inflammatory gene expression, and inhibition of NF-κB or JNK signaling.Our findings help explain the paradoxical anti-inflammatory effects of cigarette smoke exposure in allergic airways disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, College of Medicine, D205 Given Building, 89 Beaumont Ave, Burlington, VT 05405, USA. albert.van-der-vliet@uvm.edu.

ABSTRACT

Background: Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reactive electrophiles, acrolein, we explored the impact of acrolein exposure in a mouse model of ovalbumin (OVA)-induced allergic asthma.

Methods: C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection with the adjuvant aluminum hydroxide on days 0 and 7, and challenged with aerosolized OVA on days 14-16. In some cases, mice were also exposed to 5 ppm acrolein vapor for 6 hrs/day on days 14-17. Lung tissues or brochoalveolar lavage fluids (BALF) were collected either 6 hrs after a single initial OVA challenge and/or acrolein exposure on day 14 or 48 hrs after the last OVA challenge, on day 18. Inflammatory cells and Th1/Th2 cytokine levels were measured in BALF, and lung tissue samples were collected for analysis of mucus and Th1/Th2 cytokine expression, determination of protein alkylation, cellular thiol status and transcription factor activity.

Results: Exposure to acrolein following OVA challenge of OVA-sensitized mice resulted in markedly attenuated allergic airway inflammation, demonstrated by decreased inflammatory cell infiltrates, mucus hyperplasia and Th2 cytokines. Acrolein exposure rapidly depleted lung tissue glutathione (GSH) levels, and induced activation of the Nrf2 pathway, indicated by accumulation of Nrf2, increased alkylation of Keap1, and induction of Nrf2-target genes such as HO-1. Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein-exposed lungs, associated with increased carbonylation of RelA and JNK.

Conclusion: Acrolein inhalation suppresses Th2-driven allergic inflammation in sensitized animals, due to direct protein alkylation resulting in activation of Nrf2 and anti-inflammatory gene expression, and inhibition of NF-κB or JNK signaling. Our findings help explain the paradoxical anti-inflammatory effects of cigarette smoke exposure in allergic airways disease.

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Acrolein exposure suppresses mucus/goblet cell hyperplasia in response to allergen challenge. Mucus/goblet cell hyperplasia was evaluated 48 hrs after the last OVA challenge by PAS staining (A) which was scored and quantified (B). Lung tissue mRNA gene expression of Muc5ac and Gob5 was analyzed by qRT-PCR (C). Results are expressed as mean ± SEM (n = 4/group) (*, p < 0.05).
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Figure 3: Acrolein exposure suppresses mucus/goblet cell hyperplasia in response to allergen challenge. Mucus/goblet cell hyperplasia was evaluated 48 hrs after the last OVA challenge by PAS staining (A) which was scored and quantified (B). Lung tissue mRNA gene expression of Muc5ac and Gob5 was analyzed by qRT-PCR (C). Results are expressed as mean ± SEM (n = 4/group) (*, p < 0.05).

Mentions: To explore the effects of acrolein inhalation on allergic airway inflammation, we used an ovalbumin (OVA) model of asthma and exposed allergen-sensitized mice to acrolein vapor during the OVA challenge phase, and evaluated airway inflammation 48 hrs after the final OVA challenge (Figure 1). As expected, OVA challenge of sensitized mice resulted in allergic inflammation, shown by increased numbers of primarily eosinophils, as well as neutrophils and lymphocytes in BAL fluids. Exposure to acrolein immediately following allergen challenge significantly suppressed these responses, shown by decreased total numbers of BAL cells (Figure 2A), and decreased numbers of eosinophils, neutrophils and lymphocytes (Figure 2B), compared with animals that were not exposed to acrolein. A trend towards suppression of allergen-induced pulmonary cell infiltration was also observed immediately after a single exposure to acrolein following a single OVA challenge (Figure 2C and D), indicating acrolein may have direct and immediate effects on inflammatory pathways. Additionally, acrolein exposure markedly decreased allergen-induced mucus and goblet cell hyperplasia as detected by PAS staining (Figure 3A and B), and significantly decreased mRNA expression of the marker genes Muc5ac and Gob5 (Figure 3C), 48 hrs after the final OVA challenge.


Acrolein exposure suppresses antigen-induced pulmonary inflammation.

Spiess PC, Kasahara D, Habibovic A, Hristova M, Randall MJ, Poynter ME, van der Vliet A - Respir. Res. (2013)

Acrolein exposure suppresses mucus/goblet cell hyperplasia in response to allergen challenge. Mucus/goblet cell hyperplasia was evaluated 48 hrs after the last OVA challenge by PAS staining (A) which was scored and quantified (B). Lung tissue mRNA gene expression of Muc5ac and Gob5 was analyzed by qRT-PCR (C). Results are expressed as mean ± SEM (n = 4/group) (*, p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852782&req=5

Figure 3: Acrolein exposure suppresses mucus/goblet cell hyperplasia in response to allergen challenge. Mucus/goblet cell hyperplasia was evaluated 48 hrs after the last OVA challenge by PAS staining (A) which was scored and quantified (B). Lung tissue mRNA gene expression of Muc5ac and Gob5 was analyzed by qRT-PCR (C). Results are expressed as mean ± SEM (n = 4/group) (*, p < 0.05).
Mentions: To explore the effects of acrolein inhalation on allergic airway inflammation, we used an ovalbumin (OVA) model of asthma and exposed allergen-sensitized mice to acrolein vapor during the OVA challenge phase, and evaluated airway inflammation 48 hrs after the final OVA challenge (Figure 1). As expected, OVA challenge of sensitized mice resulted in allergic inflammation, shown by increased numbers of primarily eosinophils, as well as neutrophils and lymphocytes in BAL fluids. Exposure to acrolein immediately following allergen challenge significantly suppressed these responses, shown by decreased total numbers of BAL cells (Figure 2A), and decreased numbers of eosinophils, neutrophils and lymphocytes (Figure 2B), compared with animals that were not exposed to acrolein. A trend towards suppression of allergen-induced pulmonary cell infiltration was also observed immediately after a single exposure to acrolein following a single OVA challenge (Figure 2C and D), indicating acrolein may have direct and immediate effects on inflammatory pathways. Additionally, acrolein exposure markedly decreased allergen-induced mucus and goblet cell hyperplasia as detected by PAS staining (Figure 3A and B), and significantly decreased mRNA expression of the marker genes Muc5ac and Gob5 (Figure 3C), 48 hrs after the final OVA challenge.

Bottom Line: Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein-exposed lungs, associated with increased carbonylation of RelA and JNK.Acrolein inhalation suppresses Th2-driven allergic inflammation in sensitized animals, due to direct protein alkylation resulting in activation of Nrf2 and anti-inflammatory gene expression, and inhibition of NF-κB or JNK signaling.Our findings help explain the paradoxical anti-inflammatory effects of cigarette smoke exposure in allergic airways disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, College of Medicine, D205 Given Building, 89 Beaumont Ave, Burlington, VT 05405, USA. albert.van-der-vliet@uvm.edu.

ABSTRACT

Background: Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reactive electrophiles, acrolein, we explored the impact of acrolein exposure in a mouse model of ovalbumin (OVA)-induced allergic asthma.

Methods: C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection with the adjuvant aluminum hydroxide on days 0 and 7, and challenged with aerosolized OVA on days 14-16. In some cases, mice were also exposed to 5 ppm acrolein vapor for 6 hrs/day on days 14-17. Lung tissues or brochoalveolar lavage fluids (BALF) were collected either 6 hrs after a single initial OVA challenge and/or acrolein exposure on day 14 or 48 hrs after the last OVA challenge, on day 18. Inflammatory cells and Th1/Th2 cytokine levels were measured in BALF, and lung tissue samples were collected for analysis of mucus and Th1/Th2 cytokine expression, determination of protein alkylation, cellular thiol status and transcription factor activity.

Results: Exposure to acrolein following OVA challenge of OVA-sensitized mice resulted in markedly attenuated allergic airway inflammation, demonstrated by decreased inflammatory cell infiltrates, mucus hyperplasia and Th2 cytokines. Acrolein exposure rapidly depleted lung tissue glutathione (GSH) levels, and induced activation of the Nrf2 pathway, indicated by accumulation of Nrf2, increased alkylation of Keap1, and induction of Nrf2-target genes such as HO-1. Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein-exposed lungs, associated with increased carbonylation of RelA and JNK.

Conclusion: Acrolein inhalation suppresses Th2-driven allergic inflammation in sensitized animals, due to direct protein alkylation resulting in activation of Nrf2 and anti-inflammatory gene expression, and inhibition of NF-κB or JNK signaling. Our findings help explain the paradoxical anti-inflammatory effects of cigarette smoke exposure in allergic airways disease.

Show MeSH
Related in: MedlinePlus