Acrolein exposure suppresses antigen-induced pulmonary inflammation

Respiratory Research

Albert van der Vliet¹  Matthew E Poynter²  Matthew J Randall¹  Milena Hristova¹  Aida Habibovic¹  David Kasahara³  Page C Spiess¹ 

[1] Department of Pathology, College of Medicine, D205 Given Building, 89 Beaumont Ave, Burlington, VT 05405, USA;Department of Medicine, University of Vermont, Burlington, VT 05405, USA;Department of Environmental Health, Harvard School of Public Health, Boston, MA, 02115, USA

关键词: JNK;    NF-κB;    Nrf2;    COPD;    Asthma;    Inflammation;    Electrophile;    Cigarette smoke;   

Others  :  792572
DOI  :  10.1186/1465-9921-14-107

 received in 2013-05-22, accepted in 2013-10-08,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Spiess et al.; licensee BioMed Central Ltd.

【 图 表 】

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