title: Acrolein exposure suppresses antigen-induced pulmonary inflammation.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Page C
authors.initials: PC
authors.lastname: Spiess
authors.forename: David
authors.initials: D
authors.lastname: Kasahara
authors.forename: Aida
authors.initials: A
authors.lastname: Habibovic
authors.forename: Milena
authors.initials: M
authors.lastname: Hristova
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Randall
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: Department of Pathology, College of Medicine, D205 Given Building, 89 Beaumont Ave, Burlington, VT 05405, USA. albert.van-der-vliet@uvm.edu.
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
mesh_terms: D000171:Acrolein / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010047:Ovalbumin / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D058408:Th1-Th2 Balance / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D000171:Acrolein; D010047:Ovalbumin; D005978:Glutathione