title: Incomplete lung recovery following sub-acute inhalation of combustion-derived ultrafine particles in mice.
abstract: BACKGROUND
  Particulate matter (PM) is one of the six criteria pollutant classes for which National Ambient Air Quality Standards have been set by the United States Environmental Protection Agency. Exposures to PM have been correlated with increased cardio-pulmonary morbidity and mortality. Butadiene soot (BDS), generated from the incomplete combustion of 1,3-butadiene (BD), is both a model PM mixture and a real-life example of a petrochemical product of incomplete combustion. There are numerous events, including wildfires, accidents at refineries and tank car explosions that result in sub-acute exposure to high levels of airborne particles, with the people exposed facing serious health problems. These real-life events highlight the need to investigate the health effects induced by short-term exposure to elevated levels of PM, as well as to assess whether, and if so, how well these adverse effects are resolved over time. In the present study, we investigated the extent of recovery of mouse lungs 10 days after inhalation exposures to environmentally-relevant levels of BDS aerosols had ended.
  
  
  METHODS
  Female BALB/c mice exposed to either HEPA-filtered air or to BDS (5 mg/m(3) in HEPA filtered air, 4 h/day, 21 consecutive days) were sacrificed immediately, or 10 days after the final BDS exposure. Bronchoalveolar lavage fluid (BALF) was collected for cytology and cytokine analysis. Lung proteins and RNA were extracted for protein and gene expression analysis. Lung histopathology evaluation also was performed.
  
  
  RESULTS
  Sub-acute exposures of mice to hydrocarbon-rich ultrafine particles induced: (1) BALF neutrophil elevation; (2) lung mucosal inflammation, and (3) increased BALF IL-1β concentration; with all three outcomes returning to baseline levels 10 days post-exposure. In contrast, (4) lung connective tissue inflammation persisted 10 days post-exposure; (5) we detected time-dependent up-regulation of biotransformation and oxidative stress genes, with incomplete return to baseline levels; and (6) we observed persistent particle alveolar load following 10 days of recovery.
  
  
  CONCLUSIONS
  These data show that 10 days after a 21-day exposure to 5 mg/m(3) of BDS has ended, incomplete lung recovery promotes a pro-biotransformation, pro-oxidant, and pro-inflammatory milieu, which may be a starting point for potential long-term cardio-pulmonary effects.
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr., Baton Rouge, LA, 70803, USA.
authors.forename: A
authors.initials: A
authors.lastname: Noël
authors.affiliation: Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr., Baton Rouge, LA, 70803, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Perveen
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr., Baton Rouge, LA, 70803, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Zaman
authors.affiliation: United States Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Rouse
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, 70803, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Paulsen
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr., Baton Rouge, LA, 70803, USA. apenn1@lsu.edu.
authors.forename: A L
authors.initials: AL
authors.lastname: Penn
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020127:Recovery of Function; D018570:Risk Assessment; D053260:Soot / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000336:Aerosols; D002070:Butadienes; D004785:Environmental Pollutants; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D053260:Soot; C031763:1,3-butadiene