title: Cigarette smokers have exaggerated alveolar barrier disruption in response to lipopolysaccharide inhalation.
abstract: Cigarette smoke exposure is associated with an increased risk of the acute respiratory distress syndrome (ARDS); however, the mechanisms underlying this relationship remain largely unknown.
  
  
  
  To assess pathways of lung injury and inflammation in smokers and non-smokers with and without lipopolysaccharide (LPS) inhalation using established biomarkers.
  
  
  
  We measured plasma and bronchoalveolar lavage (BAL) biomarkers of inflammation and lung injury in smokers and non-smokers in two distinct cohorts of healthy volunteers, one unstimulated (n=20) and one undergoing 50 μg LPS inhalation (n=30).
  
  
  
  After LPS inhalation, cigarette smokers had increased alveolar-capillary membrane permeability as measured by BAL total protein, compared with non-smokers (median 274 vs 208 μg/mL, p=0.04). Smokers had exaggerated inflammation compared with non-smokers, with increased BAL interleukin-1β (p=0.002), neutrophils (p=0.02), plasma interleukin-8 (p=0.003), and plasma matrix metalloproteinase-8 (p=0.006). Alveolar epithelial injury after LPS was more severe in smokers than non-smokers, with increased plasma (p=0.04) and decreased BAL (p=0.02) surfactant protein D. Finally, smokers had decreased BAL vascular endothelial growth factor (VEGF) (p<0.0001) with increased soluble VEGF receptor-1 (p=0.0001).
  
  
  
  Cigarette smoke exposure may predispose to ARDS through an abnormal response to a 'second hit,' with increased alveolar-capillary membrane permeability, exaggerated inflammation, increased epithelial injury and endothelial dysfunction. LPS inhalation may serve as a useful experimental model for evaluation of the acute pulmonary effects of existing and new tobacco products.
authors.affiliation: Department of Medicine, UCSF, San Francisco, California, USA.
authors.forename: Farzad
authors.initials: F
authors.lastname: Moazed
authors.affiliation: Department of Medicine, University of Colorado, Aurora, Colorado, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Burnham
authors.affiliation: Department of Medicine, University of Colorado, Aurora, Colorado, USA.
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: O'Kane
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: Murali
authors.initials: M
authors.lastname: Shyamsundar
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: Umar
authors.initials: U
authors.lastname: Hamid
authors.affiliation: Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Abbott
authors.affiliation: Lung Injury and Fibrosis Treatment Programme, University of Birmingham, Birmingham, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Thickett
authors.affiliation: Department of Medicine, UCSF, San Francisco, California, USA.|Cardiovascular Research Institute, UCSF, San Francisco, California, USA.|Department of Anesthesia, UCSF, San Francisco, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Department of Medicine, UCSF, San Francisco, California, USA.|Cardiovascular Research Institute, UCSF, San Francisco, California, USA.|Department of Anesthesia, UCSF, San Francisco, California, USA.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D002199:Capillary Permeability / Q000187:drug effects; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D012907:Smoking / Q000378:metabolism / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D037663:Pulmonary Surfactant-Associated Protein D; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: ARDS; Tobacco and the lung
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