title: Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms.
abstract: BACKGROUND
  Exposure of human populations to ambient particulate matter (PM) air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism.
  
  
  RESULTS
  Adult, male C57BL/6 and IL-6 knock out (IL-6(-/-)) mice were exposed to either concentrated ambient PM less than 2.5 µm (CAPs) or filtered air 8 hours daily for 3 days or were exposed to either urban particulate matter or PBS via intratracheal instillation and examined 24 hours later. Exposure to CAPs or urban PM resulted in the IL-6 dependent activation of coagulation in the lung and systemically. PAI-1 mRNA and protein levels were higher in the lung and adipose tissue of mice treated with CAPs or PM compared with filtered air or PBS controls. The increase in PAI-1 was similar in wild-type and IL-6(-/-) mice but was absent in mice treated with etanercept, a TNF-α inhibitor. Treatment with etanercept did not prevent the PM-induced tendency toward thrombus formation.
  
  
  CONCLUSIONS
  Mice exposed to inhaled PM exhibited a TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of coagulation. These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Joanne L
authors.initials: JL
authors.lastname: McKell
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Nancy
authors.initials: N
authors.lastname: Foiles
authors.forename: Ivy
authors.initials: I
authors.lastname: Weiss
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Recep
authors.initials: R
authors.lastname: Nigdelioglu
authors.forename: Ece A
authors.initials: EA
authors.lastname: Mutlu
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Radigan
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.forename: Hau C
authors.initials: HC
authors.lastname: Kwaan
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D045744:Cell Line, Tumor; D002947:Cities; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D019570:Inhalation Exposure; D015850:Interleukin-6; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010316:Particle Size; D052638:Particulate Matter / Q000009:adverse effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000097:blood* / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D052638:Particulate Matter; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; D005337:Fibrin