title: Autocrine ligands of the epithelial growth factor receptor mediate inflammatory responses to diesel exhaust particles.
abstract: BACKGROUND
  Diesel exhaust is associated with cardiovascular and respiratory mortality and morbidity. Acute exposure leads to increased IL-8 expression and airway neutrophilia, however the mechanism of this response is unknown.
  
  
  OBJECTIVE
  As cigarette smoke-induced IL-8 expression by epithelial cells involves transactivation of the epidermal growth factor receptor (EGFR), we studied the effects of diesel exhaust particles (DEP) on IL-8 release and the role of the EGFR.
  
  
  METHODS
  Primary bronchial epithelial cells (PBEC) were exposed to DEPs or carbon black. IL-8 and EGFR ligand expression (transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor, and amphiregulin (AR)) were assessed by quantitative RT-PCR and ELISA.
  
  
  RESULTS
  DEP, but not carbon black, caused a dose-dependent increase in mitogen-activated protein kinase (MAPK) activation and IL-8 expression, however above 50 μg/ml there was an increase in cytotoxicity. At 50 μg/ml, DEPs stimulated transcription and release of IL-8 and EGFR ligands. IL-8 release was blocked by EGFR neutralizing antibodies, an EGFR-selective tyrosine kinase inhibitor and by the metalloprotease inhibitor, GM6001, which blocks EGFR ligand shedding. Neutralizing antibodies to AR, TGFα and heparin-binding (HB)-EGF reduced DEP-induced IL-8 by >50%. Conclusion Expression of IL-8 in response to DEPs is dependent on EGFR activation and that autocrine production of EGFR ligands makes a substantial contribution to this response.
  
  
  CONCLUSIONS
  This study identifies a mechanism whereby diesel particles stimulates IL-8 release from bronchial epithelial cells. This mechanism may help to explain the recruitment of neutrophils into the airways of people exposed to particulate air pollution.
authors.forename: Sam
authors.initials: S
authors.lastname: Parnia
authors.forename: Lynnsey M
authors.initials: LM
authors.lastname: Hamilton
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Puddicombe
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Frew
authors.affiliation: The Brooke Laboratories, Division of Infection, Inflammation and Repair, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK. donnad@soton.ac.uk.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
mesh_terms: D000328:Adult; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D001335:Vehicle Emissions / Q000633:toxicity*; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; D016209:Interleukin-8; D008024:Ligands; D001335:Vehicle Emissions; C512478:EGFR protein, human; D066246:ErbB Receptors