title: The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma.
abstract: BACKGROUND
  The extent of epithelial injury in asthma is reflected by expression of the epidermal growth factor receptor (EGFR), which is increased in proportion to disease severity and is corticosteroid refractory. Although the EGFR is involved in epithelial growth and differentiation, it is unknown whether it also contributes to the inflammatory response in asthma.
  
  
  OBJECTIVE
  Because severe asthma is characterized by neutrophilic inflammation, we investigated the relationship between EGFR activation and production of IL-8 and macrophage inhibitory protein-1 alpha (MIP-1alpha) using in vitro culture models and examined the association between epithelial expression of IL-8 and EGFR in bronchial biopsies from asthmatic subjects.
  
  
  METHODS
  H292 or primary bronchial epithelial cells were exposed to EGF or H2O2 to achieve ligand-dependent and ligand-independent EGFR activation; IL-8 mRNA was measured by real-time PCR and IL-8 and MIP-1alpha protein measured by enzyme-linked immunosorbent assay (ELISA). Epithelial IL-8 and EGFR expression in bronchial biopsies from asthmatic subjects was examined by immunohistochemistry and quantified by image analysis.
  
  
  RESULTS
  Using H292 cells, EGF and H2O2 increased IL-8 gene expression and release and this was completely suppressed by the EGFR-selective tyrosine kinase inhibitor, AG1478, but only partially by dexamethasone. MIP-1alpha release was not stimulated by EGF, whereas H2O2 caused a 1.8-fold increase and this was insensitive to AG1478. EGF also significantly stimulated IL-8 release from asthmatic or normal primary epithelial cell cultures established from bronchial brushings. In bronchial biopsies, epithelial IL-8, MIP-1alpha, EGFR and submucosal neutrophils were all significantly increased in severe compared to mild disease and there was a strong correlation between EGFR and IL-8 expression (r = 0.70, P < 0.001).
  
  
  CONCLUSIONS
  These results suggest that in severe asthma, epithelial damage has the potential to contribute to neutrophilic inflammation through enhanced production of IL-8 via EGFR- dependent mechanisms.
authors.affiliation: Division of Infection, Inflammation & Repair, School of Medicine, University of Southampton, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Hamilton
authors.forename: C
authors.initials: C
authors.lastname: Torres-Lozano
authors.forename: S M
authors.initials: SM
authors.lastname: Puddicombe
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: I
authors.initials: I
authors.lastname: Kimber
authors.forename: R J
authors.initials: RJ
authors.lastname: Dearman
authors.forename: B
authors.initials: B
authors.lastname: Vrugt
authors.forename: R
authors.initials: R
authors.lastname: Aalbers
authors.forename: S T
authors.initials: ST
authors.lastname: Holgate
authors.forename: R
authors.initials: R
authors.lastname: Djukanović
authors.forename: S J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: D E
authors.initials: DE
authors.lastname: Davies
mesh_terms: D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002908:Chronic Disease; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D066246:ErbB Receptors