title: Epidermal growth factor partially restores colonic ion transport responses in mouse models of chronic colitis.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) activation, which plays an important role in regulating intestinal ion transport, can alleviate clinical symptoms such as diarrhea in patients with ulcerative colitis and promote mucosal restitution in animal models of colitis. Here, we investigate whether EGFR can regulate colonic ion transport in the setting of colitis.
  
  
  METHODS
  Distal colon from control mice and mice with colitis was retained for immunohistochemistry or mounted in Ussing chambers. Ion transport responses across the tissues to the calcium agonist carbachol and the adenosine 3',5'-cyclic monophosphate agonist forskolin were measured with or without epidermal growth factor (EGF) pretreatment.
  
  
  RESULTS
  EGF pretreatment of normal colonic mucosa inhibited ion transport responses to carbachol and forskolin but potentiated the reduced ion transport responses seen in dextran sulfate sodium (DSS)-treated and mdr1a knockout mouse colon. Ion substitution studies and the sodium transport inhibitor amiloride showed that sodium movement primarily accounted for the potentiating effect of EGF in DSS-treated tissues, despite decreased sodium channel expression. EGF potentiation of transport responses in DSS-treated colon was completely blocked by the cytoskeletal disruptor cytochalasin D and the phosphatidylinositol 3-kinase inhibitor wortmannin, whereas the novel and conventional protein kinase C isoform inhibitor Gö6850 and the extracellular signal-regulated kinase inhibitor PD98059 partially reduced EGF effects. EGFR epithelial distribution and transforming growth factor alpha expression were also altered in DSS-treated tissues.
  
  
  CONCLUSIONS
  Chronic inflammation uncovers a potentiating effect of EGFR activation on epithelial electrogenic sodium absorption that would be expected to ameliorate diarrheal symptoms associated with colitis.
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, 92103, USA.
authors.forename: Declan F
authors.initials: DF
authors.lastname: McCole
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.forename: Kim E
authors.initials: KE
authors.lastname: Barrett
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000493:pharmacokinetics* / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011336:Probability; D012016:Reference Values; D012680:Sensitivity and Specificity; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D015222:Sodium Channels; D004815:Epidermal Growth Factor; D016264:Dextran Sulfate