title: Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro.
abstract: OBJECTIVE
  Persistent stress and life events affect the course of ulcerative colitis and irritable bowel syndrome by largely unknown mechanisms. Corticotropin-releasing hormone (CRH) has been implicated as an important mediator of stress-induced abnormalities in intestinal mucosal function in animal models, but to date no studies in human colon have been reported. The aim was to examine the effects of CRH on mucosal barrier function in the human colon and to elucidate the mechanisms involved in CRH-induced hyper-permeability.
  
  
  METHODS
  Biopsies from 39 volunteers were assessed for macromolecular permeability (horseradish peroxidase (HRP), (51)Cr-EDTA), and electrophysiology after CRH challenge in Ussing chambers. The biopsies were examined by electron and confocal microscopy for HRP and CRH receptor localisation, respectively. Moreover, CRH receptor mRNA and protein expression were examined in the human mast cell line, HMC-1.
  
  
  RESULTS
  Mucosal permeability to HRP was increased by CRH (2.8+/-0.5 pmol/cm(2)/h) compared to vehicle exposure (1.5+/-0.4 pmol/cm(2)/h), p = 0.032, whereas permeability to (51)Cr-EDTA and transmucosal electrical resistance were unchanged. The increased permeability to HRP was abolished by alpha-helical CRH (9-41) (1.3+/-0.6 pmol/cm(2)/h) and the mast cell stabilizer, lodoxamide (1.6+/-0.6 pmol/cm(2)/h). Electron microscopy showed transcellular passage of HRP through colonocytes. CRH receptor subtypes R1 and R2 were detected in the HMC-1 cell line and in lamina propria mast cells in human colon.
  
  
  CONCLUSIONS
  Our results suggest that CRH mediates transcellular uptake of HRP in human colonic mucosa via CRH receptor subtypes R1 and R2 on subepithelial mast cells. CRH-induced macromolecular uptake in human colon mucosa may have implications for stress-related intestinal disorders.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Wallon
authors.forename: P-C
authors.initials: PC
authors.lastname: Yang
authors.forename: A V
authors.initials: AV
authors.lastname: Keita
authors.forename: A-C
authors.initials: AC
authors.lastname: Ericson
authors.forename: D M
authors.initials: DM
authors.lastname: McKay
authors.forename: P M
authors.initials: PM
authors.lastname: Sherman
authors.forename: M H
authors.initials: MH
authors.lastname: Perdue
authors.forename: J D
authors.initials: JD
authors.lastname: Söderholm
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D003106:Colon / Q000378:metabolism / Q000648:ultrastructure*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008407:Mast Cells / Q000378:metabolism* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D010539:Permeability; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone