title: PG-mediated closure of paracellular pathway and not restitution is the primary determinant of barrier recovery in acutely injured porcine ileum.
abstract: Small bowel epithelium is at the frontline of intestinal barrier function. Restitution is considered to be the major determinant of epithelial repair, because function recovers in parallel with restitution after acute injury. As such, studies of intact mucosa have largely been replaced by migration assays of cultured epithelia. These latter studies fail to account for the simultaneous roles played by villous contraction and paracellular permeability in recovery of barrier function. NSAIDs result in increased intestinal permeability and disease exacerbation in patients with inflammatory bowel disease (IBD). Thus we examined the reparative attributes of endogenous PGs after injury of ileal mucosa by deoxycholate (6 mM) in Ussing chambers. Recovery of transepithelial electrical resistance (TER) from 20-40 Omega.cm2 was abolished by indomethacin (Indo), whereas restitution of 40-100% of the villous surface was unaffected despite concurrent arrest of villous contraction. In the presence of PG, resident crypt and migrating epithelial cells were tightly apposed. In tissues treated with Indo, crypt epithelial cells had dilated intercellular spaces that were accentuated in the migrating epithelium. TER was fully rescued from the effects of Indo by osmotic-driven collapse of the paracellular space, and PG-mediated recovery was significantly impaired by blockade of Cl- secretion. These studies are the first to clearly distinguish the relative contribution of paracellular resistance vs. restitution to acute recovery of epithelial barrier function. Restitution was ineffective in the absence of PG-mediated paracellular space closure. Failure of PG-mediated repair mechanisms may underlie barrier failure resulting from NSAID use in patients with underlying enteropathy.
authors.affiliation: Dept. of Molecular Biomedical Sciences, School of Veterinary Medicine, North Carolina State Univ., 4700 Hillsborough St., Raleigh, NC 27606, USA. Jody_Gookin@ncsu.edu
authors.forename: Jody L
authors.initials: JL
authors.lastname: Gookin
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Blikslager
authors.forename: Robert A
authors.initials: RA
authors.lastname: Argenzio
mesh_terms: D000818:Animals; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D005769:Gastrointestinal Motility; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008854:Microscopy, Electron; D008871:Microvilli; D010539:Permeability / Q000187:drug effects; D011453:Prostaglandins / Q000378:metabolism*; D020127:Recovery of Function; D013552:Swine; D014945:Wound Healing
chemical_list: D003902:Detergents; D011453:Prostaglandins; D003840:Deoxycholic Acid