title: Protective effects of nonionic triblock copolymers on bile acid-mediated epithelial barrier disruption.
abstract: Translocation of bacteria and other luminal factors from the intestine following surgical injury can be a major driver of critical illness. Bile acids have been shown to play a key role in the loss of intestinal epithelial barrier function during states of host stress. Experiments to study the ability of nonionic block copolymers to abrogate barrier failure in response to bile acid exposure are described. In vitro experiments were performed with the bile salt sodium deoxycholate on Caco-2 enterocyte monolayers using transepithelial electrical resistance to assay barrier function. A bisphenol A coupled triblock polyethylene glycol (PEG), PEG 15-20, was shown to prevent sodium deoxycholate-induced barrier failure. Enzyme-linked immunosorbent assay, lactate dehydrogenase, and caspase 3-based cell death detection assays demonstrated that bile acid-induced apoptosis and necrosis were prevented with PEG 15-20. Immunofluorescence microscopic visualization of the tight junctional protein zonula occludens 1 (ZO-1) demonstrated that PEG 15-20 prevented significant changes in tight junction organization induced by bile acid exposure. Preliminary transepithelial electrical resistance-based studies examining structure-function correlates of polymer protection against bile acid damage were performed with a small library of PEG-based copolymers. Polymer properties associated with optimal protection against bile acid-induced barrier disruption were PEG-based compounds with a molecular weight greater than 10 kd and amphiphilicity. The data demonstrate that PEG-based copolymer architecture is an important determinant that confers protection against bile acid injury of intestinal epithelia.
authors.affiliation: Department of Surgery, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave., Chicago, IL 60637, USA..
authors.forename: Adam
authors.initials: A
authors.lastname: Edelstein
authors.forename: David
authors.initials: D
authors.lastname: Fink
authors.forename: Mark
authors.initials: M
authors.lastname: Musch
authors.forename: Vesta
authors.initials: V
authors.lastname: Valuckaite
authors.forename: Olga
authors.initials: O
authors.lastname: Zaborina
authors.forename: Simonida
authors.initials: S
authors.lastname: Grubjesic
authors.forename: Millicent A
authors.initials: MA
authors.lastname: Firestone
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Matthews
authors.forename: John C
authors.initials: JC
authors.lastname: Alverdy
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds; D001647:Bile Acids and Salts / Q000494:pharmacology*; D018938:Caco-2 Cells; D053148:Caspase 3 / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D010636:Phenols / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D001647:Bile Acids and Salts; D053148:Caspase 3; D003840:Deoxycholic Acid; D008565:Membrane Proteins; D010636:Phenols; D010750:Phosphoproteins; D011092:Polyethylene Glycols; D011108:Polymers; D062826:Zonula Occludens-1 Protein; C569042:TJP1 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds