title: Beyond Ussing's chambers: contemporary thoughts on integration of transepithelial transport.
abstract: In the mid-20th century, Hans Ussing developed a chamber that allowed for the simultaneous measurement of current and labeled probe flux across epithelia. Using frog skin as a model, Ussing used his results to propose mechanisms of transcellular Na(+) and K(+) transport across apical (exterior/luminal) and basolateral (interior) membranes that is essentially unchanged today. Others took advantage of Ussing's chambers to study mucosal tissues, including bladder and intestines. It quickly became clear that, in some tissues, passive paracellular flux, i.e., across the tight junction, was an important component of overall transepithelial transport. Subsequent work demonstrated that activation of the apical Na(+)-glucose cotransporter SGLT1 regulated paracellular permeability such that intestinal paracellular transport could coordinate with and amplify transcellular transport. Intermediates in this process include activation of p38 MAPK, the apical Na(+)/H(+) exchanger NHE3, and myosin light chain kinase (MLCK). Investigators then focused on these processes in disease. They found that TNF induces barrier dysfunction via MLCK activation and downstream caveolin-1-dependent endocytosis of the tight junction protein occludin. TNF also inhibited NHE3, and both barrier loss and PKCα-dependent NHE3 inhibition were required for TNF-induced acute diarrhea, emphasizing the interplay between transcellular and paracellular transport. Finally, studies using immune-mediated inflammatory bowel disease models showed that mice lacking epithelial MLCK were initially protected, but became ill as epithelial damage progressed and provided a tight junction-independent means of barrier loss. None of these advances would have been possible without the insights provided by Ussing and others using Ussing's ingenious, and still useful, chambers.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois; Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Herrmann
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts jrturner@partners.org.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D010539:Permeability; D015398:Signal Transduction / Q000502:physiology*; D019108:Tight Junctions / Q000502:physiology*
keywords: TNF; cytokine; intestine; myosin; myosin light chain kinase; permeability; tight junction