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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/G43    most recent 90532.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Temmesfeld-Wollbrück, B. Articles by Hippenstiel, S. PubMed PubMed Citation Articles by Temmesfeld-Wollbrück, B. Articles by Hippenstiel, S.

INFLAMMATION/IMMUNITY/MEDIATORS

Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro

¹Departments of Internal Medicine and Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin, Berlin; ²Department of Veterinary Physiology, Freie Universität Berlin; ³NYCOMED, Konstanz, Germany

Submitted 8 September 2008 ; accepted in final form 30 April 2009

Leakage of the gut mucosal barrier in the critically ill patient may allow translocation of bacteria and their virulence factors, thereby perpetuating sepsis and inflammation. Present evidence suggests that adrenomedullin (AM) improves endothelial barrier function and stabilizes circulatory function in systemic inflammation. We tested the hypothesis that exogenously applied AM stabilizes gut epithelial barrier function. Infusion of Staphylococcus aureus -toxin induced septic shock in rats. AM infusion in a therapeutic setting reduced translocation of labeled dextran from the gut into the systemic circulation in this model. AM also reduced -toxin and hydrogen peroxide (H₂O₂)-related barrier disruption in Caco-2 cells in vitro and reduced H₂O₂-related rat colon barrier malfunction in Ussing chamber experiments. AM was shown to protect endothelial barrier function via cAMP elevation, but AM failed to induce cAMP accumulation in Caco-2 cells. cAMP is degraded via phosphodiesterases (PDE), and Caco-2 cells showed high activity of cAMP-degrading PDE3 and 4. However, AM failed to induce cAMP accumulation in Caco-2 cells even in the presence of sufficient PDE3/4 inhibition, whereas adenylyl cyclase activator forskolin induced strong cAMP elevation. Furthermore, PDE3/4 inhibition neither amplified AM-induced epithelial barrier stabilization nor affected AM cAMP-related rat colon short-circuit current, furthermore indicating that AM may act independently of cAMP in Caco-2 cells. Finally, experiments using chemical inhibitors indicated that PKC, phosphatidylinositide 3-kinase, p38, and ERK did not contribute to AM-related stabilization of barrier function in Caco-2 cells. In summary, during severe inflammation, elevated AM levels may substantially contribute to the stabilization of gut barrier function.

intestinal permeability; transepithelial resistance; cyclic AMP; sepsis