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This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 581/3/1221    most recent jphysiol.2007.129262v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, H. Articles by Vidyasagar, S. Search for Related Content PubMed PubMed Citation Articles by Zhang, H. Articles by Vidyasagar, S. Related Collections Alimentary

¹ Digestive Diseases, Department of Medicine
² Department of Pharmacology and Physiology
³ Center for Oral biology University of Rochester School of Medicine, Rochester, NY, USA
⁴ Department of Pediatrics and Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

T-cell mediated acute inflammation of the ileum may occur during Crohn's disease exacerbations. During ileal inflammation, absorption of nutrients and electrolytes by villus cells is decreased with a concomitant increase in crypt and/or villus fluid secretion. These alterations lead to fluid accumulation and the subsequent diarrhoea. Net intestinal fluid secretion consists of HCO₃^–-rich plasma-like fluid. However, the regulation and mechanisms of HCO₃^– secretion in normal and acutely inflamed ileum are not clearly understood. To study this phenomenon, anti-CD3 monoclonal antibody (mAb)- induced in vivo ileal inflammatory mouse models was used for in vitro functional studies with Ussing chamber and pH stat techniques. Three hours after anti-CD3 mAb injection, ileal mucosa stripped of muscular and serosal layers showed a significant increase in short circuit current (I_sc) (0.58 ± 0.07 µEq h^–1 cm² versus 1.63 ± 0.14 µEq h^–1 cm²). The cAMP-stimulated I_sc component was sensitive to glibenclamide but not to DIDS, suggesting that a cystic fibrosis transmembrane conductance regulator (Cftr)-mediated anion conductance was responsible. Basal Cl^–-dependent HCO₃^– secretion, measured using a pH stat technique, was decreased significantly in anti-CD3-injected mice, with a simultaneous increase in Cl^–-independent HCO₃^– secretion that was also inhibited by glibenclamide. Experiments using Cftr^–/– mice showed neither an increase in I_sc nor an increase in HCO₃^– secretion, confirming the role for Cftr protein in stimulating anion secretion following anti-CD3 treatment. Western blot analysis indicated that Cftr protein levels were unaltered by anti-CD3 treatment, at least acutely. Finally, an immunoassay for cAMP showed significant increases in intracellular cAMP in villus cells, but not in crypt cells. These studies therefore suggest a shift from a predominantly electroneutral Cl^–HCO₃^– exchange in normal mice, to a predominantly electrogenic anion secretion including HCO₃^– that occurs via functional Cftr during anti-CD3-mediated acute inflammation.

(Received 26 January 2007; accepted after revision 23 March 2007; first published online 29 March 2007)
Corresponding author S. Vidyasagar: University of Rochester School of Medicine, 601 Elmwood Ave, Box 646, Rochester, NY 14642, USA. Email: sadasivan_vidyasagar{at}URMC.Rochester.edu