Altered sodium-hydrogen exchange activity is a mechanism for acid-induced hyperproliferation in Barrett's esophagus.
Acid produces a dynamic effect on the cell phenotype of Barrett's esophagus (BE) ex vivo. An acid pulse induces hyperproliferation, whereas continuous acid exposure promotes differentiation. To examine the mechanism for acid pulse-induced hyperproliferation, we studied the Na+/H+ exchanger (NHE), which plays a role in the control of intracellular pH and cell proliferation. NHE was inhibited pharmacologically in endoscopic BE biopsies using amiloride analogs. Cell proliferation was assessed after pulsed or continuous acid exposure using tritiated thymidine incorporation assays and immunohistochemical analysis of proliferating cell nuclear antigen expression. The NHE-dependent intracellular pH response to an acid pulse was examined by pH-sensitive microfluorimetry using a Barrett's adenocarcinoma cell line TE7. NHE inhibition significantly reduced the hyperproliferative acid-pulse effect. Furthermore, the acid-pulse activation of NHE occurred via increased transporter activity (22Na uptake) without any change in NHE-1 protein levels. Inhibition of protein kinase C (PKC), an NHE activator, also reduced the hyperproliferative response. The response of TE7 cells to an acid pulse was similar to that of BE biopsies in terms of cell proliferation and NHE and PKC dependence. Acid-pulse exposure of TE7 cells resulted in intracellular acidification followed by reneutralization to an intracellular pH greater than preacidosis values. We conclude that NHE may mediate the hyperproliferative response of BE to an acid pulse via changes in intracellular pH.
Fitzgerald
R C
RC
Gastroenterology Section, Palo Alto Veterans Affairs Health Care System, Palo Alto, CA 94304, USA.
Omary
M B
MB
Triadafilopoulos
G
G
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D001471:Barrett Esophagus / Q000473:pathology* / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004947:Esophagus / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009092:Mucous Membrane / Q000473:pathology / Q000503:physiopathology; D009924:Organ Culture Techniques; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000378:metabolism*
D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C039465:5-dimethylamiloride; D000584:Amiloride; D012964:Sodium; C039614:ethylisopropylamiloride