期刊
GASTROENTEROLOGY
卷 125, 期 4, 页码 1148-1163出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/S0016-5085(03)01212-5
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资金
- NIDDK NIH HHS [DK48816] Funding Source: Medline
Background & Aims: Unlike the intestine of normal subjects, small-intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein-null (CFTR-) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption. Because CFTR-mediated anion secretion has been associated with changes in crypt cell volume, we hypothesized that CFTR-mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na+/H+ exchanger (primarily Na+/H+ exchanger 3) activity in the proximal small intestine. Methods. Transepithelial Na-22 flux across the jejuna of CFTR+, CFTR-, the basolateral membrane Na+/K+/2Cl(-) co-transporter protein NKCC1(+), and NKCC1(-) mice were correlated with changes in epithelial cell volume of the midvillus region. Results: Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na+/H+ exchanger-mediated Na+ absorption (J(ms)(NHE)) in CFTR+ jejunum but had no effect on J(ms)(NHE) across CFTR- jejunum. Cell volume indices indicated an approximately 30% volume reduction of villus epithelial cells in CFTR+ jejunum but no changes in CFTR- epithelium after intracellular cyclic adenosine monophosphate stimulation. In contrast, cell shrinkage induced by hypertonic medium inhibited J(ms)(NHE) in both CFTR+ and CFTR- mice. Bumetanide treatment to inhibit Cl- secretion by blockade of the Na+/K+/2Cl(-) co-transporter, NKCC1, of stimulated CFTR+ jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40% of J(ms)(NHE) MS. Likewise, J(ms)(NHE) and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in NKCC1(-) jejuna. Conclusions: These findings show a previously unrecognized role of functional CFTR expressed in villus epithelium: regulation of Na+/H+ exchanger 3-mediated Na+ absorption by alteration of epithelial cell volume.
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