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MUCOSAL BIOLOGY

Lateral intercellular space volume as a determinant of CFTR-mediated anion secretion across small intestinal mucosa

Dalton Cardiovascular Research Center and the Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri 65211

Submitted 5 November 2003 ; accepted in final form 29 January 2004

Studies of full-thickness, small intestinal preparations have shown that maximal anion secretion [indexed by short-circuit current (I_sc)] during intracellular cAMP (cAMP_i) stimulation is transient and followed by a decline toward baseline. Declining I_sc is preceded by decreases in transepithelial conductance (G_t), which in the small intestine reflects the lateral intercellular space (LIS) volume of the paracellular pathway. We hypothesized that decreases in LIS volume limit the magnitude and duration of cAMP_i-stimulated anion secretion. Experimental manipulations to increase the patency of the LIS (assessed by G_t and electron microscopy) were investigated for an effect on the magnitude of cAMP_i-stimulated anion secretion (assessed by the I_sc and isotopic fluxes) across murine small intestine. In control studies, changes of G_t after cAMP_i stimulation were associated with a morphological "collapse" of the LIS, which did not occur in intestine of CFTR-null mice. Removal of the outer intestinal musculature, exposure to a serosal hypertonic solution, or increased serosal hydrostatic pressure minimized reductions in G_t and increased the cAMP_i-stimulated I_sc response. Increased I_sc primarily resulted from increased Cl^– secretion that was largely bumetanide sensitive. However, bumetanide-insensitive I_sc was also increased, and similar increases occurred in the Na⁺-K⁺-2Cl^– cotransporter (NKCC1)-null intestine, indicating that activities of non-NKCC1 anion uptake proteins are also affected by LIS volume. Thus LIS patency is an important determinant of the magnitude and duration of CFTR-mediated anion secretion in murine small intestine. Decreases in LIS volume may limit the pool of available anions to basolateral transporters involved in transepithelial secretion.

bicarbonate; chloride; tight junction; Na⁺-K⁺-2Cl^– cotransporter; cystic fibrosis; mouse

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