Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect

Abstract

Due to genetic defects in apical membrane chloride channels, the cystic fibrosis (CF) intestine does not secrete chloride normally. Depressed chloride secretion leaves CF intestinal absorptive processes unopposed, which results in net fluid hyperabsorption, dehydration of intestinal contents, and a propensity to inspissated intestinal obstruction. This theory is based primarily on in vitro studies of jejunal mucosa. To determine if CF patients actually hyperabsorb fluid in vivo, we measured electrolyte and water absorption during steady-state perfusion of the jejunum. As expected, chloride secretion was abnormally low in CF, but surprisingly, there was no net hyperabsorption of sodium or water during perfusion of a balanced electrolyte solution. This suggested that fluid absorption processes are reduced in CF jejunum, and further studies revealed that this was due to a marked depression of passive chloride absorption. Although Na+-glucose cotransport was normal in the CF jejunum, absence of passive chloride absorption completely blocked glucose-stimulated net sodium absorption and reduced glucose-stimulated water absorption 66%. This chloride absorptive abnormality acts in physiological opposition to the classic chloride secretory defect in the CF intestine. By increasing the fluidity of intraluminal contents, absence of passive chloride absorption may reduce the incidence and severity of intestinal disease in patients with CF.

Figure 1

Conventional models of normal electrolyte absorption by the human jejunum and a possible explanation for chloride malabsorption in cystic fibrosis. The illustrations represent epithelial cells and the adjacent tight-junction paracellular pathways. The apical membrane is on the left and the basolateral membrane is on the right side of each cell. A Na⁺, K⁺-ATPase on the basolateral membrane pumps Na⁺ out of the cell, into the subepithelial space. For convenience, water absorption is depicted as occurring exclusively through paracellular spaces, although it may also occur through the cell. Since these are models of electrolyte absorption, the transporters and channels that mediate active chloride secretion are not depicted. Detailed explanations of the models for normal absorption and a proposed explanation for passive chloride malabsorption in cystic fibrosis are provided within the Results and Discussion sections, respectively.

Figure 2

Net absorption and secretion during perfusion of a balanced electrolyte solution. Values are mean ± SEM. Minus signs denote net absorption (disappearance from the lumen), and plus signs denote net secretion (gain to the lumen). Black bars denote normal control subjects, n = 5, and white bars denote CF patients, n = 5. There was no statistically significant difference between controls and CF patients.

Figure 3

Net chloride absorption in response to chloride-concentration gradients. Results in normal subjects are shown on the left, and results in CF patients are shown on the right. Minus signs denote net absorption (disappearance from the lumen), and plus signs denote net secretion (gain to the lumen). Linear regression for results in normal controls, r = 0.73, P < 0.001. Linear regression for results in CF patients, r = 0.16, P = 0.52. The difference in the linear regression lines was statistically significant (P < 0.001). In data not shown in the figure, PD was lower in CF patients than in normal subjects (–0.1 ± 0.04 mV versus –1.8 ± 0.2 mV, respectively; P = 0.02), in accord with reduced electrogenic chloride secretion by CF jejunum, and PD was similar at all studied levels of luminal chloride concentrations in both groups. Net sodium transport was virtually identical to net chloride transport.

Figure 4

Net absorption and PD during perfusion of a glucose-NaCl solution. Black bars denote values in normal subjects, n = 5; white bars denote values in CF patients, n = 5. Minus signs denote net absorption of solutes and water or lumen-negative PD. Units for glucose are millimoles per hour per 30 cm; units for PD are in millivolts; units for sodium and chloride are milliequivalents per hour per 30 cm; and units for water are milliliters per hour per 30 cm. P values for differences between normal and CF are as follows: glucose, P = 0.42; PD, P = 0.053; sodium, P = 0.002; chloride, P = 0.002; water, P = 0.02.

Figure 5

PD during jejunal perfusion of mannitol and sodium sulfate solutions. Minus signs denote a lumen-negative PD, plus signs denote a lumen-positive PD. Black bars denote values in normal control subjects, n = 6; white bars denote values in CF patients, n = 6. P values for differences between normal and CF are as follows: mannitol, P = 0.001; Na₂SO₄, P = 0.032.