Acute and Long-term Amiloride Inhalation in Cystic Fibrosis Lung Disease: A Rational Approach to Cystic Fibrosis Therapy

119

On the mucus-depleted bovine trachea, the ciliary transport rate of sputum from patients with cystic fibrosis and bronchiectasis of other causes was slow, but the rate was doubled by increasing the sodium chloride content by 90 mM. Increasing the sputum osmolality by inspissation or by the addition of nonelectrolytes had a similar effect. The viscoelasticity of sputum, but not the bovine ciliary beat frequency, was markedly saline dependent over the pathophysiological range. This suggests that low mucus salinity, not (as is generally assumed) its underhydration, contributes to its retention in bronchiectasis due to cystic fibrosis and other causes, probably by affecting its rheology. It also indicates how the genetic defect in cystic fibrosis might lead to impaired mucus clearance. Therapies that increase the osmolality of lung mucus might benefit patients with mucus retention. ( J. Clin. Invest. 1997. 99:9-13.)

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Sodium chloride increases the ciliary transportability of cystic fibrosis and bronchiectasis sputum on the mucus-depleted bovine trachea.

Wills

Hall²,

Chan³

et al. 1997

119

“…We also determined how fluid transport was altered by two agents previously shown to alter electrolyte transport by airway epithelia studied under voltage-clamped conditions. We examined the effect of amiloride, a diuretic that blocks Na+ channels (8); amiloride is currently being investigated for inhalation by patients with CF in an attempt to inhibit Na+ absorption (16,17). We also examined the effect of cAMP agonists (forskolin and 3-isobutyl l-methylxanthine [IBM X]); cAMP agonists are ofparticular interest because they activate phosphorylation-regulated CFTR Cl-channels in the apical membrane and, in the presence of amiloride, they stimulate Cl-and fluid secretion ( 1 5 ).…”

Section: Introductionmentioning

confidence: 99%

Defective fluid transport by cystic fibrosis airway epithelia.

Smith¹,

Karp²,

Welsh³

1994

Cystic fibrosis (CF) airway epithelia exhibit defective transepithelial electrolyte transport: cAMP-stimulated Cl-secretion is abolished because of the loss of apical membrane cystic fibrosis transmembrane conductance regulator (CFTR) Clchannels, and amiloride-sensitive Na+ absorption is increased two-to threefold because of increased amiloride-sensitive apical Na+ permeability. These abnormalities are thought to alter respiratory tract fluid, thereby contributing to airway disease, the major source of mortality in this genetic disease. However, the underlying hypothesis, that fluid transport is abnormal in CF airway epithelia, has not been tested. Most conjecture about fluid transport is based on measurements of Na + and Cltransport performed under short circuit conditions in Ussing chambers. But such studies differ from in vivo conditions in that transepithelial voltage and mucosal fluid composition are held constant. Therefore, we measured fluid transport and mucosal electrolyte composition in primary cultures of CF airway epithelia without holding transepithelial voltage and ion concentration gradients at zero. In normal epithelia, cAMP agonists plus amiloride stimulated NaCl and fluid secretion. In CF epithelia, cAMP agonists failed to stimulate fluid or electrolyte secretion, changes consistent with the loss of CFIR Cl -channels. But in striking contrast to predictions based on Ussing chamber studies, CF epithelia absorbed fluid at a rate no greater than normal epithelia. Moreover, amiloride, which inhibits Na' channels, failed to inhibit fluid absorption by CF epithelia. These results have important implications for understanding the pathogenesis of CF airway disease and for the design and evaluation of therapy. (J. Clin. Invest. 1994.

“…We also investigated the effects of amiloride, because amiloride-sensitive Na' channels at the apical surface mediate Na' absorption (measured as short-circuit current, I,,). In addition, amiloride-sensitive Na' absorption is increased in CF airways ( 12), and has been the target of pharmacological intervention for the treatment ofCF ( 13,14).…”

Section: Introductionmentioning

confidence: 99%

Fluid and electrolyte transport by cultured human airway epithelia.

Smith

Welsh²

1993

An understanding of the fluid and electrolyte transport properties of any epithelium requires knowledge of the direction, rate, and regulation of fluid transport and the composition of the fluid. Although human airway epithelia likely play a key role in controlling the quantity and composition of the respiratory tract fluid, evidence for such a role is not available. To obtain such knowledge, we measured fluid and electrolyte transport by cultured human nasal epithelia. Under basal conditions we found that epithelia absorbed Na+ and fluid; both processes were inhibited by addition of amiloride to the mucosal surface. These data suggest that active Na+ absorption is responsible for fluid absorption. Interestingly, Na+ absorption was not accompanied by the net absorption of Cl ; some other anion accompanied Na+. The combination of cAMP agonists and mucosal amiloride stimulated the secretion of NaCl-rich fluid. But surprisingly, the response to cAMP agonists in the absence of amiloride showed substantial intersubject variability: cAMP stimulated fluid secretion across some epithelia, for others, cAMP stimulated fluid absorption. The explanation for the differences in response is uncertain, but we speculate that the magnitude of apical membrane Na+ conductance may modulate the direction of fluid transport in response to cAMP. We also found that airway epithelia secrete H+ and absorb K+ under basal conditions; both processes were inhibited by cAMP agonists. Because the H+/K+-ATPase inhibitor, SCH 28080, inhibited K+ absorption, an apical membrane H+/K+-ATPase may be at least partly responsible for K+ and H+ transport. However, H+/K+ exchange could not entirely account for the luminal acidification. The finding that cAMP agonists inhibited luminal acidification may be explained by the recent finding that cAMP increases apical HCO3 conductance. These results provide new insights into how the intact airway epithelium may modify the composition of the respiratory tract fluid. (J.