Transgenic animals may help resolve a sticky situation in cystic fibrosis

Abstract

Cystic fibrosis (CF) is caused by defects in the CFTR, a cAMP-activated Cl- channel of epithelia. The resulting reduction in epithelial fluid transport creates abnormally viscous secretions from airway mucous glands that may be a major factor in CF pathology. Mouse airways have few mucous glands, and the mouse model of CF exhibits no significant airway disease. Pigs and ferrets, however, have approximately the same number of airway mucous glands as humans. In this issue of the JCI, three independent research groups conclude that changes in airway mucous gland function in CFTR-deficient animals of these species resemble the changes seen in human CF. It is expected, therefore, that these animals will develop lung disease similar to human CF and prove to be valuable models on which to test potential therapies.

Figure 1. Means by which VIP (or other cAMP-elevating agents) stimulates Cl^– secretion by airway gland serous cells.

(A) Low levels of VIP are insufficient to stimulate Cl^– secretion but do elevate cAMP sufficiently to open CFTR. Low levels of acetylcholine (ACh) (also subthreshold for secretion) raise [Ca²⁺]_i sufficiently to open basolateral K⁺ channels (G_K). Together, the two agents induce Cl^– secretion, as previously suggested by Choi et al. (10). (B) High levels of VIP elevate cAMP sufficiently to activate both Cl^– and K⁺ channels, as previously suggested by Choi et al. (10). (C) cAMP elevates [Ca²⁺]_i, which then activates basolateral K⁺ channels, as described by Lee and Foskett (9). (D) If the effects of cAMP on [Ca²⁺]_i are somehow enhanced then VIP can induce Cl^– secretion in CF cells by activating CaCC, as suggested by Lee and Foskett (9).