CL- SECRETION BY TRACHEA OF CFTR(+ -) AND CFTR(-/-) FETAL MOUSE/

The absence of pathologic changes in newborn cystic fibrosis (CF) lung suggests that the fetal CF lung is inflated with a normal volume of l iquid and that Cl- is secreted through paths other than the cystic fib rosis transmembrane conductance regulator (CFTR)-associated Cl- channe l. We studied liquid content of distal lung and transepithelial electr ical potential difference (PD) of cultured cystic tracheal explants fr om 16 to 19 day gestation fetal mice of CFTR (+/-) (heterozygous) fema les that were mated with CFTR (-/-) ''knockout'' males. Distal lung wa ter content was not affected by fetal genotype. Basal PDs were not dif ferent (CFTR (+/-), 8.6 mV, and CFTR (-/-), 9.1 mV), and PDs of both g roups were inhibited by intraluminal injection of amiloride (10(-4) M) (-25%) and after addition of bumetanide (10(-4) M) to the bath (-40%) . Terbutaline (3 x 10(-5) M) induced a similar increase in PD (about 6 5%) in both groups. Intraluminal injection of ionomycin (2 x 10(-5) an d 5 x 10(-6) M) raised PD in both groups (CFTR (+/-) by 32 and 27% and CFTR (-/-) by 41 and 11%). All of the increase in PD induced by terbu taline and ionomycin was inhibited by bumetanide. The PD response to t erbutaline was not attenuated by pretreatment with ionomycin or the Ca 2+ chelator BAPTA (10(-4) M). Ionomycin or ATP, but not terbutaline, i ncreased intracellular Ca2+ concentration of isolated cultured trachea l epithelial cells. The response of CF epithelium to beta-adrenergic a gonist suggests that cyclic AMP-activated Cl- pathways other than thos e linked to CFTR regulate liquid secretion in fetal mouse airways.