FLUID TRANSPORT ACROSS CULTURES OF HUMAN TRACHEAL GLANDS IS ALTERED IN CYSTIC-FIBROSIS

1.There is evidence that defective submucosal gland secretion contribu tes to the airway pathology of cystic fibrosis (CF). Using a capacitan ce probe technique, we have compared fluid transport across submucosal gland cultures from individuals with and without CF. 2. Under baselin e conditions, similar to 6O% of non-CF cultures secreted fluid; the re st absorbed. In secreting tissues, amiloride increased secretion, wher eas in absorbing tissues it reduced or reversed absorption. 5-Nitro-2- (3-phenylpropylamino)-benzoate (NPPB) a blocker of the CF transmembran e conductance regulator (CFTR), converted secretion to absorption. Thu s, the direction and magnitude of baseline fluid movement depended on a balance between active absorption of Na+ and cAMP-dependent secretio n of Cl-. 3. 8-(4-Chlorophenylthio)-adenosine 3',5'-cyclic monophospha te (CPT-cAMP), methacholine and luminal uridine 5'-triphosphate (UTP) all induced or increased fluid secretion across non-CF cultures. Resul ts with NPPB and with 4,4'-diisothiocyanatostilbene-2,2'-disul (DIDS), a blocker of Ca2+-activated Cl- channels, suggested that fluid secret ion induced by CPT-cAMP was mediated primarily by CFTR; UTP acted enti rely via Ca2+-activated Cl- channels, and methacholine activated both pathways. 4. All CF cultures showed baseline fluid absorption, which w as abolished by amiloride. 5. CF cultures showed a normal secretory re sponse to UTP, a reduced response to methacholine, and no response to CPT-cAMP. 6. Thus, the absorptive processes of airway glands are retai ned in CF, but the cAMP-dependent secretory process is lost. This woul d markedly reduce the water content of gland secretions. The resulting change in viscosity would contribute to the accumulation of airway mu cus which is characteristic of this disease.