EFFECT OF ANION TRANSPORT INHIBITION ON MUCUS SECRETION BY AIRWAY SUBMUCOSAL GLANDS

To model the airway glandular defect in cystic fibrosis (CF), the effe ct of anion secretion blockers on submucosal gland mucus secretion was investigated. Porcine distal bronchi were isolated, pretreated with a Cl- secretion blocker (bumetanide) and/or a combination of blockers t o inhibit HCO, secretion (dimethylamiloride, acetazolamide, and 4,4'-d iisothiocyanostilbene-2,2'-disulfonic acid), and then treated with ace tylcholine (ACh), a glandular liquid and mucus secretagogue. Bronchi w ere then fixed, sectioned, and stained for mucins. Each gland duct was ranked for mucin content from zero (no mucin) to five (duct completel y occluded with mucin). Untreated bronchi, bronchi treated only with A Ch, and ACh-treated bronchi that received either bumetanide or the HCO 3- secretion blockers all exhibited low gland duct mucin content (1.18 +/- 0.34, 0.59 +/- 0.07, 0.65 +/- 0.03, and 0.83 +/- 0.11, respective ly). However, pretreatment with both Cl- and HCO3- secretion blockers before ACh addition resulted in substantial and significant ductal muc us accumulation (3.57 +/- 0.22). In situ videomicroscopy studies of in tact airways confirmed these results. Thus inhibition of the anion (an d presumably liquid) secretion response to ACh leads to mucus obstruct ion of submucosal gland ducts that resembles the early pathological ch anges observed in CF.