title: Hypertonic saline alters ion transport across the human airway epithelium.
abstract: Aerosolized hypertonic saline is currently being investigated as a new agent for the treatment of impaired mucociliary clearance which occurs in many respiratory diseases. Mannitol aerosols, in particular dry powder inhalers, have been proposed as an alternative treatment to saline, offering the same osmotic load with other benefits. However, the effects of these hypertonic aerosols on airway epithelial ion transport processes have not been tested in human subjects in vivo. This report examines the effect of these solutions on airway ion transport using the nasal potential difference (PD) technique. Seven healthy nonsmoking adult volunteers were studied. On different days, a dose-response curve was constructed for the saline added to Krebs N-[2-hydroxyethyl] piperazine-N'-[2-ethanesulphonic acid] (HEPES) diluent. The reversibility of this saline effect was measured, and the response to additional saline (500 mM) and mannitol (1 M) compared. Hypertonic saline decreased nasal PD in a dose-related manner, with mean (SEM) decreases in PD (less negative) of 6.6 (1.5), 7.6 (1.6), 10.0 (2.0), 13.1 (2.9) and 14.8 (3.2) mV (n =4) for addition of 150 mM, 250 mM, 500 mM, 1,200 mM and 2,000 mM NaCl to the Krebs HEPES diluent, respectively. The effect of hypertonic saline was fully reversible with washout for 3 min (presaline 15.9 (0.5) mV, postwashout 15.8 (1.1) mV, (n=4)). The hypertonic saline response was rapid in onset, sustained for at least 4 min, and decreased PD from 13.7 (1.7) mV to 5.1 (1.3) mV (n = 7, p < 0.001). In contrast, addition of mannitol to the perfusate did not significantly alter nasal PD, with a nonsignificant trend towards an increase (more negative) in the PD, (premannitol 13.9 (1.6) mV, postmannitol 15.3 (2.0) mV, n=7). As the osmotic stimulus of the 1 M mannitol is similar to that of the 500 mM sodium chloride, the divergent nasal potential difference responses suggest that the response to the saline was specific to the sodium chloride itself and not the simultaneous change in osmolarity. This demonstrates that the human airway epithelium in vivo can respond to topical hypertonic saline independent of the altered osmolarity.
authors.affiliation: Dept of Respiratory Medicine, Westmead Hospital, NSW, Australia.
authors.forename: P G
authors.initials: PG
authors.lastname: Middleton
authors.forename: K A
authors.initials: KA
authors.lastname: Pollard
authors.forename: J R
authors.initials: JR
authors.lastname: Wheatley
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D017136:Ion Transport / Q000187:drug effects*; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009079:Mucociliary Clearance / Q000187:drug effects; D009296:Nasal Cavity; D009994:Osmolar Concentration; D020545:Respiratory Mucosa / Q000378:metabolism*; D012462:Saline Solution, Hypertonic / Q000494:pharmacology*
chemical_list: D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D012462:Saline Solution, Hypertonic; D008353:Mannitol