Interaction between ion transporters and the mucociliary transport system in dog and baboon

Abstract

To gain insight into the role of epithelial ion channels, pumps, and cotransporters in regulating airway water and mucociliary transport, we administered inhibitors of the Na+ channel (amiloride), 3Na-2K-adenosinetriphosphatase (acetylstrophanthidin), and Na-K-2Cl cotransporter (furosemide) to anesthetized dogs and/or baboons. Tracheal ciliary beat frequency was measured by using heterodyne laser light scattering. Tracheal mucus velocity (TMV) and bronchial mucociliary clearance (BMC) or lung mucociliary clearance were measured by using radioaerosols and nuclear imaging. Respiratory tract fluid output was collected by using a secretion-collecting endotracheal tube. In six dogs, amiloride aerosol -lung deposition, 96 +/- 11 microg (means +/- SE)- had minimal effect, whereas acetylstrophanthidin aerosol (lung deposition, 71 +/- 9 microg) increased BMC, and furosemide (40 mg iv) markedly increased TMV. In five baboons, TMV increased after iv furosemide administration (2 mg/kg) as well as by aerosol (lung deposition, 20 +/- 3 mg), coincident with increases in ciliary-mucus coupling from 11.5 +/- 0. 1 to 29.5 +/- 0.4 and 46.5 +/- 0.7 microm/beat, respectively. Furosemide also increased lung mucociliary clearance in baboons. In dogs, respiratory tract fluid output increased after intravenous furosemide from 2.2 +/- 0.5 to 6.8 +/- 1.7 mg/min. When combined with dry-air inhalation, furosemide failed to stimulate TMV and reversed the inhibition of BMC by dry air. Thus pharmacological manipulation of the Na-K-2Cl cotransporter and the 3Na-2K-adenosinetriphosphatase pump may provide increases of clinical relevance in airway hydration and mucociliary transport.

Role of proneuregulin 1 cleavage and human epidermal growth factor receptor activation in hypertonic aquaporin induction

“…In the lung, the osmolality of the aqueous surface layer covering the airway epithelium may range from being hypotonic to Ն400 milliosmolal (mOsm) (9,10). Changes in the physical properties of the surface layer, including its osmolality, can alter the effectiveness of mucociliary clearance (11), provoke airway constriction (12,13), or reduce the bactericidal activity of defensins, antibacterial peptides that are secreted into the airways (14). These events are relevant to disease development in the lung (e.g., in the pathogenesis of infections and in some forms of asthma).…”

Effects of acute hypovolaemia by furosemide on tracheal transepithelial potential difference and mucus in dogs

“…If Cl -flux is associated with water flux from mucosa into the lumen, then inhibition of NaK(Cl) 2 co-transporter may reduce mucus water content and ultimately MCT. Consistent with this hypothesis, KONDO et al [10] showed a decrease in in vitro MCT in mechanically ventilated patients that received furosemide for up to 4 h. On the contrary, WINTERS and YEATES [13] observed that furosemide (40 mg) increased in vivo MCT in dogs and baboons. These authors raised some potential mechanisms triggered by the diuretic that may have stimulated MCT, such as release of vasopressin and/or angiotensin, the inhibition of sensory nerves that regulate secretion, and the induction of microvascular leakage.…”

“…The direction of net water flux across the tracheobronchial epithelium has been suggested to result from transepithelial ion transport with secondary osmotic water movement [7,13]. PD variation might represent a mechanism for controlling water content within the airway via ion fluxes, which could be associated with modulation of mucus rheology and clearability [1].…”

“…KONDO et al [10] observed a significant decrease in in vitro MCT after furosemide had been administered to patients undergoing mechanical ventilation (MV). On the contrary, WINTERS and YEATES [13] showed an improvement in in vivo MCT in dogs and baboons after furosemide had been administered. Based on controversial results, the present study was designed to investigate the effects of acute dehydration promoted by furosemide on tracheal PD, mucus rheology and in in vitro MCT on the frog palate in anaesthetised dogs under MV.…”

“…In the respiratory epithelium, furosemide inhibits the basolateral-to-luminal water flux coupled with chloride ion (Cl -) transport at the basolateral membrane [12][13][14]. Therefore, furosemide may affect the mucus water content and MCT by a direct effect on the respiratory epithelium and, indirectly, by systemic dehydration.…”