Effect of hyperosmolarity on human isolated central airways

Anderson²,

Brannan³

et al. 1997

Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC.We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler™. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99m Tc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267±171 mg (mean±SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22±3 and 4±2% in the asthmatic and healthy subjects, respectively.The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 26.3±11.9% in the asthmatic and 18.1±4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7±9.6% and 33.6±9.4% on the mannitol and control day (p<0.002), respectively, in the asthmatic subjects and 40.5±7.1% and 24.8±7.8% (p<0.002) in the healthy subjects.In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance. Eur Respir J 1997; 10: 2449-2454. The study was supported by a grant from the National Health and Medical Research Council of Australia. A patent has been registered internationally for the use application described in this study PCT/AU 95/ 00086.Mucociliary clearance (MCC) is a physiological function of the respiratory tract to clear locally produced debris, excessive secretions or unwanted inhaled particles. For normal MCC to occur it is necessary that the epithelial cells are intact, the ciliary activity and the rheology of mucus is normal and that the depth and chemical composition of the periciliary fluid layer is optimal. An increase in the osmolarity of the airway surface fluid by inhalation of hypertonic saline aerosol has been shown to increase MCC in asthmatic and healthy subjects [1] and in patients with bronchitis [2] and cystic fibrosis [3]. It is possible that inhalation of other osmotic agents will have the same effect on MCC.We have recently developed a preparation of the osmotic agent mannitol suitable for inhalation as a dry powder [4]. Mannitol is a naturally occurring sugar alcohol (C 6 H 14 O 6 , molecular weight 182) which is not absorbed by the gastro-intestinal tract, does not cross the bloodbrain barrier and is not metabolized to any substantial extent when injected. Mannitol is stable as a powder and resists moisture resorption at relatively high humidities. These characteristics make it an ideal substance to encapsulate for inhalation, for diagnostic and therapeutic purposes [4].Like hypertonic saline, mannitol exerts osmotic effects in the lower airways and as a dry powder is easy to deliver. We therefore decided to investigate its potential to stimulate MCC. For this initial st...

Section: Discussionmentioning

confidence: 99%

Inhalation of dry-powder mannitol increases mucociliary clearance

Anderson²,

Brannan³

et al. 1997

“…substance P) from sensory nerves [18]. Animal studies, in vitro and in vivo, have shown that chemical mediators and neuropeptides can stimulate ciliary activity [19][20][21] by a mechanism which is not clearly understood but may involve neural stimulation of ciliary beat frequency via the cyclooxygenase pathway [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

“…The increase in MCC is most likely to be due to mediators released in response to hyperosmolarity of the airway surface liquid, because exposure of the human airways to a hyperosmolar stimulus causes release of histamine, prostaglandin E 2 (PGE 2 ) and leukotriene C 4 from the mast cells [15][16][17][18], and possibly neuropeptides (e.g. substance P) from sensory nerves [18].…”

Section: Discussionmentioning

confidence: 99%

Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects

Anderson²,

Gonda³

et al. 1996

161

140

Hyperosmolarity of the airway surface liquid (ASL) has been proposed as the stimulus for hyperpnoea-induced asthma. We found previously that mucociliary clearance (MCC) was increased after isocapnic hyperventilation (ISH) with dry air, and we proposed that the increase related to transient hyperosmolarity of the ASL. We investigated the effect of increasing the osmolarity of the ASL on MCC, by administering an aerosol of concentrated salt solution.MCC was measured using 99m Tc-sulphur colloid, gamma camera and computer analysis in 12 asthmatic and 10 healthy subjects on three separate days, involving administration of each of the following: 1) ultrasonically nebulized 14.4% saline; 2) ultrasonically nebulized 0.9% saline; and 3) no aerosol intervention (control).The (mean±SD) volume of nebulized 14.4% saline was 2.2±1.2 mL for asthmatics and 3.2±0.7 mL for healthy subjects. This volume was delivered over a period of 5.4±1.3 and 6.4±0.7 min for asthmatic and healthy subjects, respectively. The airway response to 14.4% saline was assessed on a separate visit and the fall in forced expiratory volume in one second (FEV1) was 22±4% in the asthmatic and 3±2% in the healthy subjects. Compared to the MCC with the 0.9% saline and control, the hypertonic aerosol increased MCC in both groups. In asthmatic subjects, MCC of the whole right lung in 1 h was 68±10% with 14.4% saline vs 44±14% with 0.9% saline and 39±13% with control. In healthy subjects, MCC of the whole right lung in 1 h was 53±12% with 14.4% saline vs 41±15% with 0.9% saline and 36±13% with control.We conclude that an increase in osmolarity of the airway surface liquid increases mucociliary clearance both in asthmatic and healthy subjects. These findings are in keeping with our previous suggestion that the increase in mucociliary clearance after isotonic hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid. Eur Respir J., 1996, 9, 725- We have previously found that mucociliary clearance (MCC) increases immediately after hyperventilation with dry air both in asthmatic and healthy subjects [1] at the time that asthmatic subjects develop airway narrowing. Although the mechanism for this increase is unknown, we postulated that the increase in MCC after hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid [1]. It is possible that the increase in MCC and the bronchoconstriction that follows hyperventilation with dry air share a common mechanism.Inhalation of hypertonic saline aerosol (7%) has been shown to increase mucociliary clearance in patients with bronchitis [2] and cystic fibrosis [3] who have impaired baseline mucociliary clearance. Although, these studies suggest that hypertonic saline stimulates the mucociliary system, there are no reported studies of the effect of hypertonic saline on the MCC in asthmatic and healthy subjects with normal baseline mucociliary clearance.The aim of the present study was to investigate the effect of a hyperosmolar stimulus on MC...

“…histamine), and sensory nerves (e.g. substance P) [32], as these mediators are known to stimulate ciliary activity and mucus transport mechanisms [33][34][35]. It is possible that inhibition or blocking of mediator release from mast cells [11], and neuropeptides from sensory nerves [36], by frusemide could cause a transient delay in the increase in MCC after ISH with dry air in asthmatic subjects.…”

Section: Discussionmentioning

confidence: 99%

Mucociliary clearance during and after isocapnic hyperventilation with dry air in the presence of frusemide

Anderson²,

Gonda³

et al. 1996

M Mu uc co oc ci il li ia ar ry y c cl le ea ar ra an nc ce e d du ur ri in ng g a an nd d a af ft te er r i is so oc ca ap pn ni ic c h hy yp pe er rv ve en nt ti il la at ti io on n w wi it th h d dr ry y a ai ir r i in n t th he e p pr re es se en nc ce e o of f f fr ru us se em mi id de e E. Daviskas*, S.D. Anderson*, I. Gonda + , D. Bailey**, G. Bautovich**, J.P. Seale ++ Mucociliary clearance during and after isocapnic hyperventilation with dry air in the presence of frusemide. E. Daviskas, S.D. Anderson, I. Gonda, D. Bailey, G. Bautovich, J.P. Seale. ©ERS Journals Ltd 1996. ABSTRACT: We have previously shown that mucociliary clearance (MCC) decreased during and increased after isocapnic hyperventilation (ISH) with dry air, both in asthmatic and healthy subjects. Inhaled frusemide, an inhibitor of the Na + /K + /2Cl -and NaCl co-transporters on the basolateral membrane of the epithelial cell, prevents the airway narrowing provoked by ISH with dry air. The co-transport system controls epithelial cell volume and chloride secretion and, thus, frusemide has the potential to modify the rate of recovery of periciliary fluid volume during and after ISH with dry air, and hence affect MCC. Frusemide also blocks mediator release from mast cells, which may also modify the increase in MCC after ISH.Eleven asthmatic and 11 healthy subjects inhaled frusemide (35.7±0.44 mg) or its vehicle, from a Fisoneb ™ ultrasonic nebulizer 30 min before ISH with dry air, on two separate occasions. MCC was measured using 99m Tc-sulphur colloid and a gamma camera. Frusemide, compared to its vehicle, did not affect MCC during or 45 min after ISH. However, in the presence of frusemide, the onset of the increase of MCC after ISH was significantly delayed for approximately 10 min in the whole right lung (p<0.002) and central region (p<0.01) in the asthmatic but not in the healthy subjects.These findings could be explained by frusemide delaying the recovery of the periciliary fluid volume after ISH with dry air and/or interfering with the stimulus that causes the increase in MCC in the asthmatic subjects after ISH. Eur Respir J., 1996, 9, 716- Isocapnic hyperventilation (ISH) with dry air results in significant water loss from the airways whilst bringing the inspired air to alveolar conditions. The water loss from the airways is the stimulus whereby hyperpnoea provokes airway narrowing [1,2]. Mucociliary clearance (MCC) decreases during and increases after ISH with dry air, compared to ISH with warm humid air and nasal breathing at rest [3]. The effect of ISH with dry air on MCC is most likely to be due to a reduction of the depth of the periciliary fluid layer, with the subsequent hyperosmolarity leading to release of mediators [4]. Frusemide, a loop diuretic known to inhibit the Na + /K + /2Cl -and NaCl co-transport systems at the basolateral membrane [5], inhibits the airway narrowing induced by exercise [6], ISH [7,8], and hypertonic saline [9]. Inhibition of the co-transport systems affects the regulatory volume increase (RVI) of the ...