The effects of hypo- and hyperosmolarity on the function of isolated human airways were studied. Changes in osmolarity induced an increasing bronchoconstriction that was proportional to the magnitude of the change in osmolarity. Hypertonicity-induced airway narrowing resulted when buffer was made hypertonic with sodium chloride or mannitol but not with urea. The airways showed no tachyphylaxis to repetitive exposure to hypo- and hypertonic buffer of 200 and 600 mosM, respectively. The bronchoconstriction was not secondary to stimulation of H1 or leukotriene C4/D4 receptors or the release of prostaglandins in the preparation. The bronchoconstriction in hypotonic buffer was totally dependent on extracellular calcium, whereas in hypertonic buffer the bronchoconstriction seemed partially dependent on intracellular calcium release. Isoprenaline prevented the bronchoconstriction in hyper- or hypotonic buffer of 450 and 250 mosM but not in buffer of 600 and 150 mosM. It is concluded that hypo- and hypertonic buffers lead to bronchoconstriction via different mechanisms, which relate to influx of extracellular calcium in hyposmolar buffer and probably to release of calcium from intracellular stores in hypertonic buffer. In strongly hypertonic buffer, part of the bronchoconstriction may be due to osmotic shrinkage. The relevance of our data for the mechanism of bronchoconstriction after inhalation of hypo- or hypertonic saline depends on whether changes in osmolarity around the airway smooth muscle occur in asthmatics but not in normal subjects, and this has not yet been established.

We studied the effect of hyperosmolarity on human isolated airways because a better understanding of the effect of hyperosmolarity on the human airway wall may improve insight into the pathophysiology of hyperosmolarity‐induced bronchoconstriction in asthma. In cartilaginous bronchial rings dissected from fresh human lung tissue, hyperosmolar Krebs‐Henseleit buffer (450 mosm, extra sodium chloride added) evoked a biphasic response: a rapid relaxation phase (peak after 5.0 ± 0.3 min) followed by a slow contraction phase (peak after 25.4 ± 0.8 min). With the histamine (H1) receptor antagonist mepyramine, the contraction phase was reduced to 41.2% of the control value (P < 0.001), with atropine to 50.0% (P < 0.01), with the local anaesthetic lignocaine to 48.7% (P < 0.05) and with mepyramine together with atropine to 19.2% (P < 0.001). With the inhibitor of neutral metalloendopeptidase, phosphoramidon, the contraction phase increased to 128.0% of the control value (P < 0.05) and after removal of the epithelium to 131.8% (P < 0.05). Indomethacin, the leukotriene C4/D4 (LTC4/D4) antagonist FPL 55712 or the blocker of nerve conduction, tetrodotoxin, had no effect on the contractile phase. The relaxation phase was not altered by any of these drugs nor by epithelial denudation. The relaxation phase was also unchanged in the presence of α‐chymotrypsin, which degrades muscle relaxing peptides such as vasoactive intestinal peptide. Hyperosmolar buffer slightly increased the sensitivity and maximal response to methacholine as well as the cholinergic twitch to electric field stimulation. We conclude that hyperosmolarity releases acetylcholine, histamine and neuropeptides in the human airway wall in sufficient quantities to contract airway smooth muscle. This release itself or its effect on airway muscle is modulated by the airway epithelium. The mechanism of the relaxation phase may be an unknown smooth muscle relaxing substance or a direct effect on the airway muscle, related to ion fluxes.

Autonomic nerves can influence airway caliber via their effects on airway smooth muscle, bronchial vessels, and mucous glands and may therefore contribute to airway narrowing in asthma or in chronic obstructive pulmonary disease (COPD). Human lungs receive cholinergic, noradrenergic, and peptidergic efferents and several types of afferents. Cholinergic nerve activity contributes to airway narrowing both in asthma and in COPD. Reflex vagal activity may be enhanced because of epithelial damage and exposition of sensory nerve endings to nonspecific irritants. Other possible mechanisms include defects in prejunctional receptors that inhibit acetylcholine release, several postjunctional factors that nonspecifically enhance the effect of a given degree of cholinergic muscle contraction on airway caliber, and interactions between inflammatory mediators and the cholinergic system. The main direct bronchodilating nerve activity in human lungs is nonadrenergic, and scanty data suggest that nonadrenergic inhibitory nerve activity may be variably reduced in asthmatics. Human airway muscle virtually lacks adrenergic innervation, but adrenergic nerves may influence airway caliber by acting on bronchial vessels, mucous glands, and parasympathetic nerves and ganglia. The response of asthmatic airways to beta-agonists seems intrinsically normal, but it may be reduced during severe asthma attacks. There are no convincing data that abnormal adrenergic control is present in the airways of patients with COPD. The physiologic relevance of excitatory neuropeptides in sensory nerves in human airways is uncertain. Tachykinins have proinflammatory and spasmogenic properties and are therefore of potential interest as a factor in the pathogenesis of obstructive airway disease. In conclusion, the data presently available support an abnormal autonomic control of the airways in asthma but not in COPD.

Several studies have suggested that in asthmatics the quantities of inflammatory mediators such as histamine, thromboxane A2 (TxA2), prostaglandin D2 (PGD2), prostaglandin F2 alpha (PGF2 alpha), and leukotriene C4 (LTC4) that are present in the airway lumen are related to the degree of bronchial responsiveness to inhaled methacholine (MCh). Therefore, we studied the effect of these mediators on the cholinergic responsiveness of isolated human airway segments. Lung tissue collected at thoracotomy from 30 patients was studied. Dose-response curves to MCh were obtained from bronchial segments before, during, and after incubation with either a subthreshold or a threshold concentration of histamine (10(-10) or 10(-8) M), the stable TxA2 analogue U46619 (10(-11) or 10(-9) M), PGD2 (5 x 10(-9) or 5 x 10(-7) M), PGF2 alpha (10(-9) or 10(-7) M), or LTC4 (10(-11) or 10(-9) M). With the exception of LTC4, the presence of any of these mediators at either concentration increased the sensitivity to MCh by a factor of 1.1 to 2 (p less than 0.05, ANOVA). This increase did not depend on the dose of the mediator (p greater than 0.05, ANOVA). These data indicate that mediator-induced muscle hypersensitivity can explain a small part of the leftward shift of the dose-response curve to inhaled MCh as observed in asthma.

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