SENSORY NEUROPEPTIDES AND THE HUMAN LOWER AIRWAYS - PRESENT STATE ANDFUTURE-DIRECTIONS

The sensory neuropeptides, substance P and neurokinin A, are present i n human airway nerves, beneath and within the epithelium, around blood vessels and submucosal glands, and within the bronchial smooth muscle layer. Studies on autopsy tissue, bronchoalveolar lavage and sputum s uggest that in asthma the substance P content of the airways may be in creased. Neurokinin A is a more potent bronchoconstrictor than substan ce P. Asthmatics are hyperresponsive to neurokinin A and substance P. The neuropeptide degrading enzyme, neutral endopeptidase is present in the airways and is involved in the degradation of endogenously releas ed and exogenously administered substance P and neurokinin A, both in normal and asthmatic subjects. As for other indirect bronchoconstricto r stimuli, the effect of neurokinin A on airway calibre in asthmatics can be inhibited by pretreatment with nedocromil sodium. Evidence is a ccumulating, not only from studies in animals but also from experiment s on human airways, that tachykinins may also cause mucus secretion an d plasma extravasation. They also have important proinflammatory effec ts, such as the chemoattraction of eosinophils and neutrophils, the ad hesion of neutrophils, and the stimulation of lymphocytes, macrophages and mast cells. The tachykinins interact with the targets on the airw ays by specific tachykinin receptors. The NK1 and the NK2 receptor hav e been characterized in human airways, both pharmacologically and by c loning. The NK2 receptor is responsible for the in vitro contraction o f normal airways, whilst the NK1 receptor is responsible for most of t he other airway effects. Because of their presence in the airways and because of their ability to mimic the various pathophysiological featu res of asthma, substance P and neurokinin A are presently considered a s possible mediators of asthma. The present development of potent and selective tachykinin antagonists will allow us to further define the r ole of tachykinins in the pathogenesis of asthma.