Effect of inflammatory mediators on airway nerves and muscle.
The neuromuscular mechanisms underlying airway hyperresponsiveness have been reviewed on the basis of studies of the changes induced by ozone inhalation in dogs. In vivo, there is increased, nonspecific airway hyperresponsiveness based on studies of the response to inhaled acetylcholine or histamine. The underlying inflammatory mechanism involves release of LTB4 and/or other chemotactic agents from epithelial or lumenal cells, ingress of macrophages, neutrophils, and platelets from the blood vessels between the muscle and epithelium, and migration of mast cells into the epithelium. The hyperresponsiveness seems to depend upon the influx of neutrophils and actions of thromboxane A2 released from the neutrophils. In vitro, there is increased responsiveness to field stimulation of cholinergic nerves and to acetylcholine (not to KCI) in tracheal strips. These effects can be mimicked by a thromboxane A2 analog (U44619). In the sucrose gap, the TxA2 analog does not affect the excitatory junction potential, but in low concentration it increases and prolongs a series of fading membrane oscillations closely related to the contractions. We consider these oscillations to reflect ongoing release and/or action of acetylcholine. In high concentrations the analog causes a small depolarization and a tonic contraction, but it does not enhance the sensitivity to acetylcholine. TxA2 may be acting either presynaptically or postsynaptically or both to produce these effects; however, changes in release of an epithelial-derived relaxing factor do not seem to be involved. We conclude that TxA2 actions probably underlie hyperresponsiveness developed in vivo and in vitro after ozone inhalation.
Daniel
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Department of Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
O'Byrne
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D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D015289:Leukotrienes / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000294:innervation / Q000503:physiopathology*; D010126:Ozone; D010972:Platelet Activating Factor / Q000502:physiology; D011453:Prostaglandins / Q000502:physiology; D012137:Respiratory System / Q000294:innervation / Q000503:physiopathology*; D013931:Thromboxanes / Q000502:physiology; D014132:Trachea / Q000503:physiopathology
D015289:Leukotrienes; D010972:Platelet Activating Factor; D011453:Prostaglandins; D013931:Thromboxanes; D010126:Ozone; D000109:Acetylcholine