The mucosa of the trachea and bronchi is very sensitive to various types of stimuli. Thus, cigarette smoke as well as mechanical or chemical irritation induce local mucosal reactions and bronchial smooth muscle spasm via sensory reflexes^1–4. However, only the chemical transmitters involved in these local or vago-vagal reflexes acting to produce bronchoconstriction are known, while the mediator of the vasodilation remains to be established². Unmyelinated sensory neurones of the C-fibre group have been associated with ‘neurogenic inflammation’, that is, increased vascular permeability and antidromic vasodilation in the skin⁵. These responses are abolished after pretreatment with capsaicin, the pungent agent of red peppers^5,6. Simultaneously, there is a loss of substance P-immunoreactive nerves⁷, which may explain the long-term effect of capsaicin, as substance P normally increases vascular permeability and blood flow⁶. Capsaicin-sensitive, substance P-immunoreactive neurones of vagal sensory origin have also recently been found in the lower respiratory tract⁸. Furthermore, preliminary observations suggest that an increase in vascular permeability occurs in the tracheal mucosa on vagal nerve stimulation^8–10. The capsaicin-sensitive afferents of vagal origin are probably also involved in local regulation of bronchial smooth muscle tone^8,11. We report here that cigarette smoke as well as light mechanical or local chemical (ether, formalin, histamine, bradykinin or capsaicin) irritation and vagal nerve stimulation induced a subepithelial oedema in the rat trachea and bronchial tree, as indicated by extravasation of Evans blue. The increase in vascular permeability induced was markedly reduced or abolished in capsaicin-pretreated animals, where substance P-containing C-fibre afferents in the respiratory tract had degenerated. Substance P had a potent direct stimulatory effect on vascular permeability in the airways. Irritation of the respiratory tract mucosa seems to activate capsaicin-sensitive neurones, which via local axon reflexes induce an interstitial oedema probably by releasing substance P. Capsaicin pretreatment induces a long-lasting desensitization of the airways to various exogenous and anaphylactic irritants. These findings may give new aspects of the pathophysiology and treatment of hyperreactive airways in man.