Alleviation of wood smoke-induced lung injury by tachykinin receptor antagonist and hydroxyl radical scavenger in guinea pigs

We recently reported that wood smoke inhalation initially (within 5 min) ca uses airway injury and subsequently produces both airway and parenchymal in jury after a delay (within 2 h). In this study, we investigated the mediato r mechanisms of this delayed smoke-induced lung injury in 126 anesthetized and artificially ventilated guinea pigs who received challenges of either a ir or 40 tidal breaths of wood smoke. Two hours after inhalation. wood smok e produced various injurious responses, including increases in alveolar-cap illary permeability, microvascular permeabilities, and histological injury scores, in airway and parenchymal tissues. Pre-treatment given before smoke challenge with CP-96,345 [a tachykinin NK, receptor antagonist; (2S,3S)-ci s-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-oct an-3-amine], dimethylthiourea (a hydroxyl radical scavenger), or a combinat ion of these two drugs largely alleviated both the airway and parenchymal r esponses. whereas pre-treatment with SR-48,968 [a tachykinin NK2 receptor a ntagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichl orophenyl)-butyl)benzamide] or a combination of CP-96,344 and SR48,965 (ina ctive enantiomers) failed to do so. Post-treatment given at 5 min after smo ke challenge with CP-96,345 or dimethylthiourea significantly alleviated th e parenchymal responses, while having no effect on the airway responses. Pr e-treatment with dimethylthiourea prevented the smoke-induced reduction in airway neutral endopeptidase activity (an enzyme for tachykinin degradation ), We concluded that (1) tachykinins and hydroxyl radical play important ro les in producing smoke-induced delayed lung injury in guinea pigs, and both may be involved in the spread of injury from the airways to the pulmonary parenchyma, and (2) the contribution of tachykinins is mediated via the act ivation of tachykinin NK 1 receptors. and is associated with the hydroxyl r adical-induced inactivation of airway neutral endopeptidase. (C) 2001 Elsev ier Science B.V. All rights reserved.