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

doi:10.1016/S0014-2999(01)01184-0

European Journal of Pharmacology

Volume 425, Issue 2, 10 August 2001, Pages 141-148

https://doi.org/10.1016/S0014-2999(01)01184-0 Get rights and content

Abstract

We recently reported that wood smoke inhalation initially (within 5 min) causes airway injury and subsequently produces both airway and parenchymal injury after a delay (within 2 h). In this study, we investigated the mediator mechanisms of this delayed smoke-induced lung injury in 126 anesthetized and artificially ventilated guinea pigs who received challenges of either air or 40 tidal breaths of wood smoke. Two hours after inhalation, wood smoke produced various injurious responses, including increases in alveolar–capillary permeability, microvascular permeabilities, and histological injury scores, in airway and parenchymal tissues. Pre-treatment given before smoke challenge with CP-96,345 [a tachykinin NK₁ receptor antagonist; (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine], dimethylthiourea (a hydroxyl radical scavenger), or a combination of these two drugs largely alleviated both the airway and parenchymal responses, whereas pre-treatment with SR-48,968 [a tachykinin NK₂ receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl)benzamide] or a combination of CP-96,344 and SR-48,965 (inactive enantiomers) failed to do so. Post-treatment given at 5 min after smoke challenge with CP-96,345 or dimethylthiourea significantly alleviated the parenchymal responses, while having no effect on the airway responses. Pre-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 roles 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 activation of tachykinin NK₁ receptors, and is associated with the hydroxyl radical-induced inactivation of airway neutral endopeptidase.

Introduction

Lung injury produced by toxic smoke has been recognized as a major cause of mortality associated with fire-related death (Crapo, 1981). Clinical and laboratory observations indicate that toxic smoke causes primary injury to the airways that advances with time to include the pulmonary parenchyma Barrow et al., 1990, Moylan et al., 1972, Traber and Herndon, 1986. Several investigators Kikuchi et al., 1996, Traber et al., 1992 have suggested that, during the initial phase following smoke inhalation, the injured airway tissues may release chemical mediators, which contribute to the subsequent parenchymal injury via bronchial circulation. While the developmental processes of toxic smoke-induced lung injury are relatively clear, the underlying mediator mechanisms are still largely unknown.

In a recent study (Lin and Kou, 2000), we demonstrated in guinea pigs that, within 5 min after wood smoke inhalation, prominent initial airway injury occurs, while the manifestations of pulmonary parenchymal injury are just about to become evident. Two hours after smoke inhalation, tissue injury progresses from the airways to the pulmonary parenchyma, resulting in delayed lung injury (Lin and Kou, 2000). Either a tachykinin receptor antagonist or a hydroxyl radical (·OH) scavenger largely attenuates the initial airway injury, suggesting the important role of tachykinins and ·OH in producing this response (Lin and Kou, 2000). However, the chemical mediators responsible for the lung (both airway and parenchyma) injury occurring in the delayed phase remain to be investigated.

Tachykinins are neuropeptides released from C-fiber sensory nerve endings Barnes, 1996, Solway and Leff, 1991, whereas ·OH is an extremely reactive oxygen radical. Tachykinins and/or ·OH have been shown to evoke other airway responses to inhaled wood smoke, including sensory irritation Kou et al., 1997, Lai and Kou, 1998, bronchoconstriction (Hsu et al., 1998a), and hyperreactivity Hsu et al., 1998b, Hsu et al., 2000. They are known as proinflammatory or inflammatory mediators that may be released to directly damage lung tissues under several pathophysiological conditions Barnes, 1996, Solway and Leff, 1991, Ward et al., 1988. They may also increase the release of other chemical mediators, which are injurious to lung tissues Barnes, 1996, Solway and Leff, 1991, Ward et al., 1988. Tachykinins produce their effects mainly via activation of tachykinin NK₁ and NK₂ receptors, and are rapidly degraded by neutral endopeptidase (Solway and Leff, 1991). This enzyme can be inhibited by oxygen radicals, leading to an amplification of pulmonary effects of tachykinins (Solway and Leff, 1991). It has been suggested that different chemical mediators may participate in different stages of smoke inhalation injury (Traber and Herndon, 1986). Therefore, the chemical mediators responsible for initial smoke-induced airway injury might not be the same as those producing delayed lung injury in our experimental model. Alternatively, after they have damaged airway tissues, tachykinins and ·OH may also produce delayed lung injury.

The present study was undertaken in anaesthetized guinea pigs to determine (1) whether tachykinins and ·OH are important in producing delayed smoke-induced lung injury in our guinea-pig experimental model and, if so, (2) whether they are the chemical mediators responsible for the spread of tissue injury from the airways to pulmonary parenchyma at the delayed phase, and (3) whether this lung injury is associated with ·OH-induced reduction in airway neutral endopeptidase activity.

Section snippets

Animal preparation

Male Hartley guinea pigs (body weight, 322±3 g; n=126) were anesthetized with chloralose (100 mg kg⁻¹; i.p.; Sigma, St. Louis, MO, USA) and urethane (500 mg kg⁻¹, i.p.; Sigma). The carotid artery and jugular vein were cannulated to record arterial blood pressure to monitor the animal's condition and to administer pharmacological agents, respectively. Supplemental doses of chloralose (20 mg kg⁻¹ h⁻¹) and urethane (100 mg kg⁻¹ h⁻¹) were administered to maintain the abolition of pain reflexes

Smoke-induced lung injury in control animals

Two hours after airway exposure, as compared to air controls, inhaled wood smoke significantly produced increases in both alveolar–capillary permeability and microvascular permeabilities of the airways and pulmonary parenchyma, as evidenced by increases in the dye concentration in lavage fluid (Fig. 1) and the dye contents in tissues (Fig. 2), respectively. Histological examinations revealed that smoke exposure produced substantial submucosa edema and an increase in cellularity in the airways,

Discussion

In this study, we demonstrate that, within 2 h after smoke inhalation, delivery of 40 tidal breaths of wood smoke induces a prominent delayed lung injury in anesthetized guinea pigs. This delayed lung injury was evidenced by increases in alveolar–capillary permeability, and in microvascular permeabilities and total injury scores of both the airway and pulmonary parenchymal tissues. This delayed lung injury contrasts to our previous findings (Lin and Kou, 2000) that, within 5 min after smoke

Acknowledgements

We thank Dr. Tien Huan Hsu (National Chung Hsing University, Taiwan) for his help with histological preparations and examinations. We thank Mr. D.P. Chamberlin for editorial assistance and Mr. Hui-Chen Lee (Veterans General Hospital-Taipei, Taiwan) for statistical consultation. We are also grateful to Dr. J.A. Lowe, III (Pfizer) for providing CP-96,345 and CP-96,344 and to Dr. X. Emonds-Alt (Sanofi) for providing SR-48,968 and SR-48,965. Y.R. Kou is the recipient of the award of Medical

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

Abstract

Introduction

Section snippets

Animal preparation

Smoke-induced lung injury in control animals

Discussion

Acknowledgements

Eur. J. Pharmacol.

Life Sci.

Life Sci.

Respir. Physiol.

Eur. J. Pharmacol.

Free Radical Biol. Med.

Free Radical Biol. Med.

Lung edema formation following inhalation injury: role of the bronchial blood flow

J. Appl. Physiol.

Role of neural mechanisms in airway defense

Selective permeability changes in the lungs and airways of sheep after toxic smoke inhalation

J. Appl. Physiol.

Tachykinins activate guinea-pig alveolar macrophages: involvement of NK2 and NK1 receptors

Br. J. Pharmacol.

The role of increased airway microvascular permeability and plasma exudation in asthma

Eur. Respir. J.

Smoke-inhalation injuries

JAMA

Ligation of the bronchial artery in sheep attenuates early pulmonary changes following exposure to smoke

J. Appl. Physiol.

Inflammatory mediators involved in antigen-induced airway microvascular leakage in guinea pigs

Am. Rev. Respir. Dis.

Exposure of the hydrophobic components of porcine lung surfactant to oxidant stress alters surface tension properties

J. Clin. Invest.

Bronchial artery ligation modifies pulmonary edema after exposure to smoke with acrolein

J. Appl. Physiol.

BW-755C diminishes smoke-induced pulmonary edema

J. Appl. Physiol.

Cyclooxygenase and lipoxygenase inhibition by BW-755C reduces acrolein smoke-induced acute lung injury

J. Appl. Physiol.

Tachykinins activate guinea-pig alveolar macrophages: involvement of NK₂ and NK₁ receptors