Sulfidopeptide leukotrienes mediate acrolein-induced bronchial hyperresponsiveness

Abstract

The sulfidopeptide leukotrienes are bronchoconstrictive lipid mediators thought to have an important role in the pathophysiology of asthma. The objective of this study was to determine if treatment with a leukotriene receptor antagonist and 5-lipoxygenase inhibitors could diminish acrolein-induced bronchial hyperresponsiveness and to determine whether leukotriene (LT) C4 generation is augmented by acrolein exposure. Guinea pigs (groups of 6-7) were exposed to 1.3 ppm acrolein for 2 h and bronchial responsiveness to intravenous acetylcholine determined twice before, and once 1, 2, 6, and 24 h after exposure. Immediately after acrolein exposure (5 min) specific total airway resistance (sRt) increased from 0.86 +/- 0.01 to 1.29 +/- 0.07 ml.cmH2O.ml-1.s. Within 1 h after exposure, the effective dose of acetylcholine sufficient to double sRt (ED200) decreased from 114.0 +/- 6.6 to 58.5 +/- 6.5 micrograms.kg-1.min-1. Bronchial hyperresponsiveness became maximal at 2 h with ED200 = 44.7 +/- 4.2 and persisted for up to 24 h after exposure (24 h ED200 = 60.2 +/- 11.6 micrograms.kg-1.min). A LTC4/LTD4 receptor antagonist, L-649,923 (10 mg/kg iv), and two putative inhibitors of 5-lipoxygenase, L-651,392 (10 mg/kg po) and U-60,257 (5 mg/kg i.v.), diminished the immediate bronchoconstriction and markedly inhibited bronchial hyperresponsiveness. Analysis of bronchoalveolar lavage fluid obtained from guinea pigs after acrolein exposure revealed a significant increase in immunoreactive LTC4 concentrations (control LTC4 = 8.8 +/- 0.3, n = 7; exposed LTC4 = 15.9 +/- 2.4 pg/ml, n = 6). Treatment with L-651,392 inhibited this response (acrolein exposed = 9.4 +/- 2.4 pg/ml, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Acrolein – a pulmonary hazard

“…Acrolein (2.0 mg/m 3 ×2 h) also increased bronchial hyperreactivity that was evident within 1 h, maximal at 2–4 h, and persisted up to 24 h after exposure 98. This exposure was accompanied by increases in bronchoconstrictive lipid mediators (thromboxane B2, prostaglandin F2 α, and leukotrienes) immediately after exposure, and delayed influx of neutrophils (24 h) 98, 99. These temporal relationships suggest that neutrophil infiltration may be a sufficient but not a necessary condition for the onset of bronchial hyperreactivity and that injury to cells normally present in the lung, e.g.…”

Acrolein induction of oxidative stress and degranulation in mast cells

“…Airborne aldehydes have been implicated as contributing factors to the increase in asthma and allergic disease in world urban populations (Leikauf,; McGwin et al,; Arif and Delclos,). In animal models, acrolein induces airway hyper‐responsiveness (Myou et al,), production of leukotrienes (Leikauf et al,), increased mucous production (Borchers et al,), and airway hypersensitivity (Roux et al,), all hallmarks of asthma. Thus, as one of the more common components of anthropogenic pollution, acrolein poses a potential health risk for the development of asthma in exposed populations.…”

Effect of cigarette smoke extract on arteriolar dilatation in vivo

“…Cigarette smoke extract contains many toxic substances, in addition to nicotine, that may contribute to impaired vascular reactivity. Acrolein and acetaldehyde are highly soluble components of cigarette smoke extract and have been shown to cause irritation of airway and ocular mucosa in humans, impair mucociliary clearance in the upper airway, produce pulmonary edema in animals, and damage epithelial cells (13,14,30,45). In addition, Holden et al (20) have shown that cigarette smoke extract increases albumin flux across cultured porcine pulmonary endothelium, and this effect was predominantly due to the vapor phase of cigarette smoke.…”