The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma.

Abstract

The cysteinyl leukotriene LTE4 has been shown to induce airway eosinophilia in asthmatics in vivo. This phenomenon has not yet been reported for LTD4. Hence, we examined the effect of inhaled LTD4 and a control bronchoconstrictor agent, methacholine, on cell differentials in hypertonic saline-induced whole sputum samples of 12 nonsmoking atopic asthmatic subjects (three women, nine men; 21 to 29 yr of age; FEV1, 74 to 120% pred; PC20FEV1 methacholine < 9.6 mg/ml). The study had a cross-over, placebo-controlled design consisting of 4 d separated by > or = 1 wk. On each randomized study day, the subjects inhaled five serial doses of either LTD4 (mean cumulative concentration: 95.7 microM) or methacholine (mean cumulative concentration: 542 mM) or five doses of their respective diluents (PBS/ethanol or PBS). The airway response was measured by FEV1, followed by sputum induction with 4.5% NaCl, 4 h postchallenge. Inflammatory cells (> or = 250) were counted twice on coded cytospins and expressed as percentages of nonsquamous cells. There was no significant difference in the maximal percent fall in FEV1 from baseline between LTD4 (mean +/- SEM, 49.5 +/- 4.4% fall) and methacholine (mean +/- SEM, 55.9 +/- 3.4% fall) (p = 0.11). LTD4 induced a significant increase in the percentage of sputum eosinophils as compared with its diluent (mean +/- SD, 26.6 +/- 21.3% and 10.2 +/- 8.8%, respectively; p = 0.025), whereas a similar trend for methacholine failed to reach significance (mean +/- SD, 19.1 +/- 22.9% and 7.8 +/- 5.8%, respectively; p = 0.11). There was no significant difference in the changes in the percentage of sputum eosinophils between LTD4 and methacholine (mean difference +/- SD, 7.5 +/- 12.5% eosinophils; p = 0.09). We conclude that LTD4 induces eosinophilia in sputum of asthmatic subjects 4 h after inhalation. Our data suggest that LTD4 recruits eosinophils into the airways of asthmatics in vivo, possibly by virtue of direct or indirect chemotactic properties, whereas an additional effect of vigourous airway narrowing per se cannot be excluded.

Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin

“…In practice, inhaled LTD 4 or LTE 4 has been shown to induce airway eosinophilia in asthmatic subjects (6,25). However, there is no report about the effect of CysLTs on eosinophilic airway inflammation in nonallergic subjects.…”

“…Substantial evidence suggests that CysLTs play an important role in eosinophilic airway inflammation. Intratracheal administration of LTD 4 promotes eosinophil sequestration into the airways (5,6). CysLTR antagonists reduce eosinophilic inflammation of the airways in asthma (7,8).…”

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

“…Moreover, treatment with zileuton or zafirleukast inhibited the influx of eosinophil in the airways induced in asthmatics by segmental bronchial challenge with antigen [240, 240a]. In view of the ability of inhaled LTE 4 [147] and LTD 4 [148] to recruit eosinophils into the airway mucosa and sputum, respectively, it appears likely that the cysteinyl-leukotrienes, rather than LTB 4 , are promoting eosinophil migration and activation in the lung. From a review of the larger published trials with antileukotrienes in mild-to-moderate asthma, it appears as if the response to treatment with antileukotrienes during 4-13 weeks is fairly similar to the effect of introducing low doses of inhaled glucocorticosteroids during similar or longer time periods in comparable groups of patients [241][242][243][244].…”

The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model

“…CysLTs are released by most cells involved in the airways inflammation and particularly by eosinophils (Shaw et al, 1984). Inhalation of LTE4 (Laitinen et al, 1993) or LTD4 (Diamant et al, 1997) induces the recruitment of eosinophils in the airways, possibly in part by inducing P-selectin expression on endothelial cells (Datta et al, 1995). CysLT1 receptors are expressed in human eosinophils (Figueroa et al, 2001), and their activation by CysLTs may lead to eosinophil recruitment to inflammatory sites.…”