Elevated Levels of Leukotriene C4in Bronchoalveolar Lavage Fluid from Atopic Asthmatics after Endobronchial Allergen Challenge

Abstract

Sulfidopeptide leukotrienes have been implicated in the pathogenesis of asthma because of their ability to induce bronchospasm, airways hyperreactivity, and increased mucus production. In the present study, the leukotrienes (LT) C₄, D₄, and E₄ were measured in bronchoalveolar lavage fluid (BALF) before and 5 min after endobronchial allergen challenge in four subject groups: nonatopic nonasthmatic, nonatopic asthmatic, atopic nonasthmatic, and atopic asthmatic. As determined by high performance liquid chromatography (HPLC), after allergen challenge, the predominant sulfidopeptide leukotriene found in BALF from atopic asthmatics was LTC₄. Smaller amounts of LTD₄ and LTE₄ were detectable. The baseline level of leukotrienes in the atopic asthmatics was 64 ± 18 pg/ml, with measurable levels being found in nine of 11 samples. Atopic nonasthmatics had measurable levels in only one of seven baseline samples, whereas five of six nonatopic subjects had undetectable levels. Allergen challenge in atopic asthmatics resulted in significant increases in LTC₄ over prechallenge levels (64 ± 18 to 616 ± 193 pg/ml) (p < 0.01) and over levels in the three control goups after challenge (p = 0.0297). The atopic nonasthmatic group also had detectable leukotriene levels after allergen challenge (88 ± 32 pg/ml), whereas leukotrienes remained undetectable in five of the six nonatopic samples. For comparison, histamine and the prostanoids prostaglandin D₂ (PGD₂) and thromboxane B₂ (TxB₂) were also measured in BALF. The levels of all three of these mediators inceased in BALF from atopic asthmatics after allergen challenge. After allergen challenge, the best correlation was found between the levels in BALF for the prostanoids PGD₂ and TxB₂ (r = 0.88). Lesser, but significant, correlations existed between LTC₄ and histamine (r = 0.66) as well as the prostanoids PGD₂ (r = 0.53) and TxB₂ (r = 0.48). Elevated levels of LTC₄, both before and after allergen challenge, were associated with the presence of the atopic asthmatic state. After allergen challenge, LTC₄ levels correlated weakly but significantly with both the ratio of FEV₁ to FVC and methacholine reactivity. These findings confirm that the 5-lipoxygenase pathway for arachidonic acid metabolism is activated after allergen challenge in atopic asthmatics, with some evidence to suggest that it is activated before challenge as well. The subsequent generation of sulfidopeptide leukotrienes in this group may be important in the production of clinical asthma.