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Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma.

RATIONALE: Asthma is associated with the over-production of leukotrienes (LT) including LTB4. Severe asthma patients can be highly responsive to 5-LO inhibition, which blocks production of both the cysteinyl LTs and LTB4. Production of LTB4 has traditionally been ascribed to neutrophils, mononuclear phagocytes and epithelial cells and acts as a chemoattractant for inflammatory cells associated with asthma. The source of LTB4 is unclear, especially in eosinophilic asthma. We speculated that the benefit of 5-LO inhibition could be mediated, in part, by inhibition of eosinophil-derived LTB4.

METHODS: LTB4 concentrations were assayed from the bronchoalveolar lavage fluid (BALF) of severe asthmatics characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4H by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 quantified by EIA. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR and IHC.

RESULTS: LTB4 concentrations were elevated in BALF of severe asthmatics, including those with isolated eosinophilic inflammation and these eosinophils displayed LTA4H via IHC. LTA4H expression by blood eosinophils was confirmed by flow cytometry, IHC and qPCR. Robust LTB4 production by blood eosinophils was observed in response to some, but not all stimuli.

CONCLUSIONS: We demonstrated that eosinophils express LTA4H transcripts and protein and can be stimulated to secrete LTB4. We speculate that in many asthmatic patients, eosinophil-derived LTB4 would be increased and that this may contribute to the efficacy of 5-LO inhibition.

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