1 Division of Pulmonary and Critical Care Medicine.
2 Department of Otorhinolaryngology, QiLu Hospital of Shandong University, Jinan, Shandong, China.
Am J Respir Cell Mol Biol. 2019 Apr;60(4):413-419. doi: 10.1165/rcmb.2018-0175OC.
Asthma is associated with the overproduction of leukotrienes (LTs), including LTB4. Patients with severe asthma can be highly responsive to 5-lipoxygenase (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. LTB4 concentrations were assayed in BAL fluid from patients with severe asthma characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4 hydrolase (LTA4H) by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 was quantified by enzyme immunoassay. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR, and IHC. LTB4 concentrations were elevated in BAL fluid from patients with severe asthma, 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. We demonstrated that eosinophils express LTA4H transcripts and protein, and can be stimulated to secrete LTB4. We speculate that in many patients with asthma, eosinophil-derived LTB4 is increased, and this may contribute to the efficacy of 5-LO inhibition.
哮喘与白三烯（LTs）的过度产生有关，包括 LTB4。严重哮喘患者对 5-脂氧合酶（5-LO）抑制高度敏感，该抑制作用阻断半胱氨酰 LT 和 LTB4 的产生。LTB4 的产生传统上归因于中性粒细胞、单核吞噬细胞和上皮细胞，并作为与哮喘相关的炎症细胞的趋化因子。LTB4 的来源尚不清楚，尤其是在嗜酸性粒细胞性哮喘中。我们推测，5-LO 抑制的益处可能部分通过抑制嗜酸性粒细胞衍生的 LTB4 来介导。在以孤立性中性粒细胞性、嗜酸性粒细胞性和少粒细胞性炎症为特征的严重哮喘患者的 BAL 液中检测 LTB4 浓度。通过免疫组织化学（IHC）确定气道嗜酸性粒细胞中的 LTA4 水解酶（LTA4H）的表达。随后，激活外周血嗜酸性粒细胞并通过酶免疫测定定量测定分泌的 LTB4。通过流式细胞术、qPCR 和 IHC 测定血嗜酸性粒细胞 LTA4H 表达。严重哮喘患者的 BAL 液中 LTB4 浓度升高，包括那些孤立性嗜酸性粒细胞性炎症患者，并且这些嗜酸性粒细胞通过 IHC 显示 LTA4H。通过流式细胞术、IHC 和 qPCR 证实血嗜酸性粒细胞中存在 LTA4H 表达。血液嗜酸性粒细胞对某些但不是所有刺激物均观察到强烈的 LTB4 产生。我们证明嗜酸性粒细胞表达 LTA4H 转录本和蛋白，并可被刺激分泌 LTB4。我们推测，在许多哮喘患者中，嗜酸性粒细胞衍生的 LTB4 增加，这可能有助于 5-LO 抑制的疗效。
