Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the current study was to determine the cellular source of the cysLTs. To achieve this aim, we exposed mice to 100 ppm of chlorine for 5 minutes. Intranasal instillation of clodronate in liposomes and of diphtheria toxin in CD11c-DTR mice was used to deplete macrophages. CCR2^−/− mice were used to assess the contribution of recruited macrophages. Eosinophils and neutrophils were depleted with specific antibodies. Platelet–neutrophil aggregation was prevented with an antibody against P-selectin. The potential roles of phagocytosis of neutrophils by macrophages and of transcellular metabolism between epithelial cells and neutrophils were explored in coculture systems. We found that depletion of neutrophils was the only intervention that inhibited the synthesis of cysLTs at 24 hours after chlorine exposure. Although macrophages did synthesize cysLTs in response to phagocytosis of neutrophils, depletion of macrophages did not reduce the increment in cysLTs triggered by chlorine exposure. However, coculture of airway epithelial cells with neutrophils resulted in a significant increase in the synthesis of cysLTs, dependent on the expression of 5-lipoxygenase by neutrophils. We conclude that cysLT synthesis following chlorine exposure may be dependent on transcellular metabolism by neutrophil–epithelial interactions.

小鼠暴露于高浓度的氯会导致半胱氨酰白三烯（cysLTs）的合成。CysLTs有助于氯诱导的气道高反应性。当前研究的目的是确定cysLTs的细胞来源。为了实现这一目标，我们将小鼠暴露于100 ppm的氯气中5分钟。鼻腔内滴入脂质体中的氯膦酸盐和CD11c-DTR小鼠中的白喉毒素被用于消耗巨噬细胞。CCR2 ^-/-小鼠用于评估募集的巨噬细胞的贡献。嗜酸性粒细胞和嗜中性粒细胞被特异性抗体清除。抗P-选择蛋白抗体可防止血小板-中性粒细胞聚集。在共培养系统中探索了巨噬细胞吞噬嗜中性粒细胞和上皮细胞与嗜中性粒细胞之间的细胞间代谢的潜在作用。我们发现，中性粒细胞耗竭是在氯暴露后24小时内唯一抑制cysLTs合成的干预措施。尽管巨噬细胞确实响应嗜中性粒细胞的吞噬作用合成了cysLTs，但巨噬细胞的耗竭并没有减少因氯暴露引起的cysLTs的增加。但是，气道上皮细胞与嗜中性粒细胞的共培养导致cysLTs的合成显着增加，依赖于嗜中性粒细胞5-脂氧合酶的表达。我们得出结论，氯暴露后cysLT的合成可能取决于嗜中性粒细胞-上皮相互作用的跨细胞代谢。