Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice.
Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice.
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DOI：
10.1165/rcmb.2008-0182oc
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发表时间：
2009-12
影响因子：
6.4
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中科院分区：
文献类型：
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几种化疗药物，如博来霉素、白消安和吉非替尼的使用，常常会引发致命的肺损伤。然而，这种药物诱导的肺损伤的确切机制仍不清楚。在本研究中，我们检测了促炎细胞因子白细胞介素 - 18（IL - 18）和白细胞介素 - 1β（IL - 1β）在博来霉素诱导的肺损伤机制中的作用。我们对5例博来霉素诱导的致命性肺损伤患者的肺组织进行了白细胞介素 - 18和白细胞介素 - 18受体（R）α链表达的免疫组化分析。在所有5例博来霉素诱导的肺损伤患者的肺组织中均观察到白细胞介素 - 18和白细胞介素 - 18Rα表达增强。为了支持从患者样本中获得的数据，我们在博来霉素诱导的肺损伤小鼠模型中检测了白细胞介素 - 1β和白细胞介素 - 18的mRNA和蛋白质水平、肺部炎症以及肺纤维化情况。静脉注射博来霉素可诱导野生型C57BL / 6小鼠血清和肺组织中白细胞介素 - 1β和白细胞介素 - 18的表达。在接受治疗的小鼠肺组织中，产生白细胞介素 - 18的F4 / 80⁺中性粒细胞大量增加，而CD3⁺ T细胞则没有。此外，与对照小鼠相比，半胱天冬酶 - 1基因敲除（caspase - 1⁻/⁻）、白细胞介素 - 18基因敲除（IL - 18⁻/⁻）和白细胞介素 - 18Rα基因敲除（IL - 18Rα⁻/⁻）小鼠的博来霉素诱导的肺损伤明显减轻。因此，我们的研究结果为白细胞介素 - 1β和白细胞介素 - 18在化疗诱导的肺损伤中起重要作用提供了证据。
Administration of several chemotherapeutic drugs, such as bleomycin, busulfan, and gefitinib, often induces lethal lung injury. However, the precise mechanisms responsible for this drug-induced lung injury are still unclear. In the present study, we examined the role of the proinflammatory cytokines IL-18 and IL-1β in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptor (R) α chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18Rα was observed in the lungs of all five patients with bleomycin-induced lung injury. To support the data obtained from patient samples, the levels of IL-1β and IL-18 mRNA and protein, pulmonary inflammation, and lung fibrosis were examined in mouse models of bleomycin-induced lung injury. Intravenous administration of bleomycin induced the expression of IL-1β and IL-18 in the serum and lungs of wild-type C57BL/6 mice. IL-18–producing F4/80+ neutrophils, but not CD3+ T cells, were greatly increased in the lungs of treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1−/−, IL-18−/−, and IL-18Rα−/− mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1β and IL-18 in chemotherapy-induced lung injury.