Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury
Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury
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DOI：
10.1152/ajplung.00120.2016
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发表时间：
2016-08-01
影响因子：
4.9
通讯作者：
Jankov, Robert P.
中科院分区：
文献类型：
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作者：
Ee, Mong Tieng;Kantores, Crystal;Jankov, Robert P.
全身给予博莱霉素可导致新生大鼠炎症、肺生长停滞和肺动脉高压（PHT），与患有严重支气管肺发育不良（BPD）的人类婴儿相似。白三烯（LT）是由肺中多种细胞类型产生的炎症脂质介质。主要的LT，LTB 4和半胱氨酰LT，被认为有助于BPD，但它们的具体作用在实验模型中仍然很大程度上未被探索。我们假设LT在博莱霉素诱导的BPD样损伤中增加，抑制LT的产生可以防止炎性细胞的流入，从而改善肺损伤。将幼鼠暴露于博来霉素（1 mg.g（-1）.第（-1）天ip）或载体（对照），并用齐留通（5-脂氧合酶抑制剂）、孟鲁司特（半胱氨酰LT 1受体拮抗剂）或SC 57461 A（LTA 4水解酶抑制剂）处理。mg.kg博莱霉素导致肺中LTB 4含量增加，但不导致半胱氨酰LT含量增加。博莱霉素诱导的组织嗜中性粒细胞和巨噬细胞的增加以及LTB 4和肿瘤坏死因子-α的肺含量的增加都被齐留通治疗所阻止。用齐留通或SC 57461 A治疗还防止了慢性PHT的血流动力学和结构标志物，包括肺血管阻力升高、富尔顿指数增加和动脉壁重塑。然而，两种治疗都不能预防继发于博来霉素的肺泡化受损或血管发育不全。孟鲁司特治疗对巨噬细胞内流、PHT或异常肺结构没有影响。我们的结论是，LTB 4在实验性BPD的肺部炎症和PHT中起着至关重要的作用。靶向LTB 4或LTB 4介导的信号传导的药物可能对有发生BPD相关PHT风险的婴儿有用。
Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury. Rat pups were exposed to bleomycin (1 mg.g(-1). day(-1) ip) or vehicle (control) from postnatal days 1-14 and were treated with either zileuton (5-lipoxygenase inhibitor), montelukast (cysteinyl LT1 receptor antagonist), or SC57461A (LTA4 hydrolase inhibitor) 10 mg.kg(-1).day(-1) ip. Bleomycin led to increased lung content of LTB4, but not cysteinyl LTs. Bleomycin-induced increases in tissue neutrophils and macrophages and lung contents of LTB4 and tumor necrosis factor-alpha were all prevented by treatment with zileuton. Treatment with zileuton or SC57461A also prevented the hemodynamic and structural markers of chronic PHT, including raised pulmonary vascular resistance, increased Fulton index, and arterial wall remodeling. However, neither treatment prevented impaired alveolarization or vascular hypoplasia secondary to bleomycin. Treatment with montelukast had no effect on macrophage influx, PHT, or on abnormal lung structure. We conclude that LTB4 plays a crucial role in lung inflammation and PHT in experimental BPD. Agents targeting LTB4 or LTB4-mediated signaling may have utility in infants at risk of developing BPD-associated PHT.