Protection from pulmonary fibrosis in leukotriene-deficient mice
Protection from pulmonary fibrosis in leukotriene-deficient mice
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DOI：
10.1164/ajrccm.165.2.2104050
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发表时间：
2002-01-15
影响因子：
24.7
通讯作者：
Moore, BB
中科院分区：
文献类型：
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作者：
Peters-Golden, M;Bailie, M;Moore, BB
虽然已经证实在肺纤维化患者的肺中过度产生促炎性5-脂氧合酶（5-LO）衍生的白三烯（LT），但尚未确定其与这种疾病的因果关系。在通过敲除5-LO基因（KO）而导致LT缺陷的小鼠和野生型（WT）对照小鼠中研究博来霉素诱导的肺纤维化。在施用博来霉素后，WT小鼠的肺灌洗液显示半胱氨酰-LT水平在第1天相对于基线水平增加了类似于5倍，并且持续升高直至第21天。与WT小鼠相比，5-LO KO小鼠表现出组织学上明显的胶原蛋白量减少，以及博莱霉素后肺羟脯氨酸水平降低约60%。与WT小鼠不同，KO小鼠在博来霉素治疗后肺部炎症细胞的数量没有增加。此外，原位表达和刺激生产的抗纤维化细胞因子干扰素-γ的混合肺白细胞显着更大的细胞从5-LO KO小鼠。最后，KO动物的前列腺素E-2和抗纤维化分子的灌洗水平显著更高。这些结果提供了强有力的证据表明，LT可能参与肺纤维化的发病机制，它们可能通过直接作用以及通过调节其他炎症介质的合成而发生的间接作用来实现这一点。
Although overproduction of proinflammatory 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) has been demonstrated in the lungs of patients with pulmonary fibrosis, their causal involvement in this condition has not been established. Bleomycin-induced pulmonary fibrosis was studied in mice rendered LT deficient by knockout of the 5-LO gene (KO) and in wild-type (WT) control mice. Following administration of bleomycin, lung lavage fluid of WT mice demonstrated an similar to 5-fold increase in levels of cysteinyl-LTs over baseline levels at Day 1, with persistent elevation up to Day 21. As compared with WT mice, 5-LO KO mice demonstrated reduced amounts of histologically evident collagen as well as an similar to 60% reduction in lung hydroxyproline levels postbleomycin. Unlike WT mice, KO mice showed no increases in the numbers of lung inflammatory cells postbleomycin. Furthermore, in situ expression and stimulated production by mixed lung leukocytes of the antifibrotic cytokine interferon-gamma were significantly greater in cells from the 5-LO KO mice. Finally, lavage levels of the antiinflammatory and antifibrotic molecule, prostaglandin E-2, were significantly greater in the KO animals. These results provide strong evidence that LTs may participate in the pathogenesis of pulmonary fibrosis, and they may do so by direct effects as well as indirect effects occurring via their modulation of the synthesis of other inflammatory mediators.