Peters-Golden Marc, Bailie Marc, Marshall Teresa, Wilke Carol, Phan Sem H, Toews Galen B, Moore Bethany B
Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0642, USA.
Am J Respir Crit Care Med. 2002 Jan 15;165(2):229-35. doi: 10.1164/ajrccm.165.2.2104050.
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 approximately 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 approximately 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.
尽管在肺纤维化患者的肺部已证实促炎的5-脂氧合酶（5-LO）衍生的白三烯（LTs）产生过多，但它们在这种疾病中的因果关系尚未确立。我们在通过敲除5-LO基因（KO）而导致LT缺乏的小鼠以及野生型（WT）对照小鼠中研究了博来霉素诱导的肺纤维化。给予博来霉素后，WT小鼠的肺灌洗液在第1天时半胱氨酰白三烯水平比基线水平增加了约5倍，并持续升高至第21天。与WT小鼠相比，5-LO KO小鼠在组织学上明显的胶原蛋白量减少，并且在博来霉素处理后肺羟脯氨酸水平降低了约60%。与WT小鼠不同，KO小鼠在博来霉素处理后肺炎症细胞数量没有增加。此外，5-LO KO小鼠的细胞中抗纤维化细胞因子干扰素-γ的原位表达和混合肺白细胞刺激产生的量明显更高。最后，KO动物中抗炎和抗纤维化分子前列腺素E（2）的灌洗水平明显更高。这些结果提供了强有力的证据，表明白三烯可能参与肺纤维化的发病机制，并且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产生的间接作用来参与。
