Wright Richard M, Ginger Lisa A, Kosila Noi, Elkins Nancy D, Essary Brendan, McManaman James L, Repine John E
Department of Pulmonary Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Am J Respir Cell Mol Biol. 2004 Apr;30(4):479-90. doi: 10.1165/rcmb.2003-0309OC. Epub 2003 Sep 25.
Acute lung injury (ALI) is characterized by increased alveolar cytokines, inflammatory cell infiltration, oxidative stress, and alveolar cell apoptosis. Previous work suggested that xanthine oxidoreductase (XOR) may contribute to oxidative stress in ALI as a product of the vascular endothelial cell. We present evidence that cytokine induced lung inflammation and injury involves activation of XOR in the newly recruited mononuclear phagocytes (MNP). We found that XOR was increased predominantly in the MNP that increase rapidly in the lungs of rats that develop ALI following intratracheal cytokine insufflation. XOR was recovered from the MNP largely converted to its oxygen radical generating, reversible O-form, and alveolar MNP exhibited increased oxidative stress as evidenced by increased nitrotyrosine staining. Cytokine insufflation also increased alveolar cell apoptosis. A functional role for XOR in cytokine-induced inflammation was demonstrated when feeding rats two different XOR inhibitors, tungsten and allopurinol, decreased MNP XOR induction, nitrotyrosine staining, inflammatory cell infiltration, and alveolar cell apoptosis. Transfer of control or allopurinol treated MNP into rat lungs confirmed a specific role for MNP XOR in promoting lung inflammation. These data indicate that XOR can contribute to lung inflammation by its expression and conversion in a highly mobile inflammatory cell population.
急性肺损伤（ALI）的特征是肺泡细胞因子增加、炎症细胞浸润、氧化应激和肺泡细胞凋亡。先前的研究表明，黄嘌呤氧化还原酶（XOR）作为血管内皮细胞的产物，可能在ALI的氧化应激中起作用。我们提供的证据表明，细胞因子诱导的肺部炎症和损伤涉及新招募的单核吞噬细胞（MNP）中XOR的激活。我们发现，在气管内注入细胞因子后发生ALI的大鼠肺中，XOR主要在迅速增加的MNP中升高。从MNP中回收的XOR大部分转化为其产生氧自由基的可逆O形式，并且肺泡MNP表现出氧化应激增加，硝基酪氨酸染色增加证明了这一点。细胞因子注入还增加了肺泡细胞凋亡。当给大鼠喂食两种不同的XOR抑制剂钨和别嘌呤醇时，MNP XOR诱导、硝基酪氨酸染色、炎症细胞浸润和肺泡细胞凋亡减少，这证明了XOR在细胞因子诱导的炎症中的功能作用。将对照或别嘌呤醇处理的MNP转移到大鼠肺中证实了MNP XOR在促进肺部炎症中的特定作用。这些数据表明，XOR可通过在高度移动的炎症细胞群体中的表达和转化来促进肺部炎症。
