Hypoxia-induced acute lung injury in murine models of sickle cell disease.
Hypoxia-induced acute lung injury in murine models of sickle cell disease.
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DOI：
10.1152/ajplung.00288.2002
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发表时间：
2004-04
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通讯作者：
K. Pritchard;J. Ou;Zhi‐jun Ou;Yang Shi;J. Franciosi;Paul R Signorino;Sushma Kaul;C. Ackland-Berglund-C.-Ackland
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作者：
K. Pritchard;J. Ou;Zhi‐jun Ou;Yang Shi;J. Franciosi;Paul R Signorino;Sushma Kaul;C. Ackland-Berglund-C.-Ackland
血管闭塞事件是镰状细胞病（SCD）发病率和死亡率的主要来源;然而，驱动这些事件的致病机制仍不清楚。使用缺氧诱导肺损伤，我们研究了镰状血红蛋白增加SCD小鼠模型肺损伤易感性的机制，其中小鼠或者专门表达人α/镰状β-珠蛋白（halphabetaS）转基因（SCD小鼠），或者是正常小鼠β-珠蛋白基因的杂合子并表达halphabetaS转基因（mbeta+/-，halphabetaS+/-;杂合子SCD小鼠）。在常氧条件下，SCD小鼠的肺中含有较高水平的黄嘌呤氧化酶（XO），硝基酪氨酸和cGMP比对照组（C57 BL/6小鼠）。缺氧可使小鼠肺组织中XO和硝基酪氨酸含量升高，cGMP含量降低。缺氧后，肺血管充血加重，XO和硝基酪氨酸含量增加。常氧条件下，SCD和杂合子SCD小鼠肺组织中热休克蛋白90（HSP 90）与内皮型一氧化氮合酶（eNOS）的相关性较对照组降低。缺氧进一步降低了SCD和杂合子SCD小鼠肺中HSP 90与eNOS的结合，但在对照肺中则不然。体外用黄嘌呤/XO预处理大鼠肺微血管内皮细胞可降低A-23187刺激的亚硝酸盐+硝酸盐生成以及HSP 90与eNOS的相互作用。这些数据支持缺氧增加XO从缺血组织释放的假设，并且XO诱导的氧化应激的局部增加然后可以抑制HSP 90与eNOS的相互作用，减少 *NO的产生并使肺易于血管闭塞。
Vaso-occlusive events are the major source of morbidity and mortality in sickle cell disease (SCD); however, the pathogenic mechanisms driving these events remain unclear. Using hypoxia to induce pulmonary injury, we investigated mechanisms by which sickle hemoglobin increases susceptibility to lung injury in a murine model of SCD, where mice either exclusively express the human alpha/sickle beta-globin (halphabetaS) transgene (SCD mice) or are heterozygous for the normal murine beta-globin gene and express the halphabetaS transgene (mbeta+/-, halphabetaS+/-; heterozygote SCD mice). Under normoxia, lungs from the SCD mice contained higher levels of xanthine oxidase (XO), nitrotyrosine, and cGMP than controls (C57BL/6 mice). Hypoxia increased XO and nitrotyrosine and decreased cGMP content in the lungs of all mice. After hypoxia, vascular congestion was increased in lungs with a greater content of XO and nitrotyrosine. Under normoxia, the association of heat shock protein 90 (HSP90) with endothelial nitric oxide synthase (eNOS) in lungs of SCD and heterozygote SCD mice was decreased compared with the levels of association in lungs of controls. Hypoxia further decreased association of HSP90 with eNOS in lungs of SCD and heterozygote SCD mice, but not in the control lungs. Pretreatment of rat pulmonary microvascular endothelial cells in vitro with xanthine/XO decreased A-23187-stimulated nitrite + nitrate production and HSP90 interactions with eNOS. These data support the hypotheses that hypoxia increases XO release from ischemic tissues and that the local increase in XO-induced oxidative stress can then inhibit HSP90 interactions with eNOS, decreasing *NO generation and predisposing the lung to vaso-occlusion.