XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis.
XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis.
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DOI：
10.14814/phy2.13377
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发表时间：
2017-08-01
影响因子：
2.5
通讯作者：
Hassoun, Paul M
中科院分区：
文献类型：
--
作者：
Damarla, Mahendra;Johnston, Laura F;Hassoun, Paul M
脓毒症是重症监护病房患者死亡的主要原因，由多器官衰竭引起。黄嘌呤氧化还原酶（XOR）是一种活性氧（ROS）产生酶，已知脓毒症非幸存者与幸存者相比其活性升高。我们之前已经证明，XOR对于呼吸机引起的肺损伤至关重要。使用非布司他，一种新的非嘌呤类XOR抑制剂，我们试图确定XOR抑制在脓毒症诱导的肺损伤和死亡率的小鼠模型中的作用。使C57 BL/6 J小鼠经受静脉内（IV）脂多糖（LPS）不同时间点，并收获肺用于分析。小鼠亚组在LPS暴露前或暴露后用非布司他或溶媒处理。在LPS暴露后，跟踪不同组的小鼠的死亡率。在IV LPS 24小时后，小鼠表现出肺组织中XOR活性的增加和肺内皮屏障破坏的显著增加。在暴露于LPS之前用非布司他预处理动物，或在LPS后4小时处理，导致XOR活性完全消除。用非布司他抑制XOR在24小时时不能防止LPS诱导的肺血管通透性，然而，它加速了响应于LPS暴露的肺内皮屏障完整性的恢复。此外，非布司他治疗导致死亡率显著降低。无论在暴露于LPS之前还是之后给予，用非布司他抑制XOR加速肺内皮屏障的恢复并防止LPS诱导的死亡。
Sepsis is a leading cause of death among patients in the intensive care unit, resulting from multi-organ failure. Activity of xanthine oxidoreductase (XOR), a reactive oxygen species (ROS) producing enzyme, is known to be elevated in nonsurvivors of sepsis compared to survivors. We have previously demonstrated that XOR is critical for ventilator-induced lung injury. Using febuxostat, a novel nonpurine inhibitor of XOR, we sought to determine the role of XOR inhibition in a murine model of sepsis-induced lung injury and mortality. C57BL/6J mice were subjected to intravenous (IV) lipopolysaccharide (LPS) for various time points, and lungs were harvested for analyses. Subsets of mice were treated with febuxostat, pre or post LPS exposure, or vehicle. Separate groups of mice were followed up for mortality after LPS exposure. After 24hr of IV LPS, mice exhibited an increase in XOR activity in lung tissue and a significant increase in pulmonary endothelial barrier disruption. Pretreatment of animals with febuxostat before exposure to LPS, or treatment 4h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS-induced pulmonary vascular permeability at 24h, however, it accelerated recovery of the pulmonary endothelial barrier integrity in response to LPS exposure. Furthermore, treatment with febuxostat resulted in significant reduction in mortality. Inhibition of XOR with febuxostat accelerates recovery of the pulmonary endothelial barrier and prevents LPS-induced mortality, whether given before or after exposure to LPS.