Damarla Mahendra, Johnston Laura F, Liu Gigi, Gao Li, Wang Lan, Varela Lidenys, Kolb Todd M, Kim Bo S, Damico Rachel L, Hassoun Paul M
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Physiol Rep. 2017 Aug;5(15). doi: 10.14814/phy2.13377.
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 24 hr 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 4 h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS-induced pulmonary vascular permeability at 24 h, 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.
脓毒症是重症监护病房患者死亡的主要原因，由多器官功能衰竭引起。黄嘌呤氧化还原酶（XOR）是一种产生活性氧（ROS）的酶，已知脓毒症非幸存者体内该酶的活性高于幸存者。我们之前已经证明，XOR对呼吸机诱导的肺损伤至关重要。我们使用新型非嘌呤类XOR抑制剂非布司他，试图确定抑制XOR在脓毒症诱导的肺损伤和死亡率小鼠模型中的作用。对C57BL/6J小鼠在不同时间点静脉注射（IV）脂多糖（LPS），然后采集肺组织进行分析。部分小鼠在LPS暴露前或暴露后用非布司他或赋形剂处理。另一组小鼠在LPS暴露后进行死亡率随访。静脉注射LPS 24小时后，小鼠肺组织中XOR活性增加，肺内皮屏障破坏显著增加。在暴露于LPS之前用非布司他预处理动物，或在LPS处理后4小时进行处理，可完全消除XOR活性。非布司他抑制XOR在24小时时并未阻止LPS诱导的肺血管通透性增加，然而，它加速了肺内皮屏障完整性对LPS暴露的恢复。此外，非布司他治疗可显著降低死亡率。无论在暴露于LPS之前还是之后给予非布司他，抑制XOR均可加速肺内皮屏障的恢复并预防LPS诱导的死亡。
