Power of Place: Intravascular Superoxide Dismutase for Prevention of Acute Respiratory Distress Syndrome.
Power of Place: Intravascular Superoxide Dismutase for Prevention of Acute Respiratory Distress Syndrome.
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地点的力量：血管内超氧化物歧化酶用于预防急性呼吸窘迫综合征。
DOI：
10.1165/rcmb.2016-0407ed
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发表时间：
2017
影响因子：
6.4
通讯作者：
Nozik-Grayck,Eva
中科院分区：
文献类型：
--
作者：
Janssen,WilliamJ;Nozik-Grayck,Eva
地球形成了Z4。50亿年前，但它的大气层基本上没有氧气，直到20亿年后，浓度急剧增加(1)。氧气的增加随之而来的是生物多样性的爆炸性增长，其中包括依赖氧气生产能量和生存的多细胞生物体的进化(2)。几乎在同一时间，处理超氧化物和其他活性氧物种(ROS)的适应也得到了进化。这些适应中的许多在今天的物种中仍然高度保守，包括催化超氧化物分解为过氧化氢的超氧化物歧化酶(3)。因此，它们的功能对于正常发育、维持体内平衡和预防疾病是绝对必要的。由于氧化剂损伤是公认的急性呼吸窘迫综合征(ARDS)和感染性休克的诱因，因此增强SOD功能的策略似乎是一种有吸引力的治疗策略。在本期杂志中，Tanaka及其同事(第179-190页)测试了卵磷脂化的超氧化物歧化酶在脓毒症和ARDS小鼠模型中预防器官损伤的有效性(4)。Tanaka及其同事使用的卵磷化超氧化物歧化酶含有人的铜/锌-超氧化物歧化酶与磷脂酰胆碱(PC)衍生物络合形成PC-SOD，这种化合物在血浆中表现出更高的稳定性和组织亲和力(5)。使用小鼠盲肠结扎和穿孔(CLP)脓毒症模型，作者令人信服地证明，术前静脉注射PC-SOD可提高存活率，减轻全身炎症，减轻肾脏损伤，并降低肾脏和肝脏的血管通透性。值得注意的是，当PC-SOD经气管内给药时，没有看到这些有益的效果。在呼吸机诱导的肺损伤和呼吸道内毒素引起的ARDS模型中，静脉注射PC-SOD也显示了良好的作用。在两种模型中，PC-SOD预处理均可减轻肺毛细血管渗漏和组织学损伤。此外，在内毒素模型中，静脉注射PC-SOD的小鼠降低了肺泡灌洗液中炎症细胞因子和白细胞的水平，并减少了肝脏的毛细血管渗漏。未测试气管内PC-SOD的剂量。最后，为了证明PC-SOD的有益作用是由ROS介导的，作者使用基于鲁米诺的化学发光探针L-012进行了体内成像。PC-SOD治疗减少了CLP后小鼠腹部和气管内LPS后肺部对该探针的摄取。总体而言，这项研究的结果支持了PC-SOD在脓毒症和ARDS治疗中的靶向作用。然而，一些关键的问题仍然没有得到回答，包括关于最佳治疗时机的问题，直接和间接导致肺损伤的原因之间的潜在差异，PC-SOD靶向的细胞间隔，以及氧化还原平衡被改变的确切机制。在临床治疗学的背景下，给药的时机可能是最关键的。问题的核心是，PC-SOD是否只作为一种预防药物有效，或者它是否可以在疾病发作后提供好处。该小组在CLP模型中的死亡率研究清楚地强调了这一问题，在该模型中，PC-SOD预治疗显著改善了存活率，但仅将治疗推迟一小时并未带来统计上的显著好处。由于许多患者在脓毒症和/或肺损伤发作后才进入急诊室或重症监护病房，因此必须更清楚地定义治疗窗口。…
The Earth formed z4. 5 billion years ago, but its atmosphere was largely devoid of oxygen until 2 billion years later, when concentrations increased dramatically (1). This increase in oxygen was followed by an explosion in biodiversity and included the evolution of multicellular organisms that depended on oxygen for energy production and survival (2). At virtually the same time, adaptations to deal with superoxide and other reactive oxygen species (ROS) also evolved. Many of these adaptations remain highly conserved among today’s species, including the superoxide dismutase (SOD) enzymes (3) that catalyze the breakdown of superoxide into hydrogen peroxide. Accordingly, their function is absolutely essential for normal development, maintenance of homeostasis, and prevention of disease. Because oxidant damage is a well-recognized contributor to acute respiratory distress syndrome (ARDS) and septic shock, strategies that enhance SOD function pose a seemingly attractive therapeutic strategy. In this issue of the Journal, Tanaka and colleagues (pp. 179–190) test the efficacy of lecithinized SOD for preventing organ damage in mouse models of sepsis and ARDS (4). The lecithinized SOD used by Tanaka and colleagues contains a human Cu/Zn-SOD complexed with phosphatidylcholine (PC) derivatives to form PC-SOD, a compound that exhibits enhanced stability in plasma and improved tissue affinity (5). Using the murine cecal ligation and puncture (CLP) model of sepsis, the authors convincingly demonstrate that administration of intravenous PC-SOD before surgery improved survival, diminished systemic inflammation, attenuated kidney injury, and reduced vascular permeability in the kidneys and liver. Notably, these beneficial effects were not seen when the PC-SOD was administered intratracheally. Salutary effects of intravenous PC-SOD were also demonstrated in ventilator-induced lung injury and intratracheal LPS models of ARDS. In both models, pretreatment with PC-SOD attenuated pulmonary capillary leak and histologically assessed injury. Moreover, in the LPS model, mice treated with intravenous PC-SOD had reduced inflammatory cytokine and leukocyte levels in alveolar lavage fluid and attenuated capillary leak in the liver. Intratracheal dosing of PC-SOD was not tested. Finally, to demonstrate that the beneficial effects of PC-SOD were mediated by ROS, the authors used in vivo imaging with the luminol-based chemiluminescent probe L-012. Treatment with PC-SOD reduced uptake of the probe in the abdomens of mice after CLP and in the lungs after intratracheal LPS. Taken as a whole, the results of this study support a role for targeted administration of PC-SOD in the treatment of sepsis and ARDS. However, several critical questions remain unanswered, including ones regarding the optimal timing of therapy, potential differences between direct and indirect causes of lung injury, the cellular compartments targeted by PC-SOD, and the precise mechanisms by which redox balance is altered. In the context of clinical therapeutics, the timing of administration is perhaps the most critical. At the heart of the matter is whether PC-SOD is only effective as a preventative agent or whether it may provide benefit after the onset of illness. This issue is clearly highlighted by the group’s mortality studies in the CLP model, in which pretreatment with PC-SOD led to striking improvements in survival, but delay of treatment by a mere hour provided no statistically significant benefit. Because many patients arrive in the emergency room or intensive care unit after the onset of sepsis and/or lung injury, the therapeutic window must be more clearly defined …
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影响因子：
7.4
作者：
Zielonka, Jacek;Lambeth, J. David;Kalyanaraman, Balaraman
通讯作者：
Kalyanaraman, Balaraman
影响因子：
9.6
作者：
Tanaka, Ken-Ichiro;Azuma, Arata;Mizushima, Tohru
通讯作者：
Mizushima, Tohru
DOI：
10.1152/ajplung.00289.2009
发表时间：
2010-03-01
影响因子：
4.9
作者：
Tanaka, Ken-Ichiro;Ishihara, Tomoaki;Mizushima, Tohru
通讯作者：
Mizushima, Tohru
血浆中细胞外超氧化物歧化酶的浓度由 LRP 介导的内吞作用维持。
影响因子：
7.4
作者：
Petersen,SteenV;Thogersen,IdaB;Valnickova,Zuzana;Nielsen,MortenS;Petersen,JaneS;Poulsen,EbbeT;Jacobsen,Christian;Oury,TimD;Moestrup,SorenK;Crapo,JamesD;Nielsen,NielsChr;Kristensen,Torsten;Enghild,JanJ
通讯作者：
Enghild,JanJ
DOI：
10.1164/rccm.201011-1802oc
发表时间：
2011-06-15
影响因子：
24.7
作者：
Calfee, Carolyn S.;Matthay, Michael A.;Cohen, Mitchell J.
通讯作者：
Cohen, Mitchell J.