Background: Sepsis, that can be modeled by LPS injections, as an acute systemic inflammation syndrome is the most common cause for acute lung injury (ALI). ALI induces acute respiratory failure leading to hypoxemia, which is often associated with multiple organ failure (MOF). During systemic inflammation, the hypothalamus-pituitary-adrenal axis (HPA) is activated and anti-inflammatory acting glucocorticoids (GCs) are released to overcome the inflammation. GCs activate the GC receptor (GR), which mediates its effects via a GR monomer or GR dimer. The detailed molecular mechanism of the GR in different inflammatory models and target genes that might be crucial for resolving inflammation is not completely identified. We previously observed that mice with attenuated GR dimerization (GRdim/dim) had a higher mortality in a non-resuscitated lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced inflammation model and are refractory to exogenous GCs to ameliorate ALI during inflammation. Therefore, we hypothesized that impaired murine GR dimerization (GRdim/dim) would further impair organ function in LPS-induced systemic inflammation under human like intensive care management and investigated genes that are crucial for lung function in this setup. Methods: Anesthetized GRdim/dim and wildtype (GR+/+) mice were challenged with LPS (10 mg·kg-1, intraperitoneal) and underwent intensive care management ("lung-protective" mechanical ventilation, crystalloids, and norepinephrine) for 6 h. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, acid-base status, and mitochondrial oxygen consumption (JO2). Western blots, immunohistochemistry, and real time quantitative polymerase chain reaction were performed to analyze lung tissue and inflammatory mediators were analyzed in plasma and lung tissue. Results: When animals were challenged with LPS and subsequently resuscitated under intensive care treatment, GRdim/dim mice had a higher mortality compared to GR+/+ mice, induced by an increased need of norepinephrine to achieve hemodynamic targets. After challenge with LPS, GRdim/dim mice also displayed an aggravated ALI shown by a more pronounced impairment of gas exchange, lung mechanics and increased osteopontin (Opn) expression in lung tissue. Conclusion: Impairment of GR dimerization aggravates systemic hypotension and impairs lung function during LPS-induced endotoxic shock in mice. We demonstrate that the GR dimer is an important mediator of hemodynamic stability and lung function, possibly through regulation of Opn, during LPS-induced systemic inflammation.

中文翻译：

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糖皮质激素受体二聚体受损加重LPS诱导的循环和肺功能障碍。

背景：脓毒症可以通过注射LPS来模拟，因为急性全身性炎症综合征是急性肺损伤（ALI）的最常见原因。ALI引起急性呼吸衰竭，导致低氧血症，这通常与多器官衰竭（MOF）相关。在全身性炎症过程中，下丘脑-垂体-肾上腺轴（HPA）被激活，抗炎作用的糖皮质激素（GCs）被释放以克服炎症。GC激活GC受体（GR），该受体通过GR单体或GR二聚体介导其作用。GR在不同炎症模型和靶基因中可能对解决炎症至关重要的详细分子机制尚未完全确定。我们先前观察到，在非复苏的脂多糖（LPS）和盲肠结扎穿刺（CLP）诱导的炎症模型中，具有减毒GR二聚化（GRdim / dim）的小鼠具有更高的死亡率，并且在外源性GC缓解难治性ALI期间炎。因此，我们假设受损的鼠GR二聚化（GRdim / dim）会进一步削弱人在LPS诱导的系统性炎症（如重症监护管理）中的器官功能，并研究了在这种情况下对肺功能至关重要的基因。方法：麻醉的GRdim / dim和野生型（GR + / +）小鼠接受LPS（10 mg·kg-1，腹膜内）攻击，并接受重症监护管理（“肺保护性”机械通气，晶体和去甲肾上腺素）6小时。评估肺力学和气体交换以及全身血流动力学，酸碱状态和线粒体耗氧量（JO2）。进行了蛋白质印迹，免疫组织化学和实时定量聚合酶链反应以分析肺组织，并分析了血浆和肺组织中的炎症介质。结果：当动物受到LPS攻击并随后在重症监护下复苏时，由于去甲肾上腺素对实现血流动力学指标的需求增加，与GR + / +小鼠相比，GRdim / dim小鼠的死亡率更高。用LPS攻击后，GRdim / dim小鼠还显示出ALI恶化，表现为气体交换，肺力学和肺组织中骨桥蛋白（Opn）表达增加的更明显损害。结论：GR二聚化的损害加重了LPS诱导的小鼠内毒素休克期间的系统性低血压并损害了肺功能。我们证明，在LPS诱导的全身性炎症过程中，GR二聚体是血液动力学稳定性和肺功能的重要调节剂，可能通过调节Opn发挥作用。