Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany.
Institute for Anesthesiologic Pathophysiology and Process Engineering, Ulm University, 89081 Ulm, Germany.
Cells. 2021 Dec 30;11(1):112. doi: 10.3390/cells11010112.
We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GR). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GR mice compared to wildtype mice (GR). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GR mice. Lungs of GR mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective compared to GR after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GR mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GR mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GR mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage.
我们之前的研究表明，失血性休克（HS）后肺损伤减轻与猪肺组织中糖皮质激素（GC）受体（GR）水平升高有关。在这里，我们使用功能失调的 GR 小鼠模型（GR）研究了 GR 信号转导受损对复苏 HS 期间肺的影响。在小鼠重症监护病房中，与野生型小鼠（GR）相比，HS 导致 GR 小鼠的肺力学受损和肺炎症加重。在 HS 后，GR 小鼠的肺样本中发现促炎和促凋亡转录因子 STAT1/pSTAT1 水平升高。GR 小鼠的肺显示出凋亡，这很可能是由于肺保护基因的表达降低所致。与 HS 后相比，GR 中的表达降低。RNA 测序显示 GR 小鼠肺组织中促凋亡和细胞因子信号相关基因的表达增加。此外，GR 小鼠的肺中还发现了高水平的促炎细胞因子和 iNOS。我们的研究结果表明，GR 小鼠中由于 GR 信号转导功能失调导致 STAT1/pSTAT1 的抑制作用受损，从而导致肺部炎症和细胞凋亡增加。这些数据强调了功能性 GR 信号转导在减轻 HS 诱导的肺损伤中的关键作用。
