Department of Anesthesiology, University Medical Centre, Mainz, Germany.
Department of Cardiology, University Medical Centre, Mainz, Germany.
BMC Anesthesiol. 2021 Sep 13;21(1):224. doi: 10.1186/s12871-021-01436-0.
Many patients with acute respiratory distress syndrome (ARDS) suffer from cognitive impairment after hospital discharge. Different mechanisms have been implicated as potential causes for this impairment, inter alia cerebral inflammation. A class of drugs with antioxidant and anti-inflammatory properties are β-HMG-CoA-reductase inhibitors ("statins"). We hypothesized that treatment with rosuvastatin attenuates cerebral cytokine mRNA expression and nitro-oxidative stress in an animal model of acute lung injury.
After approval of the institutional and state animal care committee, we performed this prospective randomized controlled animal study in accordance with the international guidelines for the care and use of laboratory animals. Thirty-two healthy male pigs were randomized to one of four groups: lung injury by central venous injection of oleic acid (n = 8), statin treatment before and directly after lung injury (n = 8), statin treatment after lung injury (n = 8), or ventilation-only controls (n = 8). About 18 h after lung injury and standardized treatment, the animals were euthanised, and the brains and lungs were collected for further examinations. We determined histologic lung injury and cerebral and pulmonal cytokine and 3-nitrotyrosine production.
We found a significant increase in hippocampal IL-6 mRNA after lung injury (p < 0.05). Treatment with rosuvastatin before and after induction of lung injury led to a significant reduction of hippocampal IL-6 mRNA (p < 0.05). Cerebral 3-nitrotyrosine was significantly higher in lung-injured animals compared with all other groups (p < 0.05 vs. animals treated with rosuvastatin after lung injury induction; p < 0.001 vs. all other groups). 3-Nitrotyrosine was also increased in the lungs of the lung-injured pigs compared to all other groups (p < 0.05 each).
Our findings highlight cerebral cytokine production and nitro-oxidative stress within the first day after induction of lung injury. The treatment with rosuvastatin reduced IL-6 mRNA and 3-nitrotyrosine concentration in the brains of the animals. In earlier trials, statin treatment did not reduce mortality in ARDS patients but seemed to improve quality of life in ARDS survivors. Whether this is attributable to better cognitive function because of reduced nitro-oxidative stress and inflammation remains to be elucidated.
许多急性呼吸窘迫综合征（ARDS）患者在出院后会出现认知障碍。有多种机制被认为是导致这种障碍的潜在原因，包括脑炎症。一类具有抗氧化和抗炎特性的药物是β-HMG-CoA 还原酶抑制剂（“他汀类药物”）。我们假设，在急性肺损伤的动物模型中，使用瑞舒伐他汀治疗可以减轻大脑细胞因子 mRNA 的表达和硝基氧化应激。
在获得机构和州动物护理委员会的批准后，我们按照国际实验室动物护理和使用指南进行了这项前瞻性随机对照动物研究。32 只健康雄性猪被随机分为四组之一：静脉注射油酸引起的肺损伤（n=8）、肺损伤前和直接后给予他汀类药物治疗（n=8）、肺损伤后给予他汀类药物治疗（n=8）或仅通气对照组（n=8）。肺损伤后约 18 小时，对动物进行安乐死，并采集大脑和肺部进行进一步检查。我们测定了组织学肺损伤以及大脑和肺部的细胞因子和 3-硝基酪氨酸的产生。
我们发现肺损伤后海马体 IL-6 mRNA 显著增加（p<0.05）。在诱导肺损伤之前和之后给予瑞舒伐他汀治疗可显著降低海马体 IL-6 mRNA（p<0.05）。与所有其他组相比，肺损伤动物的大脑 3-硝基酪氨酸明显更高（p<0.05 与肺损伤诱导后接受瑞舒伐他汀治疗的动物相比；p<0.001 与所有其他组相比）。与所有其他组相比，肺损伤猪的肺部 3-硝基酪氨酸也增加（p<0.05 各）。
我们的研究结果强调了肺损伤后第一天大脑细胞因子产生和硝基氧化应激。瑞舒伐他汀治疗降低了动物大脑中的 IL-6 mRNA 和 3-硝基酪氨酸浓度。在早期试验中，他汀类药物治疗并未降低 ARDS 患者的死亡率，但似乎改善了 ARDS 幸存者的生活质量。这是否归因于硝基氧化应激和炎症减少导致的认知功能改善，仍有待阐明。
