CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain Critical Patient Translational Research Group, Department of Anesthesiology, Intensive Care and Pain Management, Hospital Clínico Universitario, Instituto de Investigación Sanitaria (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, 15706, Spain.
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain.
Exp Biol Med (Maywood). 2015 Jan;240(1):135-42. doi: 10.1177/1535370214547156. Epub 2014 Aug 18.
Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome.
脓毒症是急性呼吸窘迫综合征（ARDS）最常见的病因，ARDS 是一种严重的肺部炎症性疾病，发病率和死亡率都很高。脓毒症和 ARDS 涉及炎症介质向全身循环的释放，从而引发细胞和分子反应，并影响包括大脑在内的远端器官。由于已经报道脓毒症和 ARDS 会导致脑功能障碍，因此我们使用体外气道上皮细胞和脑细胞损伤模型研究了肺-脑的相互作用。随后，将从人 A549 肺泡细胞的体外脂多糖诱导的气道上皮细胞损伤模型中收集的条件培养基以递增浓度（无条件培养基、2%、5%、10%、15%、25%和 50%）添加到含有星形胶质细胞和神经元的大鼠混合脑细胞培养物中。在处理前、处理后 6 小时和 24 小时收集培养基样本和混合脑细胞培养物中的细胞进行分析。处理后 24 小时，15%的条件培养基显著增加了脑细胞培养物中的细胞凋亡，而 25%和 50%的条件培养基则显著增加了细胞坏死和凋亡。用≥2%的条件培养基处理脑细胞后，脑损伤标志物 S100 钙结合蛋白 B 和神经元特异性烯醇化酶、白细胞介素-6、巨噬细胞炎症蛋白-2 以及基质金属蛋白酶-9 的水平显著升高。我们的研究结果表明，受到细菌脂多糖刺激的人上皮肺细胞释放出的炎症介质能够在脑细胞中引发一种具有临床相关性的有害反应。这些结果支持脓毒症和脓毒症诱导的 ARDS 期间发生的肺-脑相互作用。
