Mokra D, Kosutova P, Balentova S, Adamkov M, Mikolka P, Mokry J, Antosova M, Calkovska A
Biomedical Center Martin and Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
Department of Histology and Embryology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
J Physiol Pharmacol. 2016 Dec;67(6):919-932.
Diffuse alveolar injury, edema, and inflammation are fundamental signs of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Whereas the systemic administration of corticosteroids previously led to controversial results, this study evaluated if corticosteroids given intratracheally may improve lung functions and reduce edema formation, migration of cells into the lung and their activation in experimentally-induced ALI. In oxygen-ventilated rabbits, ALI was induced by repetitive saline lung lavage, until PaO2 decreased to < 26.7 kPa in FiO 1.0. Then, one group of animals was treated with corticosteroid budesonide (Pulmicort susp inh, AstraZeneca; 0.25 mg/kg) given intratracheally by means of inpulsion regime of high-frequency jet ventilation, while another group was non-treated, and both groups were oxygen-ventilated for following 5 hours. Another group of animals served as healthy controls. After sacrifice of animals, left lung was saline-lavaged and protein content was measured and cells in the lavage fluid were determined microscopically. Right lung tissue was used for estimation of edema formation (expressed as wet/dry weight ratio), for histomorphological investigation, immunohistochemical determination of apoptosis of lung cells, and for determination of markers of inflammation and lung injury (IL-1β, IL-6, IL-8, TNF-α, IFNγ, esRAGE, caspase-3) by ELISA methods. Levels of several cytokines were estimated also in plasma. Repetitive lung lavage worsened gas exchange, induced lung injury, inflammation and lung edema and increased apoptosis of lung epithelial cells. Budesonide reduced lung edema, cell infiltration into the lung and apoptosis of epithelial cells and decreased concentrations of proinflammatory markers in the lung and blood. These changes resulted in improved ventilation. Concluding, curative intratracheal treatment with budesonide alleviated lung injury, inflammation, apoptosis of lung epithelial cells and lung edema and improved lung functions in a lavage model of ALI. These findings suggest a potential of therapy with inhaled budesonide also for patients with ARDS.
弥漫性肺泡损伤、水肿和炎症是急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的基本体征。虽然先前全身应用皮质类固醇导致了有争议的结果，但本研究评估了经气管内给予皮质类固醇是否可改善肺功能并减少水肿形成、细胞向肺内迁移及其在实验性诱导的ALI中的激活。在氧通气的兔子中，通过重复盐水肺灌洗诱导ALI，直到在FiO₂ 1.0条件下PaO₂降至<26.7 kPa。然后，一组动物通过高频喷射通气的脉冲给药方式经气管内给予皮质类固醇布地奈德（普米克令舒吸入混悬液，阿斯利康；0.25 mg/kg），而另一组不进行治疗，两组均进行接下来5小时的氧通气。另一组动物作为健康对照。动物处死后，用盐水灌洗左肺并测量蛋白质含量，显微镜下确定灌洗液中的细胞。右肺组织用于评估水肿形成（以湿/干重比表示）、进行组织形态学研究、免疫组化测定肺细胞凋亡，以及通过ELISA方法测定炎症和肺损伤标志物（IL-1β、IL-6、IL-8、TNF-α、IFNγ、esRAGE、caspase-3）。还测定了血浆中几种细胞因子的水平。重复肺灌洗使气体交换恶化，诱导肺损伤、炎症和肺水肿，并增加肺上皮细胞凋亡。布地奈德减轻了肺水肿、细胞向肺内浸润和上皮细胞凋亡，并降低了肺和血液中促炎标志物的浓度。这些变化导致通气改善。总之，布地奈德经气管内治疗可减轻ALI灌洗模型中的肺损伤、炎症、肺上皮细胞凋亡和肺水肿，并改善肺功能。这些发现提示吸入布地奈德治疗ARDS患者也具有潜力。
