Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 14 Save Mrkalja St., 78000 Banja Luka, Bosnia and Herzegovina.
Center for Biomedical Research, Faculty of Medicine, University of Banja Luka, 14 Save Mrkalja St., 78000 Banja Luka, Bosnia and Herzegovina.
Int J Mol Sci. 2022 Feb 26;23(5):2596. doi: 10.3390/ijms23052596.
Disruption of the alveolar−endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10−40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar−endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL.
炎症导致的肺泡-内皮屏障破坏可导致脓毒症性急性肺损伤（ALI）进展。在本研究中，我们研究了辛伐他汀对脂多糖（LPS）诱导的 ALI 的有益作用及其相关机制。在通过腹腔注射单次非致死性 LPS 剂量建立实验性脓毒症后，用短期辛伐他汀预处理（口服 10-40mg/kg）来诱导 ALI 模型。肺组织炎症损伤的严重程度用肺损伤评分（PDS）表示。用 TUNEL 检测（DNA 片段化）和凋亡指数（AI）来确认肺泡上皮细胞凋亡，并通过免疫组化检测裂解的 caspase-3、细胞色素 C 和凋亡抑制因子 Bcl-xL、凋亡抑制剂 survivin、转录因子 NF-kB/p65。LPS 攻击后，肺实质出现严重的炎症损伤（PDS 3.33±0.48），而辛伐他汀能显著地、剂量依赖性地减轻 LPS 后的肺组织病理学损伤（p<0.01）。40mg/kg 辛伐他汀在改善肺泡上皮细胞凋亡方面表现出最显著的效果，表现为 AI（p<0.01 与 LPS 相比）、细胞色素 C 和裂解的 caspase-3 表达明显降低。此外，辛伐他汀还显著增强了 Bcl-xL 和 survivin 的表达。最后，各组间肺泡上皮细胞中 survivin 及其调节因子 NF-kB/p65 的表达呈强正相关。辛伐他汀可对 LPS 诱导的 ALI 和肺泡-内皮屏障的凋亡发挥保护作用。总之，这些作用似乎是通过抑制 caspase 3 和细胞色素 C 介导的，这可能与细胞存活的 survivin/NF-kB/p65 途径和 Bcl-xL 的上调有关。
