Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Shizuoka, Japan.
Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Shizuoka, Japan.
Int J Mol Sci. 2022 Aug 12;23(16):8996. doi: 10.3390/ijms23168996.
Pulmonary fibrosis is a progressive and fatal disorder characterized by dysregulated repair after recurrent injury. Destruction of the lung architecture with excess extracellular matrix deposition induces respiratory failure with hypoxia and progressive dyspnea. The impact of hypoxia on pulmonary endothelial cells during pulmonary fibrogenesis is unclear. Using a magnetic-activated cell sorting system, pulmonary endothelial cells were isolated from a mouse model of pulmonary fibrosis induced by intratracheally administered bleomycin. When endothelial cells were exposed to hypoxic conditions, a hypoxia-inducible factor (HIF)-2α protein was detected in CD31- and α-smooth muscle actin (SMA)-positive cells. Levels of plasminogen activator inhibitor 1, von Willebrand factor, and matrix metalloproteinase 12 were increased in endothelial cells isolated from bleomycin-treated mice exposed to hypoxic conditions. When endothelial cells were cultured under hypoxic conditions, levels of fibrotic mediators, transforming growth factor-β and connective tissue growth factor, were elevated only in endothelial cells from bleomycin-treated and not from saline-treated lungs. The increased expression of α-SMA and mesenchymal markers and collagen production in bleomycin- or hypoxia-stimulated endothelial cells were further elevated in endothelial cells from bleomycin-treated mouse lungs cultured under hypoxic conditions. Exposure to hypoxia damaged endothelial cells and enhanced fibrogenesis-related damage in bleomycin-treated pulmonary endothelial cells.
肺纤维化是一种进行性和致命性疾病，其特征是反复损伤后的失调修复。肺结构的破坏伴有细胞外基质的过度沉积，导致缺氧和进行性呼吸困难的呼吸衰竭。缺氧对肺纤维化过程中的肺内皮细胞的影响尚不清楚。本研究通过磁激活细胞分选系统，从博来霉素气管内给药诱导的肺纤维化小鼠模型中分离出肺内皮细胞。当内皮细胞暴露于低氧环境时，在 CD31 和α-平滑肌肌动蛋白（α-SMA）阳性细胞中检测到缺氧诱导因子（HIF）-2α蛋白。在低氧条件下培养的来自博莱霉素处理的小鼠的内皮细胞中，纤溶酶原激活物抑制剂 1、血管性血友病因子和基质金属蛋白酶 12 的水平增加。当内皮细胞在低氧条件下培养时，纤维化介质转化生长因子-β和结缔组织生长因子的水平仅在来自博莱霉素处理而非生理盐水处理的肺的内皮细胞中升高。在低氧条件下培养的来自博莱霉素处理的小鼠肺的内皮细胞中，博莱霉素或低氧刺激的内皮细胞中α-SMA 和间充质标志物的表达增加，以及胶原产生进一步增加。低氧暴露损伤内皮细胞，并增强博莱霉素处理的肺内皮细胞中的纤维生成相关损伤。
