Kim Kyung Hoon, Hur Jung, Lee Hwa Young, Lee Eung Gu, Lee Sook Young
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of South Korea.
Division of Allergy, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of South Korea.
Exp Lung Res. 2021 Dec;47(10):494-506. doi: 10.1080/01902148.2021.2015011. Epub 2021 Dec 10.
In the context of asthma, airway bronchial remodeling and angiogenesis in the bronchial mucosa are well established. Cyclopeptidic-vascular endothelial growth inhibitor (cyclo-VEGI) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor that increases the proliferation of endothelial cells and the formation of new vessels. However, changes in the bronchial arteries of patients with asthma have not been clearly elucidated. We investigated whether structural changes occurred in bronchial arteries, as well as the effects of cyclo-VEGI in a mouse model of chronic asthma () and human fibroblasts (). A validated mouse model of allergic airway inflammation with ovalbumin (OVA) as the causative allergen was used for the study. Mice were treated with cyclo-VEGI or fluticasone during OVA challenge. experiments were conducted to determine whether fibroblasts proliferated following elastin exposure and the effects of cyclo-VEGI on them. OVA sensitization and challenge led to greater perivascular smooth muscle area, more elastic fibers, and elevated expression of vascular cell adhesion molecule (VCAM)-1 antigen. These phenomena indicated changes to bronchial arteries. Cyclo-VEGI and fluticasone treatment both inhibited airway hyper-responsiveness and inflammation. Cyclo-VEGI-treated mice exhibited decreased perivascular smooth muscle area, elastin fibers, and VCAM-1 expression. Fluticasone-treated mice exhibited reductions in perivascular smooth muscle but not in perivascular elastin or VCAM-1 expression. , fibroblast proliferation was enhanced by elastin treatment, which was inhibited by cyclo-VEGI treatment. Eotaxin expression was elevated in elastin-treated fibroblasts and decreased with cyclo-VEGI treatment. Vascular remodeling occurred in our mouse model of chronic asthma. Cyclo-VEGI could reduce airway inflammation and hyper-responsiveness by inhibiting VCAM-1 expression and elastin deposition around the bronchial arteries.
在哮喘的背景下，气道支气管重塑和支气管黏膜中的血管生成已得到充分证实。环肽血管内皮生长抑制剂（cyclo-VEGI）是血管内皮生长因子（VEGF）受体的抑制剂，可增加内皮细胞的增殖和新血管的形成。然而，哮喘患者支气管动脉的变化尚未得到明确阐明。我们研究了支气管动脉是否发生结构变化，以及cyclo-VEGI在慢性哮喘小鼠模型（）和人成纤维细胞（）中的作用。以卵清蛋白（OVA）作为致敏变应原的经过验证的过敏性气道炎症小鼠模型用于该研究。在OVA激发期间，小鼠接受cyclo-VEGI或氟替卡松治疗。进行实验以确定弹性蛋白暴露后成纤维细胞是否增殖以及cyclo-VEGI对其的影响。OVA致敏和激发导致血管周围平滑肌面积增大、弹性纤维增多以及血管细胞黏附分子（VCAM）-1抗原表达升高。这些现象表明支气管动脉发生了变化。cyclo-VEGI和氟替卡松治疗均抑制气道高反应性和炎症。接受cyclo-VEGI治疗的小鼠血管周围平滑肌面积、弹性纤维和VCAM-1表达降低。接受氟替卡松治疗的小鼠血管周围平滑肌减少，但血管周围弹性蛋白或VCAM-1表达未降低。此外，弹性蛋白处理可增强成纤维细胞增殖，而cyclo-VEGI处理可抑制这种增殖。弹性蛋白处理的成纤维细胞中嗜酸性粒细胞趋化因子表达升高，而cyclo-VEGI处理则降低。在我们的慢性哮喘小鼠模型中发生了血管重塑。cyclo-VEGI可通过抑制VCAM-1表达和支气管动脉周围弹性蛋白沉积来减轻气道炎症和高反应性。
