Département Effets Biologiques des Rayonnements, unité de Radiobiologie, IRBA (Institut de Recherche Biomédicale des Armées), Brétigny-sur-Orge, France.
INSERM unité mixte de Recherche-Santé 1176, université Paris-Saclay, Le Kremlin-Bicêtre, France.
Biochem Biophys Res Commun. 2022 Apr 30;602:127-134. doi: 10.1016/j.bbrc.2022.02.096. Epub 2022 Feb 25.
The immunosuppressant drug Cyclosporin A (CsA) has been widely used to prevent the development of Graft-versus-Host Disease (GvHD) that can occur after transplantation, including allogeneic graft after accidental high-dose irradiation in humans. Here, we show that CsA alone stimulates ICAM-1 overexpression in human pulmonary microvascular endothelial cells (HPMECs) through Toll-Like Receptor 4 (TLR4) and NF-κB activation. In HPMECs, CsA treatment significantly worsened the overexpression of ICAM-1 induced by high-dose irradiation (15 Gy). This additive effect of CsA was also observed when ICAM-1 overexpression was induced by another pathway (Ca entry) in macrovascular endothelial cells. In addition, CsA triggered apoptosis as well as rearrangement of the actin cytoskeleton and adherens junctions (VE-Cadherin) in microvascular endothelial monolayers. High-dose irradiation triggered similar deleterious effects in endothelial monolayers and, again, CsA treatment strongly aggravated the effects of irradiation. Altogether, these results suggest that post-transplant CsA treatment may exacerbate the deleterious effects of irradiation on the endothelium.
免疫抑制剂环孢素 A（CsA）已被广泛用于预防移植物抗宿主病（GvHD）的发生，包括人类意外大剂量照射后的同种异体移植物。在这里，我们表明 CsA 可通过 Toll 样受体 4（TLR4）和 NF-κB 激活单独刺激人肺微血管内皮细胞（HPMEC）中细胞间黏附分子 1（ICAM-1）的过度表达。在 HPMEC 中，CsA 处理显著加重了高剂量照射（15Gy）诱导的 ICAM-1 过度表达。在大血管内皮细胞中，当 ICAM-1 过度表达由另一种途径（Ca 内流）诱导时，也观察到 CsA 的这种附加作用。此外，CsA 在微血管内皮单层中触发细胞凋亡以及肌动蛋白细胞骨架和黏附连接（VE-钙黏蛋白）的重排。高剂量照射在内皮单层中引发类似的有害作用，并且 CsA 处理强烈加剧了照射的作用。总之，这些结果表明移植后 CsA 治疗可能会加剧照射对内皮的有害影响。
