Soroush Fariborz, Tang Yuan, Zaidi Hasan M, Sheffield Joel B, Kilpatrick Laurie E, Kiani Mohammad F
Department of Mechanical Engineering, College of Engineering, Temple University, Philadelphia, Pennsylvania, USA.
Department of Bioengineering, College of Engineering, Temple University, Philadelphia, Pennsylvania, USA.
FASEB J. 2018 Jun 13:fj201701099. doi: 10.1096/fj.201701099.
In the event of a radiologic catastrophe, endothelial cell and neutrophil dysfunction play important roles in tissue injury. Clinically available therapeutics for radiation-induced vascular injury are largely supportive. PKCδ was identified as a critical regulator of the inflammatory response, and its inhibition was shown to protect critical organs during sepsis. We used a novel biomimetic microfluidic assay (bMFA) to interrogate the role of PKCδ in radiation-induced neutrophil-endothelial cell interaction and endothelial cell function. HUVECs formed a complete lumen in bMFA and were treated with 0.5, 2, or 5 Gy ionizing radiation (IR). At 24 h post-IR, the cells were treated with a PKCδ inhibitor for an additional 24 h. Under physiologic shear flow, the role of PKCδ on endothelium function and neutrophil adherence/migration was determined. PKCδ inhibition dramatically attenuated IR-induced endothelium permeability increase and significantly decreased neutrophil migration across IR-treated endothelial cells. Moreover, neutrophil adhesion to irradiated endothelial cells was significantly decreased after PKCδ inhibition in a flow-dependent manner. PKCδ inhibition downregulated IR-induced P-selectin, intercellular adhesion molecule 1, and VCAM-1 but not E-selectin overexpression. PKCδ is an important regulator of neutrophil-endothelial cell interaction post-IR, and its inhibition can serve as a potential radiation medical countermeasure.-Soroush, F., Tang, Y., Zaidi, H. M., Sheffield, J. B., Kilpatrick, L. E., Kiani, M. F. PKCδ inhibition as a novel medical countermeasure for radiation-induced vascular damage.
在发生放射灾难时，内皮细胞和中性粒细胞功能障碍在组织损伤中起重要作用。临床上用于治疗辐射诱导的血管损伤的疗法大多只是支持性的。蛋白激酶Cδ（PKCδ）被确定为炎症反应的关键调节因子，其抑制作用在脓毒症期间可保护重要器官。我们使用一种新型的仿生微流控分析方法（bMFA）来探究PKCδ在辐射诱导的中性粒细胞与内皮细胞相互作用及内皮细胞功能中的作用。人脐静脉内皮细胞（HUVECs）在bMFA中形成完整的管腔，并接受0.5、2或5 Gy的电离辐射（IR）。在IR照射后24小时，细胞再用PKCδ抑制剂处理24小时。在生理剪切流条件下，确定PKCδ对内皮功能和中性粒细胞黏附/迁移的作用。抑制PKCδ可显著减轻IR诱导的内皮通透性增加，并显著减少中性粒细胞穿过经IR处理的内皮细胞的迁移。此外，抑制PKCδ后，中性粒细胞对受照射内皮细胞的黏附以流量依赖的方式显著降低。抑制PKCδ可下调IR诱导的P-选择素、细胞间黏附分子1和血管细胞黏附分子1的表达，但不会下调E-选择素的过表达。PKCδ是IR后中性粒细胞与内皮细胞相互作用的重要调节因子，抑制它可作为一种潜在的辐射医学对策。-索鲁什，F.，唐，Y.，扎伊迪，H.M.，谢菲尔德，J.B.，基尔帕特里克，L.E.，基亚尼，M.F.抑制PKCδ作为辐射诱导血管损伤的新型医学对策
