PKC inhibition as a novel medical countermeasure for radiation-induced vascular damage

摘要

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. PKC 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 PKC 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 PKC inhibitor for an additional 24 h. Under physiologic shear flow, the role of PKC on endothelium function and neutrophil adherence/migration was determined. PKC 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 PKC inhibition in a flow-dependent manner. PKC inhibition downregulated IR-induced P-selectin, intercellular adhesion molecule 1, and VCAM-1 but not E-selectin overexpression. PKC 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. PKC inhibition as a novel medical countermeasure for radiation-induced vascular damage.