PKCδ inhibition as a novel medical countermeasure for radiation‐induced vascular damage

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. FASEB J. 32, 6436–6444 (2018). www.fasebj.org