AZD 9668, a neutrophil elastase inhibitor, promotes wound healing in the irradiated skin by inhibiting NET-derived vascular dysfunction

Despite the increasing awareness of the health risks associated with radiation exposure such as radiotherapy and accidents, effective treatments remain limited except for bone marrow damage. Radiation-induced skin damage is a critical concern as it is often accompanied by severe inflammation and delayed wound healing. Endothelial cells have emerged as a promising therapeutic target for addressing such radiation-induced damage. Neutrophils, as key mediators of the early inflammatory response, play a pivotal role in this process. The formation of neutrophil extracellular trap (NET) is particularly noteworthy, as it may directly contribute to exacerbating vascular damage. However, studies specifically exploring the role of NETs in radiation-induced skin injury and their impact on endothelial barrier function are limited. Therefore, this study aimed to evaluate the use of AZD9668, an orally administered NE inhibitor, as a therapeutic agent to mitigate NET-induced endothelial and skin damage. Irradiated skin showed increased neutrophil infiltration, NET formation, and vascular permeability in the mouse model. Neutrophil Elastase (NE) inhibitor, AZD9668, decreased NET formation and NET-derived NE activity. And AZD9668 treatment restored endothelial dysfunction and regulated antioxidative factors in NET-treated irradiated HUVECs. In mouse model of radiation-induced skin injury, oral administration of AZD9668 improved endothelial tight junction expression, vascular leakage, and inflammatory reaction. Therefore, skin wound healing accelerated in the AZD9668-treated group. This study highlights the critical role of NET in radiation-induced skin damage and endothelial barrier disruption, addressing a previously underexplored area. AZD9668 effectively mitigated radiation-induced damage by preventing NET formation, preserving tight junction integrity, and reducing inflammation. These findings underscore the therapeutic potential of NET and NET-derived NE in the management of radiation-induced vascular and skin injuries.