Decitabine Reactivation of FoxM1-Dependent Endothelial Regeneration and Vascular Repair for Potential Treatment of Elderly ARDS and COVID-19 Patients

Huang, Xiaojia; Zhang, Xianming; Machireddy, Narsa; Mutlu, Gökhan M.; Fang, Yun; Wu, David; Zhao, You-Yang

Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS) and COVID-19. We repot that aging impairs the intrinsic FoxM1-dependent endothelial regeneration and vascular repair program and causes persistent lung injury and high mortality following sepsis. Therapeutic gene transduction of FOXM1 in vascular endothelium or treatment with FDA-approved drug Decitabine was sufficient to reactivate FoxM1-dependent lung endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. In COVID-19 lung autopsy samples, FOXM1 expression was not induced in vascular endothelial cells of elderly patients in contrast to mid-age patients. Thus, Decitabine reactivation of FoxM1-dependent vascular repair represents a potential effective therapy for elderly COVID-19 and non-COVID-19 ARDS patients.