Post-Exposure JNJ-26366821 Treatment Attenuates Systemic Inflammation and Limits Cardiotoxic Risk.

INTRODUCTION: Thrombopoietin mimetics (TPOm) are known to increase blood cell counts, thereby ameliorating various diseases, including cardiomyopathy-a leading cause of mortality because of delayed radiotoxic effects. Previous preclinical studies demonstrated significant survival enhancement following lethal radiation exposure with a single dose of JNJ-26366821 in two mouse strains, CD2F1 and C57BL/6. MATERIALS AND METHODS: In this study, a single dose of JNJ-26366821 (1.0 mg/kg) or saline was administered 24 h post-8.0 Gy total body irradiation (TBI) to male C57BL/6 mice. Mice were euthanized on days 1, 7, 15, and 30 post-TBI, and serum and heart samples were collected. Unirradiated mice treated with saline served as baseline controls. Inflammatory serum cytokines/chemokines, growth factors and multi-omics analyses, including proteomics, metabolomics, and lipidomics, were evaluated to assess therapeutic impacts. RESULTS: JNJ-26366821 demonstrated overall positive effects, restraining radiation-induced inflammatory surges by 7 days post-TBI. Functional analysis revealed that JNJ-26366821 treatment in unirradiated mice activated cellular homeostasis, which persisted after post-exposure intervention in irradiated mice. The drug immediately reduced cell death, but networks supporting cardiovascular health, such as angiogenesis and vasculogenesis, remained inhibited 2 h post-intervention. By 7 days post-TBI, JNJ-26366821 mobilized molecules in heart tissue to reconstitute cellular development and maintenance. Protein synthesis and metabolism were activated between 15 and 30 days post-TBI, potentially compensating for radiation-induced muscle wasting. CONCLUSIONS: JNJ-26366821 demonstrated promising mitigating effects on cellular homeostasis and cardiovascular health when administered as a single dose at 24 h post-exposure.