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

Vollständiger Abstract

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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.