RESUMEN

Modulating SYK has been demonstrated to have impacts on pathogenic neutrophil responses in COVID-19. During sepsis, neutrophils are vital in early bacterial clearance but also contribute to the dysregulated immune response and organ injury when hyperactivated. Here, we evaluated the impact of R406, the active metabolite of fostamatinib, on neutrophils stimulated by LPS. We demonstrate that R406 was able to effectively inhibit NETosis, degranulation, ROS generation, neutrophil adhesion, and the formation of CD16low neutrophils that have been linked to detrimental outcomes in severe sepsis. Further, the neutrophils remain metabolically active, capable of releasing cytokines, perform phagocytosis, and migrate in response to IL-8. Taken together, this data provides evidence of the potential efficacy of utilizing fostamatinib in bacterial sepsis.

Asunto(s)

Aminopiridinas , Lipopolisacáridos , Activación Neutrófila , Neutrófilos , Lipopolisacáridos/farmacología , Lipopolisacáridos/inmunología , Humanos , Neutrófilos/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Activación Neutrófila/efectos de los fármacos , Aminopiridinas/farmacología , Piridinas/farmacología , Quinasa Syk/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/efectos de los fármacos , Trampas Extracelulares/metabolismo , Fagocitosis/efectos de los fármacos , Morfolinas/farmacología , Interleucina-8/metabolismo , Pirimidinas/farmacología , SARS-CoV-2/inmunología , COVID-19/inmunología , Degranulación de la Célula/efectos de los fármacos , Sepsis/inmunología , Sepsis/tratamiento farmacológico , Receptores de IgG/metabolismo , Receptores de IgG/inmunología , Imidazoles/farmacología , Adhesión Celular/efectos de los fármacos