The Pyruvate Kinase Activator Etavopivat (FT-4202) Limits Pulmonary and Systemic Sequelae of Sepsis in a Mouse LPS Model

Sepsis is frequently characterized by abnormal O 2 uptake by red blood cells (RBCs) in the lung and/or dysregulated tissue O 2 delivery by RBCs. New approaches are needed to improve O 2 transport and clinical outcomes in sepsis with or without anemia. FT-4202 (etavopivat) is an allosteric RBC pyruvate kinase (PKR) activator (PKRA) previously shown to increase RBC ATP and decrease 2,3-BPG (bisphosphoglycerate), a negative allosteric effector of O2-binding by hemoglobin. We hypothesized that PKR activation could mitigate LPS (lipopolysaccharide)-induced sepsis/ALI (acute lung injury) by preserving ATP and/or lowering BPG levels to promote O 2 uptake. We measured systemic (body weight change, cytokines), renal/inflammatory (neutrophil gelatinase-associated lipocalin; NGAL), and respiratory responses to LPS ± FT-4202. FT-4202 protected mice from LPS-induced weight loss but not the hypoxemia. LPS-induced increases in albumin and neutrophilic myeloperoxidase (MPO) in mouse bronchoalveolar lavage fluid were significantly blunted in mice pre-treated with FT-4202. FT-4202 attenuated LPS-induced elevations in the proinflammatory cytokines IFN-γ, IL-6, and TNF-α. FT-4202 attenuated LPS-induced elevations in the acute kidney injury (and/or inflammatory) marker NGAL. In RBCs from healthy mice, ex vivo FT-4202 treatment significantly increased intra-RBC ATP and ATP export. We conclude that the PKRA FT-4202 protected against systemic and respiratory (capillary permeability and neutrophil influx) features of sepsis induced by LPS in mice. FT-4202 promoted RBC ATP generation and export ex vivo, which could contribute to the favorable effects in LPS-induced sepsis.