The pyruvate kinase activator etavopivat (FT-4202) limits pulmonary and systemic sequelae of sepsis in a mouse LPS model.

Abstract

Sepsis is frequently characterized by abnormal O2 uptake by red blood cells (RBCs) in the lung and/or dysregulated tissue O2 delivery by RBCs. New approaches are needed to improve O2 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-bisphosphoglycerate (2,3-BPG), a negative allosteric effector of O2-binding by hemoglobin. We hypothesized that PKR activation could mitigate lipopolysaccharide (LPS)-induced sepsis/acute lung injury (ALI) by preserving ATP and/or lowering BPG levels to promote O2 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 hypoxemia. LPS-induced increases in albumin and neutrophilic myeloperoxidase (MPO) in mouse bronchoalveolar lavage fluid were significantly blunted in mice pretreated 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.NEW & NOTEWORTHY Etavopivat (FT-4202), a RBC-selective pyruvate kinase activator (PKRA), limited weight loss, inflammatory cytokines, neutrophil gelatinase-associated lipocalin (NGAL) elevation, and neutrophilia in a mouse sepsis model. We show for the first time that a PKRA promotes ATP export from mouse RBCs, and this could contribute to the benefits of this RBC-directed therapeutic.