The pyruvate kinase activator etavopivat (FT-4202) limits pulmonary and systemic sequelae of sepsis in a mouse LPS model.
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2026-06
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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.
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Chen, Youwei, Hongmei Zhu, Lisheng Zhang, Weijia Mai, Shein-Chung Chow, Desmond Wai Loon Chin, Sylvie Guichard, Marcus Carden, et al. (2026). The pyruvate kinase activator etavopivat (FT-4202) limits pulmonary and systemic sequelae of sepsis in a mouse LPS model. American journal of physiology. Lung cellular and molecular physiology, 330(6). pp. L673–L684. 10.1152/ajplung.00389.2025 Retrieved from https://hdl.handle.net/10161/34802.
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Scholars@Duke
Lisheng Zhang
My research efforts involves studying the pathogenesis of vein graft neointimal hyperplasia and atherosclerosis.
The greatest amount of my time in the past years has been devoted to developing and characterizing our interposition vein graft model in mice. This model allows us to use IVC to carotid artery transplants between congenic mice. These transplants allow us to ask the questions about which gene products contribute to the pathogenesis of vein graft disease. In addition, I have used carotid artery to carotid artery transplants to study the role of TNF receptors in atherosclerosis. For these studies, we have used apolipoprotein E-deficient mice as graft recipients.
By using mouse vein graft model we demonstrate that most of the neointimal cells in vein grafts originate from cellular pools outside of the vein graft at the time of its implantation. The importance of this work relates to our persistent inability to treat vein graft disease in human beings. The second work demonstrates that expression of the tumor necrosis factor receptor-1, even in just in the vein graft cells themselves, contributes to the pathogenesis of vein graft neointimal hyperplasia. In this project, I surgically created chimeric mice to demonstrate molecular mechanisms by which the tumor necrosis factor receptor-1 aggravates neointimal hyperplasia, a process that is believed to lay the foundation for accelerated atherosclerosis in vein grafts.
I have also adapted my vein graft procedure in mice to ask questions about the arterial wall’s role in atherosclerosis. This atherosclerosis model involves making carotid interposition grafts not with veins, but with the carotid artery of congenic mice, and placing them into the carotid artery of spontaneously atherogenic mice that are deficient in apolipoprotein E.
I plan to continue our studies related to the role of inflammatory cytokine receptors in neointimal hyperplasia and atherosclerosis. In addition, I envision extending this work with the surgical models I have created in mice.
Shein-Chung Chow
My research interest includes statistical methodology development and application in the area of biopharmaceutical/clinical statistics such as bioavailability and bioequivalence, clinical trials, bridging studies, medical devices, and translational research/medicine. Most recently, I am interested in statistical methodology development for the use of adaptive design methods in clinical trials and methodology development for assessment of biosimilarity of follow-on biologics. In addition, I am also interested in methodology development for statistical evaluation of traditional Chinese medicine (TCM) clinical trials.
Ian James Welsby
As a practicing cardiothoracic anesthesiologist, I have contributed to the better understanding of the management and of perioperative thrombosis (particularly HIT). This has been as a Duke site PI for the Rare Thrombotic Diseases Consortium led by Dr T.L Ortel and a clinical collaborator with the basic and translational science approach to HIT led by Dr G Arepally. I have also championed novel approaches to dealing with perioperative HIT such as plasmaperesis.
Similarly, I have been a local leader in establishing management of transfusion approaches to major cardiac surgery including the novel introduction of autologous plateletpheresis to limit exposure to allogeneic platelet transfusions in this highly transfused population, identifying the transfusion requirements during thoracic aortic reconstruction and promoting use of a lower dose of rFVIIa use in this population, changing established clinical practice.
My research interests focus on perioperative transfusion and hematology concerns. Recently, Dr Kor (Mayo Clinic) and I received a multiple PI R-01 award to evaluate point-of-care/bedside washing of packed red blood cells to reduce perioperative lung injury. This novel repurposing of commonly available “cell-saver” technology is, for most surgical cases, the only practical means of delivering a washed product, and promises to be a critical advancement in perioperative transfusion medicine. I also have a longstanding interest in the rejuvenation of RBCs to normalize oxygen delivery capacity of transfused RBCs. Such a development will be of tremendous importance to transfusion practice, particularly for highly transfused populations and with current threats to blood banking inventory.
In summary, I have dedicated my research career to improving the outcome of patients undergoing cardiothoracic surgery, understanding perioperative coagulopathy, and optimizing transfusion practice.
Timothy Joseph McMahon
The McMahon Lab at Duke University and Durham VA Medical Center is investigating novel roles of the red blood cell (RBC) in the circulation. The regulated release of the vasodilator SNO (a form of NO, nitric oxide) by RBCs within the respiratory cycle in mammals optimizes nutrient delivery at multiple levels, especially in the lung (gas exchange) and the peripheral microcirculation (O2 transport to tissues). Deficiency of RBC SNO bioactivity (as in human RBCs banked for transfusion), for example, appears to contribute to the serious lung and circulatory problems associated with RBC transfusion in some settings. We have also demonstrated benefit in the use of treatments that exploit RBCs as a vehicle for delivery of SNOs, in both human patients and in model animals.
RBCs also release ATP in response to stimuli including deformation and hypoxia, and the exported ATP also participates in the maintenance of a healthy circulation, according to mechanisms that we are now unraveling.
We use basic and translational approaches to understand the molecular mechanisms by which these RBC-derived signals effect circulatory changes in human health and disease, particularly in the lung. Disease states driving this research include acute and chronic lung diseases such as sepsis (severe infection, such as COVID-19), transfusion-related respiratory problems, sickle cell disease, and pulmonary hypertension of adults and newborns.
Funding: VA and NIH.
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