D101-11 The Ptp4a3 Inhibitor, Kvx-053, Protects Against the Development of Sepsis-induced Ali

Abstract Purpose Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), are major causes of mortality in patients with sepsis. The pathogenesis involves disruption of the pulmonary endothelial and epithelial barriers, leading to vascular leakage, inflammation, and respiratory failure. Despite advances in supportive care, no targeted pharmacological therapy currently exists to prevent or reverse sepsis-induced ALI. Protein tyrosine phosphatase 4A3 (PTP4A3; also known as PRL-3) has emerged as a key regulator of endothelial permeability and inflammatory signaling. Our recent work demonstrated that the PTP4A3 inhibitor, KVX-053, protects against lung injury induced by SARS-CoV-2 spike protein and live virus exposure. In the present study, we evaluated the therapeutic potential of KVX-053 in preventing sepsis-induced ALI using the cecal ligation 2-puncture (CL2P) mouse model. Methods C57Bl/6J mice were anesthetized with ketamine/xylazine (50 mg/kg and 3 mg/kg, i.p., respectively). Under aseptic conditions, a midline laparotomy was performed, and the cecum was ligated below the ileocecal valve and punctured twice with a 19-gauge needle. A small amount of cecal content was extruded before returning the cecum to the peritoneal cavity, and the incision was closed. Sham controls underwent laparotomy and ligation without cecal puncture. Mice received KVX-053 (1 mg/kg, i.v.) or vehicle at 1 h, 24 h, and 48 h post-surgery. After 72 h, airway mechanics were assessed by FlexiVent, and bronchoalveolar lavage fluid (BALF) and lung tissue were collected for histological and molecular analyses of sepsis-induced lung injury. Results In mice subjected to cecal ligation and puncture, sepsis induced marked physiological and histopathological signs of ALI. Animals exhibited significant weight loss and mortality, reduced pressure-volume (PV) loops, reduced static and dynamic compliance, and increased respiratory resistance and elastance. Histological analysis revealed alveolar wall thickening, edema, and inflammatory cell infiltration. BALF analysis showed elevated cellularity, protein concentration, and levels of proinflammatory cytokines, consistent with activation of inflammatory pathways in lung tissue. KVX-053 treatment significantly improved survival, restored lung mechanics, and reduced histological injury, BALF protein leakage, and cytokine production, indicating substantial protection against sepsis-induced ALI. Conclusions PTP4A3 contributes critically to sepsis-induced ALI. Pharmacologic inhibition with KVX-053 effectively mitigated pulmonary inflammation, vascular leakage, and mechanical dysfunction in CL2P mice. Targeting PTP4A3 may represent a novel therapeutic strategy to preserve lung function and improve outcomes in sepsis-associated ALI and related inflammatory lung disorders. This abstract is funded by: HT9425-24-1-0284