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• W4387247904 abstract "SESSION TITLE: Pathology of Lung Disease: Under the Microscope SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/10/2023 12:55 pm - 01:40 pm PURPOSE: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition, with up to 40% mortality. Due to the COVID-19 pandemic ARDS incidence has increased dramatically. One newly discovered player in ARDS pathophysiology is extracellular vesicles (EVs), biologically active liposome-like particles, ubiquitously produced by cells. EVs have been shown to increase endothelial permeability and to induce alveolo-capillary barrier dysfunction, responsible for fluid leak into the alveolar space leading to respiratory failure. Protein Tyrosine Phosphatase Type IVA3 (PTP4A3, also known as PRL-3) is involved in several cellular processes, some of which require association with plasma membrane via its prenylation moiety. This is the case for its involvement with early endosome formation. We hypothesized that KVX-053, a novel selective PTP4A3 inhibitor, via inhibition of the early endocytic pathway, would impact EVs internalization and subsequent cargo release. We further hypothesized that the resultant lower EV uptake will result in a tighter endothelial barrier and reduced permeability in human lung microvascular endothelial cells (HLMVEC). We tested this hypothesis in vitro in (HLMVEC) and in a mouse model of ARDS. METHODS: EVs were isolated from healthy controls or patients with sepsis-related ARDS admitted to the ICU of Sentara Norfolk General Hospital and characterized regarding their concentration and size. HLMVEC monolayers were incubated with EVs and KVX-053. The ability of KVX-053 to block EV uptake was measured using imaging flow cytometry assay (AMNIS Image Stream Mark II). The functional effect of EVs on HLMVEC barrier function was measured using an Electric Cells-Substrate Impedance Sensing (ECIS) assay, following pre-treatment with KVX-053 (5-10 µM) or vehicle. Finally, to test its therapeutic potential in vivo, wild type mice where intratracheally instilled with lipopolysaccharide (1 mg/kg), treated with KVX-053 (10 mg/kg/day, i.p.) or vehicle, and histological and molecular (Western Blotting) outcomes were investigated 72 hours after. RESULTS: EVs isolated from patients with ARDS showed higher circulating concentration but smaller size compared to healthy controls and were able to dose-dependently provoke endothelial barrier dysfunction in HLMVEC. Pre-treatment with KVX-053 (24h, 10 µM) was able to significantly reduce EV uptake and protected HLMVEC from EV-induced endothelial barrier dysfunction. KVX-053 ameliorated lipopolysaccharide-induced alveolar inflammation, proteinosis, neutrophil infiltration, cellular lung injury, and the activation (phosphorylation) of pro-inflammatory STAT3 pathway in mice. CONCLUSIONS: Our preliminary data suggest that KVX-053 inhibits the uptake of circulating EVs, their harmful effects on lung endothelial barrier function, and the development of ARDS in mice. CLINICAL IMPLICATIONS: KVX-053 represents a promising, novel therapeutic approach for mitigating pulmonary inflammation in ARDS. Further study in this area is warranted. DISCLOSURES: No relevant relationships by Matthew Bavuso No relevant relationships by John Catravas No relevant relationships by Ruben Manuel Luciano Colunga Biancatelli No disclosure on file for Anca Dobrian No disclosure on file for John Lazo No relevant relationships by Noel Miller Owner/Founder relationship with KeViRx, Inc. Please note: 2016-present Added 03/15/2023 by Elizabeth Sharlow, source=Web Response, value=Salary No relevant relationships by Joshua Sill, value=Honoraria Removed 03/15/2023 by Joshua Sill, source=Web Response No relevant relationships by Pavel Solopov" @default.
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• W4387247904 date "2023-10-01" @default.
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• W4387247904 title "KVX-053, A PTP4A3 INHIBITOR, MODULATES THE ENDOCYTIC PATHWAY, EXTRACELLULAR VESICLE UPTAKE, ENDOTHELIAL BARRIER DYSFUNCTION, AND THE DEVELOPMENT OF ARDS IN VITRO AND IN VIVO" @default.
• W4387247904 doi "https://doi.org/10.1016/j.chest.2023.07.2959" @default.
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