KVX-053, a PTP4A3 Inhibitor, as a New Therapeutic Agent Against LPS-induced Lung Injury

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Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition caused by inflammatory insult to the lung parenchyma. It is characterized by hypoxemia secondary to the exudation of protein-rich fluid into alveolar spaces. ARDS treatment is limited to fluid management and oxygen therapy and exhibits an estimated 40% mortality rate. Lipopolysaccharide (LPS) is used as an ARDS model in animals and induces the severe inflammation, hyperpermeability hallmarks in the bronchoalveolary anatomy.

Protein Tyrosine Phosphatase inhibitors are novel therapeutics being investigated for their immunomodulatory effects on inflammation. In this study we employed KVX-053, a potent PTP4A3 inhibitor, as a potential treatment for ARDS.

C57BL/6j wild type mice were intratracheally instilled with saline or LPS (1 mg/kg, 2µl/g) and treated with KVX-053 (10 mg/kg/day i.p.) or vehicle. Then, molecular, functional, and histological signs of injury were investigated at 72 hours post-exposure. LPS elicited substantial proteinosis and cellularity (p≤ 0.001), remodeling of bronchoalveolar spaces, edema, neutrophil infiltration, and activation (phosphorylation) of proinflammatory proteins STAT3, NLRP3, and IKB (p ≤ 0.01, p ≤ 0.001, p ≤ 0.05). KVX-053 administration protected bronchoalveolar architecture and reduced both white blood cell and protein concentrations in broncho-alveolar lavage fluid (BALF) (p ≤ 0.001, p ≤ 0.05). Additionally, KVX-053 downregulated the LPS-induced expression of pSTAT3, and mmp8 (p ≤ 0.01, p≤ 0.05). This data suggests that KVX-053 blocks the activation of multiple inflammatory pathways and could represent a promising therapeutic strategy against the inflammatory effects of ARDS.


0000-0002-1705-027X (Solopov), 0000-0002-1174-3876 (Colunga Biancatelli), 0000-0002-5098-295X (Catravas)

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