Authors:

Raman Ghotra Singh

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About Paper:

Severe COVID-19 pneumonia causes persistent damage to the alveolar epithelium, disrupting the alveolar-capillary barrier and leading to pulmonary edema. Despite the role of endothelial dysfunction in COVID-19 pathology, only a few therapeutic strategies specifically target vascular repair mechanisms. The goal of this study was to determine whether VT-109, an allosteric inhibitor of end-binding protein-3 (EB3) that blocks pathological calcium signaling in endothelial cells and stabilizes VE-cadherin junctions, can restore lung vascular integrity and support epithelial repair following COVID-19-related lung injury. Using preclinical models of SARS-CoV-2 pneumonia, we assessed pulmonary vascular leakage, lung edema, and structural injury to both endothelial and epithelial barriers. VT-109 treatment was administered following infection, and outcomes were measured using albumin extravasation assays, histological analysis, and bronchoalveolar lavage protein quantification. VT-109 treatment significantly reduced albumin extravasation, indicating restoration of endothelial barrier function. Importantly, VT-109 promoted regeneration of damaged alveolar epithelial cells, resulting in improved lung structure and function, assessed by histopathological scoring. Mechanistically, VT-109 inhibited calcium-dependent NFAT/NFKB signaling in endothelial cells, promoting reannealing of VE-cadherin junctions. Results in mice model of COVID-19 demonstrated that VT-109 rapidly restored the pulmonary endothelial barrier as reduced protein levels in bronchoalveolar lavage. These results identify endothelial calcium signaling as a key regulator of lung barrier dysfunction in COVID-19 and establish VT-109 as a promising therapeutic candidate capable of accelerating recovery by promoting vascular repair. This work advances our understanding of post-acute sequelae of COVID-19 and provides a mechanistic foundation for developing targeted therapies that address persistent lung injury. This work was supported by the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (Award No. W81XWH-21-1-0639). Opinions and recommendations are those of the author, not necessarily endorsed by the Department of Defense. Animal research adhered to U.S. laws and Department of Agriculture regulations.

Source:

University of Illinois Chicago

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Co-authors:

Raman Ghotra Singh