Lipopolysaccharide-induced murine lung injury results in long-term pulmonary changes and downregulation of angiogenic pathways

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Abstract

Acute respiratory distress syndrome is the most severe form of acute lung injury (ALI) and is associated with significant mortality. Lipopolysaccharide (LPS)-induced injury is a valuable murine model of ALI but there is a paucity of data on lung regeneration and the role of angiogenic signaling involving vascular endothelial growth factor (VEGF). Eight-week-old male C57BL/6J mice were randomized to receive intratracheal instillation of either LPS or isovolumetric phosphate buffered saline as a vehicle control. Mice were observed at a single follow-up time-point that was either short-term (24 h or 4 days) or long-term (7 days or 4 weeks). On pulmonary function testing, LPS-treated mice had increased compliance at 4 weeks post-instillation, which correlated with decreased vascularization and with time-dependent, progressive decrease in alveolarization. Treadmill exercise tolerance testing demonstrated impaired performance at 24 h, 4 days and 4 weeks following LPS exposure. On lung protein analysis, LPS instillation decreased VEGF expression at up to 4 weeks, and decreased activation of its key receptor, VEGFR2 at 7 days and 4 weeks post-instillation. Together, these data provide insight on long-term pulmonary functional outcomes 4 weeks after ALI and identify angiogenic proteins as possible therapeutic targets following lung injury.

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Tsikis, S. T., Fligor, S. C., Hirsch, T. I., Pan, A., Yu, L. J., Kishikawa, H., … Puder, M. (2022). Lipopolysaccharide-induced murine lung injury results in long-term pulmonary changes and downregulation of angiogenic pathways. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-14618-8

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