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.
Infants with congenital diaphragmatic hernia (CDH) may require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We investigated the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. In vitro assays of lung endothelial cell proliferation and apoptosis were performed. C57BL/6 J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin and outcomes were assessed on postoperative day 8. Heparin administration inhibited endothelial cell proliferation in vitro and significantly decreased lung volume in vivo, while bivalirudin and argatroban preserved lung growth. These findings correlated with changes in alveolarization on morphometric analysis. Treadmill exercise tolerance testing demonstrated impaired exercise performance in heparinized mice; bivalirudin/argatroban did not affect exercise tolerance. On lung protein analysis, heparin decreased angiogenic signaling which was not impacted by bivalirudin or argatroban. Together, this data supports the use of DTIs as alternatives to heparin for systemic anticoagulation in CDH patients on bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted.
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