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Heparin Impairs Lung Development in Neonatal Mice
Thomas I Hirsch1,2, Savas T Tsikis,1,2, Sarah Z Wang1,2, Scott C Fligor1,2, Amy Pan1,2 Mikayla Quigley1,2, Srujan Dadi3, Paul D Mitchell4, and Mark Puder1,2 1Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA 2Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA 02115, USA 3Rowan-Virtua School of Osteopathic Medicine, Stratford, NJ 08084, USA 4Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA 02115, USA

Background: Preterm infants undergo rapid lung growth and alveolarization. This process is heavily dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling pathway. We previously demonstrated in a murine model, that compensatory lung growth (CLG) after left pneumonectomy is severely inhibited by systemic heparinization, which prevents VEGF receptor 2 (VEGFR2) activation. We hypothesized that heparin would also inhibit lung growth, pulmonary function, and decrease alveolarization in newborn mice.

Methods: Newborn C57BL/6J mice from two litters received either therapeutic heparin or normal saline (control) for the first seven days of life. On day 30, mice underwent lung volume measurement, pulmonary function testing, and morphometric analysis. A separate cohort of mice was sacrificed at day 7 to evaluate angiogenic signaling.

Results: Heparin administration decreased lung volume and produced an emphysematous lung phenotype characterized by decreased elastance, increased compliance and inspiratory capacity (A-D). On morphometric analysis, heparin decreased alveolar volume and septal surface area (E-F), the area available for gas exchange. At day 7 of life, heparin reduced activation of VEGFR2 (G).

Conclusion: Heparin administration in newborn mice impaired lung growth and function and reduced VEGFR2 activation, a key signaling pathway in lung growth and development. This data establishes the negative effect of heparin in normal developing mice. Based on this work, clinical studies on the effects of heparin in the infant population are warranted.
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