PMID- 36195630 OWN - NLM STAT- MEDLINE DCOM- 20230703 LR - 20230703 IS - 1530-0447 (Electronic) IS - 0031-3998 (Linking) VI - 93 IP - 7 DP - 2023 Jun TI - Effects of systemic anticoagulation in a murine model of compensatory lung growth. PG - 1846-1855 LID - 10.1038/s41390-022-02323-1 [doi] AB - BACKGROUND: Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG). METHODS: Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined. RESULTS: UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls. CONCLUSIONS: UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia. IMPACT: Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes. CI - (c) 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc. FAU - Yu, Lumeng J AU - Yu LJ AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Ko, Victoria H AU - Ko VH AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Tsikis, Savas T AU - Tsikis ST AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Dao, Duy T AU - Dao DT AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Secor, Jordan D AU - Secor JD AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Pan, Amy AU - Pan A AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Cho, Bennet S AU - Cho BS AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Michell, Paul D AU - Michell PD AD - Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA. FAU - Fligor, Scott C AU - Fligor SC AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Kishikawa, Hiroko AU - Kishikawa H AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. FAU - Puder, Mark AU - Puder M AD - Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. mark.puder@childrens.harvard.edu. AD - Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA, USA. mark.puder@childrens.harvard.edu. LA - eng PT - Journal Article DEP - 20221004 PL - United States TA - Pediatr Res JT - Pediatric research JID - 0100714 RN - 9005-49-6 (Heparin) RN - 0 (Heparin, Low-Molecular-Weight) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (Anticoagulants) SB - IM MH - Animals MH - Mice MH - *Heparin/pharmacology MH - Heparin, Low-Molecular-Weight/pharmacology MH - Vascular Endothelial Growth Factor A MH - Endothelial Cells MH - Disease Models, Animal MH - Anticoagulants/pharmacology MH - Lung MH - *Hernias, Diaphragmatic, Congenital EDAT- 2022/10/05 06:00 MHDA- 2023/07/03 06:41 CRDT- 2022/10/04 23:19 PHST- 2022/05/08 00:00 [received] PHST- 2022/09/11 00:00 [accepted] PHST- 2022/09/06 00:00 [revised] PHST- 2023/07/03 06:41 [medline] PHST- 2022/10/05 06:00 [pubmed] PHST- 2022/10/04 23:19 [entrez] AID - 10.1038/s41390-022-02323-1 [pii] AID - 10.1038/s41390-022-02323-1 [doi] PST - ppublish SO - Pediatr Res. 2023 Jun;93(7):1846-1855. doi: 10.1038/s41390-022-02323-1. Epub 2022 Oct 4.