Shahana Perveen1, Kamesh Ayasolla2, Nahla Zagloul2, Hardik Patel2, Kanta Ochani3, David Orner2, Helene Benveniste4, Michael Salerno5, Paul Vaska5,6, Zhang Zuo7, Yousef Alabed8, Mansoor Nasim9, Edmund J Miller3, Mohamed Ahmed2. 1. Division of Neonatal-Perinatal Medicine, Cohen Children's Medical Center, and Lilling Family Neonatal Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA. sperveen1@northwell.edu. 2. Division of Neonatal-Perinatal Medicine, Cohen Children's Medical Center, and Lilling Family Neonatal Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA. 3. Heart and Lung Research Unit, Feinstein Institute for Medical Research, Manhasset, NY, USA. 4. Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA. 5. Department of Radiology, Stony Brook University, Stony Brook, NY, USA. 6. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA. 7. Department of Chemistry, Stony Brook University, Stony Brook, NY, USA. 8. Department of Medicinal Chemistry, Center for Molecular Innovation, Manhasset, NY, USA. 9. Department of Pathology, Northwell Health, New Hyde Park, NY, USA.
Abstract
BACKGROUND: Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN. We hypothesized that antenatal inhibition of MIF in CDH fetuses, would reduce vascular remodeling, and improve angiogenesis and lung development. METHODS: Pregnant rats were randomized into three groups: Control, nitrofen, and nitrofen + ISO-92. Lung volumes of pups were measured by CT scanning. Right ventricular systolic pressure (RVSP) and vascular wall thickness (VWT) were measured together with MIF concentration, angiogenesis markers, lung morphometry, and histology. RESULTS: Prenatal treatment with ISO-92, an MIF inhibitor, improved normalization of static lung volume, lung volume-to-body weight ratio, decreased alveolar septal thickness, RVSP and VWT and improved radial alveolar count as compared to the non-treated group. Expression of MIF was unaffected by ISO-92; however, ISO-92 increased p-eNOS and VEGF activities and reduced arginase 1, 2 and Sflt-1. CONCLUSION: Prenatal inhibition of MIF activity in CDH rat model improves angiogenesis and lung development. This selective intervention may be a future therapeutic strategy to reduce the morbidity and mortality of this devastating condition.
BACKGROUND:Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN. We hypothesized that antenatal inhibition of MIF in CDH fetuses, would reduce vascular remodeling, and improve angiogenesis and lung development. METHODS: Pregnant rats were randomized into three groups: Control, nitrofen, and nitrofen + ISO-92. Lung volumes of pups were measured by CT scanning. Right ventricular systolic pressure (RVSP) and vascular wall thickness (VWT) were measured together with MIF concentration, angiogenesis markers, lung morphometry, and histology. RESULTS: Prenatal treatment with ISO-92, an MIF inhibitor, improved normalization of static lung volume, lung volume-to-body weight ratio, decreased alveolar septal thickness, RVSP and VWT and improved radial alveolar count as compared to the non-treated group. Expression of MIF was unaffected by ISO-92; however, ISO-92 increased p-eNOS and VEGF activities and reduced arginase 1, 2 and Sflt-1. CONCLUSION: Prenatal inhibition of MIF activity in CDH rat model improves angiogenesis and lung development. This selective intervention may be a future therapeutic strategy to reduce the morbidity and mortality of this devastating condition.
Authors: Maria Hurskainen; Ivana Mižíková; David P Cook; Noora Andersson; Chanèle Cyr-Depauw; Flore Lesage; Emmi Helle; Laurent Renesme; Robert P Jankov; Markku Heikinheimo; Barbara C Vanderhyden; Bernard Thébaud Journal: Nat Commun Date: 2021-03-10 Impact factor: 14.919