MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia

Shahana Perveen, Kamesh Ayasolla, Nahla Zagloul, Hardik Patel, Kanta Ochani, David Orner, Helene Benveniste, Michael Salerno, Paul Vaska, Zhang Zuo, Yousef Alabed, Mansoor Nasim, Edmund J. Miller, Mohamed Ahmed

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)711-718
Number of pages8
JournalPediatric Research
Volume85
Issue number5
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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