Circulating microRNAs are associated with Pulmonary Hypertension and Development of Chronic Lung Disease in Congenital Diaphragmatic Hernia

Marisol Herrera-Rivero,Rong Zhang,Andreas Mueller,Florian Kipfmueller,Stefan Holdenrieder,Heiko M Reutter,Stefanie Heilmann-Heimbach,Till Dresbach,Lukas Schröder,Soyhan Bagci

doi:10.1038/s41598-018-29153-8

Marisol Herrera-Rivero, Rong Zhang + Show 8 more

Open Access

https://doi.org/10.1038/s41598-018-29153-8

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Abstract

Pulmonary hypertension (PH) contributes to high mortality in congenital diaphragmatic hernia (CDH). A better understanding of the regulatory mechanisms underlying the pathology in CDH might allow the identification of prognostic biomarkers and potential therapeutic targets. We report the results from an expression profiling of circulating microRNAs (miRNAs) in direct post-pulmonary blood flow of 18 CDH newborns. Seven miRNAs differentially expressed in children that either died or developed chronic lung disease (CLD) up to 28 days after birth, compared to those who survived without developing CLD during this period, were identified. Target gene and pathway analyses indicate that these miRNAs functions include regulation of the cell cycle, inflammation and morphogenesis, by targeting molecules responsive to growth factors, cytokines and cellular stressors. Furthermore, we identified hub molecules by constructing a protein-protein interaction network of shared targets, and ranked the relative importance of the identified miRNAs. Our results suggest that dysregulations in miRNAs let-7b-5p, -7c-5p, miR-1307-3p, -185-3p, -8084, -331-3p and -210-3p may be detrimental for the development and function of the lungs and pulmonary vasculature, compromise cardiac function and contribute to the development of CLD in CDH. Further investigation of the biomarker and therapeutic potential of these circulating miRNAs is encouraged.

Highlights

The development of chronic lung disease (CLD) can be considered to be, in a large proportion, induced by the morphological changes leading to Pulmonary hypertension (PH) and lung hypoplasia, and mechanical ventilation-induced lung damage[7,8]
Animal and cellular models of PH suggest that dysregulations of certain miRNAs contribute to the pathogenesis of PH, which might be a predecessor of the development of CLD in CDH5
We identified seven miRNAs differentially expressed at 24 h of life in the blood of congenital diaphragmatic hernia (CDH) newborns who developed CLD or died within 28 days after birth, and showed that these correlate with different measures of pulmonary dysfunction, and interconnect to participate in processes crucial to establish proper morphology and function of the heart and lungs

Summary

Introduction

The development of CLD can be considered to be, in a large proportion, induced by the morphological changes leading to PH and lung hypoplasia, and mechanical ventilation-induced lung damage[7,8]. The understanding of the underlying mechanisms for the development of CLD in CDH might lead to the identification of novel biomarkers and drug targets to therapeutically promote lung and vascular growth, which may improve outcome of CDH11. MicroRNAs (miRNAs), a class of non-coding RNAs that suppress gene translation (most commonly through promoting mRNA degradation or disrupting mRNA translation), might serve as biomarker for disease severity in CDH5. In the present preliminary study, we sought to identify circulating miRNAs as a potential biomarker associated with severe outcomes in CDH newborns, and to uncover specific contributor genes and biological pathways that may aid our understanding of the condition

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