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PLoS One. 2018 Nov 12;13(11):e0206975. doi: 10.1371/journal.pone.0206975. eCollection 2018.

Prenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic hernia.

Author information

1
National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
2
Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.
3
The Royal London Hospital, London, United Kingdom.
4
Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
5
Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
6
Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom.
7
Agri-Food and Biosciences Institute, Belfast, Northern Ireland, United Kingdom.
8
School of Medicine and Medical Science and Conway Institute of Biomedical Research, University College Dublin, Dublin, Ireland.

Abstract

INTRODUCTION:

Extensive vascular remodeling causing pulmonary hypertension (PH) represents a major cause of mortality in patients with congenital diaphragmatic hernia (CDH). The chemokine monocyte chemoattractant protein-1 (MCP-1) is a biomarker for the severity of PH and its activation is accompanied by pulmonary influx of monocytes and extensive vascular remodeling. MCP-1 activation can be reversed by application of rosiglitazone (thiazolidinedione). We performed this study to evaluate the role of MCP-1 for the pathogenesis of PH in experimental CDH. We hypothesized that vascular remodeling and MCP-1 activation is accompanied by pulmonary influx of fetal monocytes and can be attenuated by prenatal treatment with rosiglitazone.

METHODS:

In a first set of experiments pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetal lungs were harvested on D21 and divided into CDH and control. Quantitative real-time polymerase chain reaction, Western blot (WB), and immunohistochemistry (IHC) were used to evaluate MCP-1 expression, activation, and localization. Quantification and localization of pulmonary monocytes/macrophages were carried out by IHC. In a second set of experiments nitrofen-exposed dams were randomly assigned to prenatal treatment with rosiglitazone or placebo on D18+D19. Fetal lungs were harvested on D21, divided into control, CDH+rosiglitazone, and CDH+placebo and evaluated by WB as well as IHC.

RESULTS:

Increased thickness of pulmonary arteries of CDH fetuses was accompanied by increased systemic and perivascular MCP-1 protein expression and significantly higher amounts of pulmonary monocytes/macrophages compared to controls (p<0.01). These effects were reversed by prenatal treatment with rosiglitazone (p<0.01 vs. CDH+P; control).

CONCLUSION:

Prenatal treatment with rosiglitazone has the potential to attenuate activation of pulmonary MCP-1, pulmonary monocyte influx, and vascular remodeling in experimental CDH. These results provide a basis for future research on prenatal immunomodulation as a novel treatment strategy to decrease secondary effects of PH in CDH.

PMID:
30418988
PMCID:
PMC6231640
DOI:
10.1371/journal.pone.0206975
[Indexed for MEDLINE]
Free PMC Article

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