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

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dc.contributor.authorGosemann, Jan-Hendrik
dc.contributor.authorFriedmacher, Florian
dc.contributor.authorHofmann, Alejandro
dc.contributor.authorZimmer, Julia
dc.contributor.authorKuebler, Joachim F.
dc.contributor.authorRittinghausen, Susanne
dc.contributor.authorSuttkus, Anne
dc.contributor.authorLacher, Martin
dc.contributor.authorAlvarez, Luis
dc.contributor.authorCorcionivoschi, Nicolae
dc.contributor.authorPuri, Prem
dc.date.accessioned2021-06-11T14:51:56Z
dc.date.available2021-06-11T14:51:56Z
dc.date.issued2018-11-12
dc.descriptionPublication history: Accepted - 23 October 2018; Published online - 12 November 2018.en_US
dc.description.abstractIntroduction 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.en_US
dc.description.sponsorshipThis work was supported by Children’s Medical & Research Foundation, Dublin, Ireland, https://cmrf.org/, Senior Research Fellowship JG, awarded to JG; German Research Foundation and Leipzig University within the program of Open Access Publishing, awarded to JG, https://www.ub.uni-leipzig.de/open-science/publikationsfonds/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_US
dc.identifierhttp://hdl.handle.net/20.500.12518/278
dc.identifier.citationGosemann, J.-H., Friedmacher, F., Hofmann, A., Zimmer, J., Kuebler, J. F., Rittinghausen, S., Suttkus, A., Lacher, M., Alvarez, L., Corcionivoschi, N. and Puri, P. (2018) ‘Prenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic hernia’, PLOS ONE. Edited by J. West, 13(11), p. e0206975. doi: 10.1371/journal.pone.0206975.en_US
dc.identifier.issn1932-6203
dc.identifier.urihttps://doi.org/10.1371/journal.pone.0206975
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.rights© 2018 Gosemann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.titlePrenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic herniaen_US
dc.typeArticleen_US
dcterms.dateAccepted2018-10-23
dcterms.dateSubmitted2018-06-21

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