PMID- 30418988 OWN - NLM STAT- MEDLINE DCOM- 20190416 LR - 20190416 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 13 IP - 11 DP - 2018 TI - Prenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic hernia. PG - e0206975 LID - 10.1371/journal.pone.0206975 [doi] LID - e0206975 AB - 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. FAU - Gosemann, Jan-Hendrik AU - Gosemann JH AUID- ORCID: 0000-0001-9919-0251 AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. FAU - Friedmacher, Florian AU - Friedmacher F AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - The Royal London Hospital, London, United Kingdom. FAU - Hofmann, Alejandro AU - Hofmann A AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany. FAU - Zimmer, Julia AU - Zimmer J AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany. FAU - Kuebler, Joachim F AU - Kuebler JF AD - Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany. FAU - Rittinghausen, Susanne AU - Rittinghausen S AD - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany. FAU - Suttkus, Anne AU - Suttkus A AD - Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. FAU - Lacher, Martin AU - Lacher M AD - Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany. FAU - Alvarez, Luis AU - Alvarez L AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom. FAU - Corcionivoschi, Nicolae AU - Corcionivoschi N AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - Agri-Food and Biosciences Institute, Belfast, Northern Ireland, United Kingdom. FAU - Puri, Prem AU - Puri P AD - National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland. AD - School of Medicine and Medical Science and Conway Institute of Biomedical Research, University College Dublin, Dublin, Ireland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181112 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Chemokine CCL2) RN - 0 (Phenyl Ethers) RN - 0 (RNA, Messenger) RN - 05V02F2KDG (Rosiglitazone) RN - N71UYG034A (nitrofen) SB - IM MH - Animals MH - Chemokine CCL2/blood/genetics/metabolism MH - Disease Models, Animal MH - Female MH - Gene Expression MH - Hernias, Diaphragmatic, Congenital/drug therapy/*etiology/*metabolism/pathology MH - Immunohistochemistry MH - Lung/*metabolism/pathology MH - Macrophages/immunology/metabolism MH - Monocytes/*drug effects/*metabolism MH - Phenyl Ethers/adverse effects MH - Pregnancy MH - Prenatal Care MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Rosiglitazone/*pharmacology MH - Vascular Remodeling/*drug effects PMC - PMC6231640 COIS- The authors have declared that no competing interests exist. EDAT- 2018/11/13 06:00 MHDA- 2019/04/17 06:00 PMCR- 2018/11/12 CRDT- 2018/11/13 06:00 PHST- 2018/06/21 00:00 [received] PHST- 2018/10/23 00:00 [accepted] PHST- 2018/11/13 06:00 [entrez] PHST- 2018/11/13 06:00 [pubmed] PHST- 2019/04/17 06:00 [medline] PHST- 2018/11/12 00:00 [pmc-release] AID - PONE-D-18-18519 [pii] AID - 10.1371/journal.pone.0206975 [doi] PST - epublish SO - PLoS One. 2018 Nov 12;13(11):e0206975. doi: 10.1371/journal.pone.0206975. eCollection 2018.