PMID- 35779494 OWN - NLM STAT- MEDLINE DCOM- 20220719 LR - 20220720 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 81 DP - 2022 Jul TI - Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia. PG - 104106 LID - S2352-3964(22)00287-0 [pii] LID - 10.1016/j.ebiom.2022.104106 [doi] LID - 104106 AB - BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH.900, 38.5+/- 8.4%; CDH.1500, 40.2+/-9.7%; CDH, 46.6+/-8.2%; both p < 0.0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36.6+/-11.1%; C.T.1500, 36.9+/-9.3%; C.P., 26.9+/-6.2%; both p < 0.001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. INTERPRETATION: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. FUNDING: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879). CI - Copyright (c) 2022. Published by Elsevier B.V. FAU - De Bie, Felix Rafael AU - De Bie FR AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium. FAU - Halline, Christopher Gates AU - Halline CG AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Kotzur, Travis AU - Kotzur T AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Hayes, Kevin AU - Hayes K AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Rouse, Christopher Copeland AU - Rouse CC AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Chang, Jonathan AU - Chang J AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Larson, Abby Christine AU - Larson AC AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Khan, Sameer Ahmad AU - Khan SA AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Spina, Ashley AU - Spina A AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Tilden, Samantha AU - Tilden S AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Russo, Francesca Maria AU - Russo FM AD - Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium. FAU - Hedrick, Holly Lee AU - Hedrick HL AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. FAU - Deprest, Jan AU - Deprest J AD - Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, Leuven, Belgium; Institute of Women's Health, University College London, London, UK. FAU - Partridge, Emily Anne AU - Partridge EA AD - Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States. Electronic address: partridgee@chop.edu. LA - eng PT - Journal Article DEP - 20220629 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - DCR9Z582X0 (Epoprostenol) RN - RUM6K67ESG (treprostinil) SB - IM MH - Animals MH - Disease Models, Animal MH - Epoprostenol/analogs & derivatives MH - Female MH - *Hernias, Diaphragmatic, Congenital/etiology/genetics MH - *Hypertension, Pulmonary/drug therapy/etiology/metabolism MH - Lung/metabolism MH - *Lung Diseases/metabolism MH - Phenotype MH - Pregnancy MH - Rats PMC - PMC9244734 OTO - NOTNLM OT - Congenital diaphragmatic hernia OT - Foetal therapy OT - Remodulin OT - Treprostinil COIS- Declaration of interests United Therapeutics Corporation provided treprostinil and financial support for this study (ISS-2020-10879). FRDB was supported by the Flanders Research Foundation (FWO-1S31720N) to conduct this work. The authors state that there are no other conflicts of interest. EDAT- 2022/07/03 06:00 MHDA- 2022/07/20 06:00 PMCR- 2022/06/29 CRDT- 2022/07/02 18:32 PHST- 2022/03/12 00:00 [received] PHST- 2022/05/27 00:00 [revised] PHST- 2022/05/27 00:00 [accepted] PHST- 2022/07/03 06:00 [pubmed] PHST- 2022/07/20 06:00 [medline] PHST- 2022/07/02 18:32 [entrez] PHST- 2022/06/29 00:00 [pmc-release] AID - S2352-3964(22)00287-0 [pii] AID - 104106 [pii] AID - 10.1016/j.ebiom.2022.104106 [doi] PST - ppublish SO - EBioMedicine. 2022 Jul;81:104106. doi: 10.1016/j.ebiom.2022.104106. Epub 2022 Jun 29.