PMID- 33055583
OWN - NLM
STAT- MEDLINE
DCOM- 20220217
LR  - 20220217
IS  - 1528-1140 (Electronic)
IS  - 0003-4932 (Linking)
VI  - 275
IP  - 3
DP  - 2022 Mar 1
TI  - Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves 
      Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.
PG  - e586-e595
LID - 10.1097/SLA.0000000000003943 [doi]
AB  - OBJECTIVE: To evaluate the effect of combining antenatal sildenafil with fetal 
      tracheal occlusion (TO) in fetal rabbits with surgically induced congenital 
      diaphragmatic hernia (CDH). BACKGROUND: Although antenatal sildenafil 
      administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, 
      it only partially improves airway morphometry. We hypothesized that we could 
      additionally stimulate lung growth by combining this medical treatment with fetal 
      TO. METHODS: CDH was created on gestational day (GD)23 (n=54). Does were 
      randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous 
      injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or 
      sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and 
      finally harvested for histological and molecular analyses. Unoperated littermates 
      served as controls. RESULTS: The lung-to-body-weight ratio was significantly 
      reduced in sham-CDH fetuses either (1.2 +/- 0.3% vs 2.3 +/- 0.3% in controls, 
      P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses 
      undergoing TO had a lung-to-body-weight ratio comparable to that of controls 
      (2.5 +/- 0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean 
      terminal bronchiolar density (2.5 +/- 0.8 br/mm2 vs 3.5 +/- 0.9 br/mm2, P=0.043) and 
      lung mechanics (static elastance 61 +/- 36 cmH2O /mL vs 113 +/- 40 cmH2O/mL, 
      P=0.008), but both effects were more pronounced in fetuses undergoing additional 
      TO (2.1 +/- 0.8 br/mm2, P=0.001 and 31 +/- 9 cmH2O/mL, P<0.0001 respectively). Both 
      CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall 
      thickness of peripheral pulmonary vessels (41.9 +/- 2.9% and 41.8 +/- 3.2%, vs 
      24.0 +/- 2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either 
      with or without TO, had a medial thickness in the normal range (29.4% +/- 2.6%). 
      Finally, TO reduced gene expression of vascular endothelial growth factor and 
      surfactant protein A and B, but this effect was counteracted by sildenafil. 
      CONCLUSION: In the rabbit model for CDH, the combination of maternal sildenafil 
      and TO has a complementary effect on vascular and parenchymal lung development.
CI  - Copyright (c) 2020 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Russo, Francesca Maria
AU  - Russo FM
AUID- ORCID: 0000-0002-5029-7899
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
AD  - Department of Obstetrics and Gynecology, University Hospitals of Leuven, Leuven, 
      Belgium.
FAU - Da Cunha, Marina Gabriela Monteiro Carvalho Mori
AU  - Da Cunha MGMCM
AUID- ORCID: 0000-0001-6658-7797
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
FAU - Jimenez, Julio
AU  - Jimenez J
AUID- ORCID: 0000-0001-6260-2814
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
AD  - Department of Obstetrics and Gynaecology, Clinica Alemana University Desarrollo, 
      Santiago, Chile.
FAU - Lesage, Flore
AU  - Lesage F
AUID- ORCID: 0000-0001-8578-9650
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
FAU - Eastwood, Mary Patrice
AU  - Eastwood MP
AUID- ORCID: 0000-0002-6437-8972
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
FAU - Toelen, Jaan
AU  - Toelen J
AUID- ORCID: 0000-0001-9339-5408
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
FAU - Deprest, Jan
AU  - Deprest J
AUID- ORCID: 0000-0002-4920-945
AD  - Cluster Woman and Child, Department of Development and Regeneration, Biomedical 
      Sciences, KU Leuven, Leuven, Belgium.
AD  - Department of Obstetrics and Gynecology, University Hospitals of Leuven, Leuven, 
      Belgium.
AD  - Department of Obstetrics and Gynecology, Institute of Women's Health, University 
      College London, London, UK.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann Surg
JT  - Annals of surgery
JID - 0372354
RN  - BW9B0ZE037 (Sildenafil Citrate)
SB  - IM
MH  - Animals
MH  - Combined Modality Therapy
MH  - Disease Models, Animal
MH  - Female
MH  - Fetus
MH  - *Hernias, Diaphragmatic, Congenital
MH  - Lung/*growth & development
MH  - Pregnancy
MH  - Rabbits
MH  - Random Allocation
MH  - Sildenafil Citrate/*administration & dosage
MH  - Trachea/*surgery
COIS- The authors report no conflicts of interest.
EDAT- 2020/10/16 06:00
MHDA- 2022/02/19 06:00
CRDT- 2020/10/15 17:22
PHST- 2020/10/16 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2020/10/15 17:22 [entrez]
AID - 00000658-202203000-00039 [pii]
AID - 10.1097/SLA.0000000000003943 [doi]
PST - ppublish
SO  - Ann Surg. 2022 Mar 1;275(3):e586-e595. doi: 10.1097/SLA.0000000000003943.