TY - JOUR
T1 - Congenital diaphragmatic hernia
T2 - phosphodiesterase-5 and Arginase inhibitors prevent pulmonary vascular hypoplasia in rat lungs
AU - Toso, Alberto
AU - Aránguiz, Oscar
AU - Céspedes, Carlos
AU - Navarrete, Orieta
AU - Hernández, Cherie
AU - Vio, Carlos P.
AU - Luco, Matías
AU - Casanello, Paola
AU - Kattan, Javier
N1 - Funding Information:
This research was supported by the following grants: FONDECYT N° 1171406 (P.C.) and Grant PIA CONICYT ACE210009 to CARE-UC and a donation of SQM to the Pontificia Universidad Católica de Chile (PUC). The UC CINBIOT Animal Facility is funded by PIA CONICYT ECM-07. Grant Faculty of Medicine, Pediatric Division at PUC. We thank MECESUP PUC0815 grant – Equipamiento Científico Mayor Centro de Investigaciones Médicas of Pontificia Universidad Católica de Chile for the access to Synergy II microplate fluorescence reader (BioTek Instruments, Winooski, VT) and Carl Zeiss Axio Imager A1 fluorescence microscope (Göttingen, Germany).
Funding Information:
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) #1171406, Grant PIA CONICYT AFB170005, Proyecto Semilla Interdisciplinario PS 14/15, DIDEMUC, Faculty of Medicine and Research grant from the Pediatric Division at PUC.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.
PY - 2024/3
Y1 - 2024/3
N2 - Background: Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. Objective: To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. Methods: Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring’s lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I–II expression, and activity. Results: In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. Conclusion: These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. Impact: This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments’ synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.
AB - Background: Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. Objective: To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. Methods: Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring’s lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I–II expression, and activity. Results: In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. Conclusion: These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. Impact: This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments’ synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.
UR - http://www.scopus.com/inward/record.url?scp=85142447724&partnerID=8YFLogxK
U2 - 10.1038/s41390-022-02366-4
DO - 10.1038/s41390-022-02366-4
M3 - Article
AN - SCOPUS:85142447724
SN - 0031-3998
VL - 95
SP - 941
EP - 948
JO - Pediatric Research
JF - Pediatric Research
IS - 4
ER -