Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery Dilation in Mice.
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
25
01
2019
revised:
29
04
2019
accepted:
02
05
2019
pubmed:
28
5
2019
medline:
12
3
2020
entrez:
25
5
2019
Statut:
ppublish
Résumé
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-β signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.
Identifiants
pubmed: 31125551
pii: S0002-9440(19)30076-8
doi: 10.1016/j.ajpath.2019.05.003
pmc: PMC6997843
pii:
doi:
Substances chimiques
Sildenafil Citrate
BW9B0ZE037
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1536-1546Subventions
Organisme : NHLBI NIH HHS
ID : R15 HL145646
Pays : United States
Organisme : CIHR
ID : G15-9211
Pays : Canada
Organisme : CIHR
ID : PJT159511
Pays : Canada
Informations de copyright
Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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