Faculty, Staff and Student Publications
Language
English
Publication Date
3-1-2023
Journal
American Journal of Respiratory Cell and Molecular Biology
DOI
10.1165/rcmb.2021-0541OC
PMID
36476191
PMCID
PMC12042145
PubMedCentral® Posted Date
12-7-2022
PubMedCentral® Full Text Version
Post-print
Abstract
Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the time of lung transplantation, and control tissue was obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies and organ collection were performed 3 weeks after instillation. Only significant results (P < 0.05) are presented. In PF lung tissue, GCN2 protein expression was decreased compared with control tissue. GCN2 expression was reduced in CD31+ endothelial cells. In line with human data, GCN2 protein expression was decreased in the lung of bleomycin rats compared with saline. EIF2AK4-mutated rats treated with bleomycin showed increased parenchymal fibrosis (hydroxyproline concentrations) and vascular remodeling (media wall thickness) as well as increased right ventricular systolic pressure compared with wild-type animals. Our data show that GCN2 is dysregulated in both humans and in an animal model of combined PF and PH. The possibility of a causative implication of GCN2 dysregulation in PF and/or PH development should be further studied.
Keywords
Animals, Humans, Male, Rats, Bleomycin, Endothelial Cells, Hypertension, Pulmonary, Lung, Protein Serine-Threonine Kinases, Pulmonary Fibrosis, Rats, Sprague-Dawley, Protein Kinases, lung diseases, vascular disease, right ventricular dysfunction
Published Open-Access
yes
Recommended Citation
Santos-Ribeiro, Diana; Lecocq, Marylène; de Beukelaer, Michèle; et al., "Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis" (2023). Faculty, Staff and Student Publications. 5958.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5958
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