Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Rajesh, R; Mooslechner, AA; Schweighofer, H; Pahernik, S; Lanz, I; Atallah, R; Platzer, W; Aigner, C; Benazzo, A; Angiari, S; Marsh, L; Kwapiszewska, G; Heinemann, A; Bärnthaler, T.
Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis.
Am J Physiol Lung Cell Mol Physiol. 2025;
Doi: 10.1152/ajplung.00286.2024
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Bärnthaler Thomas
- Rajesh Rishi
- Co-Autor*innen der Med Uni Graz
- Angiari Stefano
- ATALLAH Reham
- Heinemann Akos
- Kwapiszewska-Marsh Grazyna
- Lanz Ilse
- Marsh Leigh
- Mooslechner Agnes Anna
- Pahernik Svetlana
- Platzer Wolfgang
- Schweighofer Hannah
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- Abstract:
- INTRODUCTION: Idiopathic pulmonary fibrosis(IPF) is a chronic progressive lung disease that leads to destruction of alveoli and replacement by fibrotic tissue. Metabolic profiling of lung tissue and serum from IPF patients has revealed that levels of tricarboxylic acid (TCA) cycle metabolites such as succinate are altered in patients with IPF. In our study, we aim to evaluate the role of succinate and its receptor- succinate receptor 1 (SUCNR1) in the pathogenesis of lung fibrosis, with a focus on fibroblasts, a central cell in IPF. METHODS: SUCNR1 expression was investigated using Western blots, qPCR, and FISH. In vitro assays with IPF and normal human lung fibroblasts(NHLF) were used to evaluate the effect of succinate treatment on the expression of fibrotic markers, fibroblast-myofibroblast transition, apoptosis and signaling mechanisms. Studies with the bleomycin mouse model of PF were used to evaluate the effect of succinate in vivo. RESULTS: Several cell types in the lung express SUCNR1 including ATII cells, fibroblasts, and macrophages. In IPF patient fibroblasts, succinate treatment increased expression of fibrosis associated markers such as alpha smooth muscle actin and collagen. Moreover, succinate exaggerated TGF-β-mediated fibroblast-to-myofibroblast transition in NHLF. In vivo, succinate treatment significantly increased collagen accumulation in the lung and enhanced weight loss in bleomycin-treated mice. Importantly, succinate-mediated elevation of fibrosis-associated markers was lost upon knockdown of SUCNR1 or inhibition of ERK activation in IPF patient-derived fibroblasts. CONCLUSION: Succinate exerted pro-fibrotic effects in vitro and in vivo. Thus, SUCNR1 antagonism may be a potential therapeutic target for the treatment of IPF.
- Find related publications in this database (Keywords)
- fibroblast biology
- idiopathic pulmonary fibrosis
- metabolism
- pulmonary fibrosis