Fructose-1,6-bisphosphate prevents pulmonary fibrosis by regulating extracellular matrix deposition and inducing phenotype reversal of lung myofibroblasts


Autoři: Henrique Bregolin Dias aff001;  Jarbas Rodrigues de Oliveira aff001;  Márcio Vinícius Fagundes Donadio aff001;  Shioko Kimura aff002
Působiště autorů: Laboratory of Cellular Biophysics and Inflammation, PUCRS, Porto Alegre, RS, Brazil aff001;  Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222202

Souhrn

Pulmonary fibrosis (PF) is the result of chronic injury where fibroblasts become activated and secrete large amounts of extracellular matrix (ECM), leading to impaired fibroblasts degradation followed by stiffness and loss of lung function. Fructose-1,6-bisphosphate (FBP), an intermediate of glycolytic pathway, decreases PF development, but the underlying mechanism is unknown. To address this issue, PF was induced in vivo using a mouse model, and pulmonary fibroblasts were isolated from healthy and fibrotic animals. In PF model mice, lung function was improved by FBP as revealed by reduced collagen deposition and downregulation of ECM gene expression such as collagens and fibronectin. Fibrotic lung fibroblasts (FLF) treated with FBP for 3 days in vitro showed decreased proliferation, contraction, and migration, which are characteristic of myofibroblast to fibroblast phenotype reversal. ECM-related genes and proteins such as collagens, fibronectin and α-smooth muscle actin, were also downregulated in FBP-treated FLF. Moreover, matrix metalloproteinase (MMP) 1, responsible for ECM degradation, was produced only in fibroblasts obtained from healthy lungs (HLF) and FBP did not alter its expression. On the other hand, tissue inhibitor of metalloproteinase (TIMP)-1, a MMP1 inhibitor, and MMP2, related to fibroblast tissue-invasion, were predominantly produced by FLF and FBP was able to downregulate its expression. These results demonstrate that FBP may prevent bleomycin-induced PF development through reduced expression of collagen and other ECM components mediated by a reduced TIMP-1 and MMP2 expression.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Connective tissue cells – Fibroblasts – Anatomy – Biological tissue – Connective tissue – Biochemistry – Proteins – Collagens – Developmental biology – Organism development – Organogenesis – Lung development – Fibrosis – Pulmonary fibrosis – Genetics – Gene expression – Medicine and health sciences – Pulmonology – Pulmonary function – Diagnostic medicine – Diagnostic radiology – Pulmonary imaging – Radiology and imaging – Research and analysis methods – Imaging techniques


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2019 Číslo 9
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