Longitudinal assessment of bleomycin-induced pulmonary fibrosis by evaluating TGF-β1/Smad2, Nrf2 signaling and metabolomic analysis in mice.

Autor: Washimkar KR; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Tomar MS; Centre for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow 226003, India., Kulkarni C; Division of Endocrinology, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Verma S; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Shrivastava A; Centre for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow 226003, India., Chattopadhyay N; Division of Endocrinology, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India., Mugale MN; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: madhav.mugale@cdri.res.in.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2023 Oct 15; Vol. 331, pp. 122064. Date of Electronic Publication: 2023 Aug 30.
DOI: 10.1016/j.lfs.2023.122064
Abstrakt: Introduction: Pulmonary fibrosis (PF) is characterized by an increase in collagen synthesis and deposition of extracellular matrix. Several factors, including transforming growth factor-β1 (TGF-β1), mothers against decapentaplegic homolog family proteins (Smad), and alpha-smooth muscle actin (α-SMA) trigger extracellular matrix (ECM) accumulation, fibroblast to myofibroblasts conversion, and epithelial-to-mesenchymal-transition (EMT) leading to PF. However, the role of cellular defense mechanisms such as the role of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling during the onset and progression of PF is not understood completely.
Aim: The present study aims to analyze the involvement of TGF-β1/Smad signaling, and Nrf2 in the EMT and metabolic alterations that promote fibrosis in a time-dependent manner using bleomycin (BLM)-induced PF model in C57BL/6 mice.
Key Findings: Histopathological studies revealed loss of lung architecture and increased collagen deposition in BLM-exposed mice. BLM upregulated TGF-β1/Smad signaling and α-SMA at all time-points. The gradual increase in the accumulation of α-SMA and collagen implied the progression of PF. BLM exposure raises Nrf2 throughout each specified time-point, which suggests that Nrf2 activation might be responsible for TGF-β1-induced EMT and the development of PF. Further, metabolomic studies linked the development of PF to alterations in metabolic pathways. The pentose phosphate pathway (PPP) was consistently enriched across all the time-points. Additionally, alterations in 22 commonly enriched pathways, associated with fatty acid (FA) and amino acid metabolism were observed in 30- and 60-days.
Significance: This study elucidates the association of TGF-β1/Smad and Nrf2 signaling in the EMT and metabolic alterations associated with the etiology and progression of PF.
Competing Interests: Declaration of competing interest The authors declare no conflict of interests.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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