Dataset Information

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis.

ABSTRACT: Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain incompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (?1.0?M) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including ?-smooth muscle actin (?-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to low-dose Cd (0.3 and 1.0mg/L in drinking water) showed increased ?-SMA protein level with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4-dependent signaling. The results indicate that dietary Cd intake could be an important variable contributing to pulmonary fibrosis in humans.

SUBMITTER: Hu X

PROVIDER: S-EPMC5470547 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis.

Hu Xin X Fernandes Jolyn J Jones Dean P DP Go Young-Mi YM

Toxicology 20170321

Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposu ...[more]

PMID: 28341147

Similar Datasets

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-?1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition.To identify the mechanism of Arsenic trioxide's (ATO)'s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-?1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as ?-smooth muscle actin (?-SMA) and ?-1 type I collagen.Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-?1-induced ?-smooth muscle actin (?-SMA) and ?-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-?1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-?1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-?1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung ?-1 type I collagen mRNA and protein expression.In summary, these data indicate that low concentrations of ATO inhibit TGF-?1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.

Dataset Information

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis.

Publications

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets