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      Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

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          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 μM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including α-smooth muscle actin (α-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 Cd (0.3 and 1.0 mg/L in drinking water) showed increased α-SMA staining 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.

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          Author and article information

          Journal
          0361055
          7770
          Toxicology
          Toxicology
          Toxicology
          0300-483X
          1879-3185
          12 April 2017
          21 March 2017
          15 May 2017
          15 May 2018
          : 383
          : 50-56
          Affiliations
          Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322
          Author notes
          Correspondence: Young-Mi Go, Ph.D., Department of Medicine, Pulmonary Division, Emory University, 225 Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, Tel.: 404-727-5984, Fax: 404-712-2974. ygo@ 123456emory.edu
          Article
          PMC5470547 PMC5470547 5470547 nihpa867819
          10.1016/j.tox.2017.03.018
          5470547
          28341147
          cbdace61-bff8-4a30-a933-14f0a4ca1328
          History
          Categories
          Article

          human fetal lung fibroblast,Environmental stress,lung disease

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