title: Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP).
abstract: Several experimental studies have shown that carbon nanotubes (CNT) can induce respiratory effects, including lung fibrosis. The cellular and molecular events through which these effects develop are, however, not clearly elucidated. The purpose of the present review was to analyze the key events involved in the lung fibrotic reaction induced by CNT and to assess their relationships. We thus address current knowledge and gaps with a view to draft an Adverse Outcome Pathway (AOP) concerning the fibrotic potential of CNT.As for many inhaled particles, CNT can indirectly activate fibroblasts through the release of pro-inflammatory (IL-1β) and pro-fibrotic (PDGF and TGF-β) mediators by inflammatory cells (macrophages and epithelial cells) via the induction of oxidative stress, inflammasome or NF-kB. We also highlight here direct effects of CNT on fibroblasts, which appear as a new mode of toxicity relatively specific for CNT. Direct effects of CNT on fibroblasts include the induction of fibroblast proliferation, differentiation and collagen production via ERK 1/2 or Smad signaling. We also point out the physico-chemical properties of CNT important for their toxicity and the relationship between in vitro and in vivo effects. This knowledge provides evidence to draft an AOP for the fibrogenic activity of CNT, which allows developing simple in vitro models contributing to predict the CNT effects in lung fibrosis, and risk assessment tools for regulatory decision.
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Avenue E. Mounier, 52 - bte B1.52.12, 1200, Brussels, Belgium. giulia.vietti@uclouvain.be.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vietti
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Avenue E. Mounier, 52 - bte B1.52.12, 1200, Brussels, Belgium. dominique.lison@uclouvain.be.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Avenue E. Mounier, 52 - bte B1.52.12, 1200, Brussels, Belgium. sybille.vandenbrule@uclouvain.be.
authors.forename: Sybille
authors.initials: S
authors.lastname: van den Brule
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D037742:Nanotubes, Carbon / Q000009:adverse effects*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D037742:Nanotubes, Carbon