title: Towards predicting the lung fibrogenic activity of MWCNT: Key role of endocytosis, kinase receptors and ERK 1/2 signaling.
abstract: Carbon nanotubes (CNT) have been reported to induce lung inflammation and fibrosis in rodents. We investigated the direct and indirect cellular mechanisms mediating the fibrogenic activity of multi-wall (MW) CNT on fibroblasts. We showed that MWCNT indirectly stimulate lung fibroblast (MLg) differentiation, via epithelial cells and macrophages, whereas no direct effect of MWCNT on fibroblast differentiation or collagen production was detected. MWCNT directly stimulated the proliferation of fibroblasts primed with low concentrations of growth factors, such as PDGF, TGF-β or EGF. MWCNT prolonged ERK 1/2 phosphorylation induced by low concentrations of PDGF or TGF-β in fibroblasts. This phenomenon and the proliferative activity of MWCNT on fibroblasts was abrogated by the inhibitors of ERK 1/2, PDGF-, TGF-β- and EGF-receptors. This activity was also reduced by amiloride, an endocytosis inhibitor. Finally, the lung fibrotic response to several MWCNT samples (different in length and diameter) correlated with their in vitro capacity to stimulate the proliferation of fibroblasts and to prolong ERK 1/2 signaling in these cells. Our findings point to a crosstalk between MWCNT, kinase receptors, ERK 1/2 signaling and endocytosis which stimulates the proliferation of fibroblasts. The mechanisms of action identified in this study contribute to predict the fibrogenic potential of MWCNT.
authors.affiliation: a Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain , Avenue E. Mounier , Brussels , Belgium .
authors.forename: Giulia
authors.initials: G
authors.lastname: Vietti
authors.affiliation: a Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain , Avenue E. Mounier , Brussels , Belgium .
authors.forename: Saloua
authors.initials: S
authors.lastname: Ibouraadaten
authors.affiliation: a Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain , Avenue E. Mounier , Brussels , Belgium .
authors.forename: Mihaly
authors.initials: M
authors.lastname: Palmai-Pallag
authors.affiliation: a Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain , Avenue E. Mounier , Brussels , Belgium .
authors.forename: Yousof
authors.initials: Y
authors.lastname: Yakoub
authors.affiliation: b Namur Nanosafety Center, Université de Namur, rue de Bruxelles , Namur , Belgium , and.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Piret
authors.affiliation: c De Duve Institute, Université Catholique de Louvain , Brussels , Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Marbaix
authors.affiliation: a Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain , Avenue E. Mounier , Brussels , Belgium .
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
authors.affiliation: a Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain , Avenue E. Mounier , Brussels , Belgium .
authors.forename: Sybille
authors.initials: S
authors.lastname: van den Brule
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D037742:Nanotubes, Carbon / Q000633:toxicity*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D037742:Nanotubes, Carbon; D010982:Platelet-Derived Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000584:Amiloride; D003094:Collagen; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor
keywords: Carbon nanotube; fibroblast proliferation; growth factor; lung fibrosis