title: Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin.
abstract: Particulate pollution is suspected to contribute to obstructive lung diseases characterized by chronic inflammation, mucus hypersecretion and bronchial remodeling. Our aim was to study the effect of real-world particulate matter (PM) on the expression of a mucin, MUC5AC, focusing on the role of the epidermal growth factor receptor (EGFR) pathway. MUC5AC induction was studied in vivo in mice trachea and in vitro in human bronchial epithelial cells (HBEC) exposed to urban fine PM. Fine PM were able to induce MUC5AC mRNA in mice trachea after 48 h of exposure (50 μg PM/mouse), and MUC5AC mRNA and protein in HBEC after 24 h of exposure (from 5 μg PM/cm(2)). It was associated with the increased expression of amphiregulin (AREG), an EGFR ligand. Experiments with conditioned media (media from PM-treated cells) demonstrated the involvement of AREG on MUC5AC induction as MUC5AC induction by media from PM-treated cells was prevented in the presence of either EGFR- or AREG-neutralizing antibodies. The effect of an inhibitor of a metalloprotease involved in the AREG shedding confirmed the autocrine loop made by AREG leading to MUC5AC induction by fine PM. We also demonstrated that IL-8 pro-inflammatory cytokine induction was dependent on the same autocrine mechanisms. We demonstrate for the first time that MUC5AC expression and production is increased by short-term exposure to fine PM through an autocrine effect of AREG. Our study provides mechanistic explanations to the exacerbation of obstructive lung diseases induced by particulate pollution characterized by mucus hypersecretion and chronic inflammation.
authors: Laboratory of Molecular and Cellular Responses to Xenobiotics, Unit of Functional and Adaptive Biology, BFA, EAC CNRS 4413, University Paris Diderot, Sorbonne Paris Cité, 75013, Paris, France. stf.val@gmail.com
authors: Stéphanie
authors: S
authors: Val
authors: Esther
authors: E
authors: Belade
authors: Isabelle
authors: I
authors: George
authors: Jorge
authors: J
authors: Boczkowski
authors: Armelle
authors: A
authors: Baeza-Squiban
mesh_terms: D066258:Amphiregulin; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects*; D002460:Cell Line; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006023:Glycoproteins / Q000502:physiology*; D007278:Injections, Spinal; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D055271:Mucin 5AC / Q000096:biosynthesis*; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D052638:Particulate Matter; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors