PMID- 22820758 OWN - NLM STAT- MEDLINE DCOM- 20130220 LR - 20181202 IS - 1432-0738 (Electronic) IS - 0340-5761 (Linking) VI - 86 IP - 12 DP - 2012 Dec TI - Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin. PG - 1851-9 LID - 10.1007/s00204-012-0903-6 [doi] AB - 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 mug PM/mouse), and MUC5AC mRNA and protein in HBEC after 24 h of exposure (from 5 mug 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. FAU - Val, Stephanie AU - Val S AD - Laboratory of Molecular and Cellular Responses to Xenobiotics, Unit of Functional and Adaptive Biology, BFA, EAC CNRS 4413, University Paris Diderot, Sorbonne Paris Cite, 75013, Paris, France. stf.val@gmail.com FAU - Belade, Esther AU - Belade E FAU - George, Isabelle AU - George I FAU - Boczkowski, Jorge AU - Boczkowski J FAU - Baeza-Squiban, Armelle AU - Baeza-Squiban A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120722 PL - Germany TA - Arch Toxicol JT - Archives of toxicology JID - 0417615 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (Culture Media, Conditioned) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Interleukin-8) RN - 0 (Muc5ac protein, mouse) RN - 0 (Mucin 5AC) RN - 0 (Particulate Matter) RN - 0 (Transforming Growth Factor alpha) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Amphiregulin MH - Animals MH - Autocrine Communication/*drug effects MH - Cell Line MH - Culture Media, Conditioned MH - EGF Family of Proteins MH - Enzyme-Linked Immunosorbent Assay MH - ErbB Receptors/biosynthesis/genetics MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - Glycoproteins/*physiology MH - Injections, Spinal MH - Intercellular Signaling Peptides and Proteins/*physiology MH - Interleukin-8/metabolism MH - Lung/cytology/drug effects/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microscopy, Fluorescence MH - Mucin 5AC/*biosynthesis MH - Particle Size MH - Particulate Matter/*toxicity MH - Signal Transduction/drug effects MH - Transforming Growth Factor alpha/metabolism EDAT- 2012/07/24 06:00 MHDA- 2013/02/21 06:00 CRDT- 2012/07/24 06:00 PHST- 2012/04/19 00:00 [received] PHST- 2012/07/02 00:00 [accepted] PHST- 2012/07/24 06:00 [entrez] PHST- 2012/07/24 06:00 [pubmed] PHST- 2013/02/21 06:00 [medline] AID - 10.1007/s00204-012-0903-6 [doi] PST - ppublish SO - Arch Toxicol. 2012 Dec;86(12):1851-9. doi: 10.1007/s00204-012-0903-6. Epub 2012 Jul 22.