title: Didecyldimethylammonium chloride induces pulmonary fibrosis in association with TGF-β signaling in mice.
abstract: Didecyldimethylammonium chloride (DDAC) is a representative dialkyl-quaternary ammonium compound that is used as a disinfectant against several pathogens and is also used in commercial, industrial, and residential settings. We previously investigated toxicity on air way system following single instillation of DDAC to the lungs in mice, and found that DDAC causes pulmonary injury, which is associated with altered antioxidant antimicrobial responses; the inflammatory phase is accompanied or followed by fibrotic response. The present study was conducted to monitor transforming growth factor-β (TGF-β) signaling in pulmonary fibrosis induced by DDAC. Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment to measure TGF-β signaling. In order to further evaluate TGF-β signaling, we treated isolated mouse lung fibroblasts with DDAC. Fibrotic foci were observed in the lungs on day 3, and were widely extended on day 7, with evidence of increased α-smooth muscle actin-positive mesenchymal cells and upregulation of Type I procollagen mRNA. Developing fibrotic foci were likely associated with increased expression of Tgf-β1 mRNA, in addition to decreased expression of Bone morphogenetic protein-7 mRNA. In fibrotic lung samples, the expression of phosphorylated SMAD2/3 was considerably higher than that of phosphorylated SMAD1/5. In isolated lung fibroblasts, the mRNA levels of Tgf-β1 were specifically increased by DDAC treatment, which prolonged phosphorylation of SMAD2/3. These effects were abolished by treatment with SD208 - a TGF-βRI kinase inhibitor. The results suggest that DDAC induces pulmonary fibrosis in association with TGF-β signaling.
authors.affiliation: Laboratory of Pathology, Toxicology Division, The Institute of Environmental Toxicology, Uchimoriya-machi 4321, Joso, Ibaraki 303-0043, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ohnuma-Koyama
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.forename: Haruka
authors.initials: H
authors.lastname: Tajima-Horiuchi
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Ohtsuka
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Takeuchi-Kashimoto
authors.forename: Maki
authors.initials: M
authors.lastname: Kuwahara
authors.forename: Makio
authors.initials: M
authors.lastname: Takeda
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Nakashima
authors.forename: Takanori
authors.initials: T
authors.lastname: Harada
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004202:Disinfectants / Q000633:toxicity*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D004202:Disinfectants; D000644:Quaternary Ammonium Compounds; D016212:Transforming Growth Factor beta; C027118:didecyldimethylammonium
keywords: Bone morphogenetic protein; Dialkyl-quaternary ammonium; Pulmonary fibrosis; SMAD; Transforming growth factor-β