title: Pathologic and molecular profiling of rapid-onset fibrosis and inflammation induced by multi-walled carbon nanotubes.
abstract: Multi-walled carbon nanotubes (MWCNT) are new materials with a wide range of industrial and commercial applications. However, their nano-scaled size and fiber-like shape render them respirable and potentially fibrogenic if inhaled into the lungs. To understand MWCNT fibrogenesis, we analyzed the pathologic and molecular aspects of the early phase response to MWCNT in mouse lungs. MWCNT induced rapid and pronounced lesions in the lungs characterized by increased cellularity and formation of fibrotic foci, most notably near where MWCNT deposited, within 14 days post-exposure. Deposition of collagen fibers was markedly increased in the alveolar septa and fibrotic foci, accompanied by elevated expression of fibrotic genes Col1a1, Col1a2, and Fn1 at both mRNA and protein levels. Fibrosis was induced rapidly at 40 μg, wherein fibrotic changes were detected on day 1 and reached a maximal intensity on day 7 through day 14. Induction of fibrosis was dose-dependent at the dose range of 5-40 μg, 7 days post-exposure. MWCNT elicited rapid and prominent infiltrations of neutrophils and macrophages alongside fibrosis implicating acute inflammation in the fibrotic response. At the molecular level, MWCNT induced elevated expression of proinflammatory cytokines TNFα, IL1α, IL1β, IL6, and CCL2 in lung tissues as well as the bronchoalveolar lavage fluid, in a dose- and time-dependent manner. MWCNT also increased the expression of fibrogenic growth factors TGF-β1 and PDGF-A in the lungs significantly. These findings underscore the interplay between acute inflammation and the early fibrotic response in the initiation and propagation of pulmonary fibrosis induced by MWCNT.
authors.affiliation: Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Mailstop 3014, Morgantown, WV, 26505, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.forename: Dale W
authors.initials: DW
authors.lastname: Porter
authors.forename: Lori A
authors.initials: LA
authors.lastname: Batteli
authors.forename: Michael G
authors.initials: MG
authors.lastname: Wolfarth
authors.forename: Diana L
authors.initials: DL
authors.lastname: Richardson
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines / Q000032:analysis; D005353:Fibronectins / Q000235:genetics; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D013997:Time Factors
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines; D005353:Fibronectins; D037742:Nanotubes, Carbon