title: Bacterial lipopolysaccharide enhances PDGF signaling and pulmonary fibrosis in rats exposed to carbon nanotubes.
abstract: Engineered multi-walled carbon nanotubes (MWCNT) represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung. We postulated that bacterial lipopolysaccharide (LPS), a ubiquitous agent in the environment that causes lung inflammation, would enhance fibrosis caused by MWCNT. Rats were exposed to LPS and then intratracheally instilled with MWCNT or carbon black (CB) nanoparticles 24 hours later. Pulmonary fibrosis was observed 21 days after MWCNT exposure, but not with CB. LPS alone caused no fibrosis but enhanced MWCNT-induced fibrosis. LPS plus CB did not significantly increase fibrosis. MWCNT increased platelet-derived growth factor-AA (PDGF-AA), a major mediator of fibrosis. PDGF-AA production in response to MWCNT, but not CB, was synergistically enhanced by LPS. Immunostaining showed PDGF-AA in bronchiolar epithelial cells and macrophages. Since macrophages engulfed MWCNT, were positive for PDGF-AA, and mediate fibroblast responses, experiments were performed with rat lung macrophages (NR8383 cells) and rat lung fibroblasts in vitro. LPS exposure increased PDGF-A mRNA levels in NR8383 cells and enhanced MWCNT-induced PDGF-A mRNA levels. Moreover, LPS increased MWCNT- or CB-induced PDGF receptor-alpha (PDGF-Ralpha) mRNA in fibroblasts. Our data suggest that LPS exacerbates MWCNT-induced lung fibrosis by amplifying production of PDGF-AA in macrophages and epithelial cells, and by increasing PDGF-Ralpha on pulmonary fibroblasts. Our findings also suggest that individuals with pre-existing pulmonary inflammation are at greater risk for the potential adverse effects of MWCNT.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, 27695-7633, USA.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cesta
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Ryman-Rasmussen
authors.forename: Duncan G
authors.initials: DG
authors.lastname: Wallace
authors.forename: Tiwanda
authors.initials: T
authors.lastname: Masinde
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hurlburt
authors.forename: Alexia J
authors.initials: AJ
authors.lastname: Taylor
authors.forename: James C
authors.initials: JC
authors.lastname: Bonner
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D036103:Nanotechnology / Q000379:methods; D037742:Nanotubes, Carbon / Q000737:chemistry*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D053260:Soot / Q000737:chemistry
chemical_list: D008070:Lipopolysaccharides; D037742:Nanotubes, Carbon; D010982:Platelet-Derived Growth Factor; D053260:Soot; C075278:platelet-derived growth factor A; D017479:Receptors, Platelet-Derived Growth Factor