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Published ahead of print on March 26, 2008, doi:10.1165/rcmb.2008-0057OC

Am. J. Respir. Cell Mol. Biol., Volume 39, Number 2, August 2008, 198-207

A more recent version of this article appeared on August 1, 2008
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Submitted on January 31, 2008
Revised on March 20, 2008

Soot Nanoparticles Promote Biotransformation, Oxidative Stress, and Inflammation in Murine Lungs

Rodney L Rouse1, Gleeson Murphy2, Marc J Boudreaux3, Daniel B Paulsen4, and Arthur L Penn1*

1 Louisiana State University, School of Veterinary Medicine, Comparative Biomedical Sciences, Baton Rouge, LA, USA, 2 Louisiana State University, School of Veterinary Medicine, Comparative Biomedical Sciences, Baton Rouge, LA, USA; Analytical Toxicology Division, USAMRICD, U.S. Army Veterinary Medical Corps, Aberdeen, MD, USA, 3 Division of Biotechnology and Molecular Medicine (BioMMED), Louisiana State University, School of Veterinary Medicine, Baton Rouge, LA, USA, 4 Department of Pathobiological Sciences, Louisiana State University, School of Veterinary Medicine, Baton Rouge, LA, USA

* To whom correspondence should be addressed. E-mail: apenn{at}vetmed.lsu.edu.

We previously described physicochemical characteristics [particle size, adsorbed polynuclear aromatic hydrocarbons (PAHs), oxygen and metal content] of butadiene soot (BDS) nanoparticles generated during incomplete combustion of the high-volume industrial petrochemical, 1,3-butadiene. We demonstrated localization of BDS-delivered PAHs to lipid droplets of murine and human respiratory cells in vitro and up-regulation of biotransformation and oxidative stress responses in these cells. Here, the objective was to determine whether inhalation of BDS nanoparticles promotes up-regulation of Phase I biotransformation enzymes, oxidative stress responses, and inflammation in the lungs of mice. Female Balb/c mice exposed to BDS (5 mg/m3; 4 hr/day; 4 days) were sacrificed immediately or one day following final exposure; bronchoalveolar lavage fluid (BALF) was collected from the lungs; total RNA was extracted from one lung and histopathology performed on the other. Histopathology and BALF analysis revealed particle-laden macrophages in airways of BDS treated mice, accompanied by neutrophilia and epithelial damage. Microarray and qRT-PCR analyses revealed up-regulation of a) aryl hydrocarbon receptor (AhR)-responsive genes: AhR repressor (Ahrr) and cytochrome P450 IA1 and IB1(Cyp1a1, Cyp1b1); b) oxidative stress response genes: heme oxygenase 1 (Hmox1), nuclear factor erythroid-derived 2 like 2 (Nfe2l2), NADPH dehydrogenase quinone 1 (Nqo1), and glutathione peroxidase 2 (Gpx2); and c) pro-inflammatory genes: interleukin-6 (IL-6), C-X-C motif ligand 2 (Cxcl2; analog to human IL-8) and ligand 3 (Cxcl3), and granulocyte chemotactic protein (Cxcl6). Inhalation of PAH-rich, petrochemical combustion-derived nanoparticles causes airway inflammation and induces expression of AhR-associated and oxidative stress response genes, as seen in vitro, plus pro-inflammatory genes.






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