? Carbon nanoparticles (CNPs) are finding increased use in commercial, diagnostic, clinical and other applications. CNP production is anticipated to greatly increase and there is evidence of CNP formation by anthropogenic activity. However, evidence of their potential toxicity is also increasing and respiratory exposure is considered one route of exposure. A number of studies have now demonstrated that manufactured CNP (single walled carbon nanotubes (SWNT), multi-walled carbon nanotubes (MWNT) and to a lesser extent C60 carbon spheres (C60CS)) all cause pulmonary toxicity ranging from inflammation, granuloma formation, fibrosis and airway changes. Macrophages are considered potential targets of CNP in the Jung that may contribute to pathologic outcomes. In vitro toxicity of these particles has been demonstrated with a suggested rank order of potency most often SWNT> MWNT> C60CS. Although reports of nanoparticle toxicity are increasing, the results are often difficult to correlate since the sources (and compositions) and methods of suspension are different for CNP, and often only one particle type is examined. Furthermore, the mechanism(s) by which these uniquely hydrophobic particles are acting is unknown. Based on the unusual physical properties and size of the carbon nanoparticles, as well as our preliminary results with SWNT, MWNT and C60CS, we postulate that CNP are causing membrane disruption leading to changes in macrophage function contributing to lung inflammation. Furthermore, the different sizes of the CNPs may contribute to the rank order of potency and effects. In order to test these hypotheses and gain new information on mechanisms of action we propose the following goals. ? ? 1) Compare and evaluate how much variability in biological activity of CNP stems from differences in sources and methods of suspension. ? 2) Demonstrate that CNP cause alteration of membrane properties and function. ? 3) Evaluate the effects of CNP on macrophage function related to membrane activity. ? ? The results of these studies will provide important new information regarding the roles that different CNP sources, suspension (disaggregation) protocols and CNP types have on membrane disruption. In addition, the studies will provide information on the mechanism of action in membranes how that translates to alterations of macrophage function. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015497-02
Application #
7291568
Study Section
Special Emphasis Panel (ZES1-SET-D (D1))
Program Officer
Nadadur, Srikanth
Project Start
2006-09-30
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$129,467
Indirect Cost
Name
University of Montana
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
Hamilton Jr, Raymond F; Xiang, Chengcheng; Li, Ming et al. (2013) Purification and sidewall functionalization of multiwalled carbon nanotubes and resulting bioactivity in two macrophage models. Inhal Toxicol 25:199-210
Hamilton Jr, Raymond F; Buford, Mary; Xiang, Chengcheng et al. (2012) NLRP3 inflammasome activation in murine alveolar macrophages and related lung pathology is associated with MWCNT nickel contamination. Inhal Toxicol 24:995-1008