Single Walled Carbon NanoTubes (SWCNT)are new materials of emerging technological importance. Thier manufacturing requires iron resulting in its high content in SWCNT. Because iron is a catalyst of oxidative stress, iron-containing SWCNTare likely more toxic than iron-free SWCNT. Our central hypothesisis that SWCNT are toxic to the lung and the toxicity is dependenton their content of iron. The major toxicity mechanisms include inflammatory response synergistically enhanced by oxidative stress exacerbatedby iron. SWCNTtoxic effects are further augmented by microbially-induced inflammation. The apoptotic/necrotic target cell death ratio dependent on the SWCNT iron is also a regulator of SWCNT toxicity via production of anti-/pro-inflammatory cytokines, respectively.
Specific Aim 1 is to establish the extent to which SWCNT alone are pro-inflammatory to lung cells and tissue and characterizethe role of iron in these effects using genetically manipulated cells and animals as well as antioxidant interventions.
Specific Aim 2 is to determine the potential for SWCNT and microbial stimuli to synergistically interact to promote macrophageactivation, oxidative stress, and lung inflammation.
Specific Aim 3 is to reveal the extent to which SWCNTare effective in inducing apoptosis and whether apoptotic cells exert their macrophage-dependent anti-inflammatory potential during in vitro and in vivo SWCNTexposure. The project involves a team ofinterdisciplinary investigators with unique expertise in redox chemistry/biochemistry (V. Kagan), cell and molecular biology of inflammation (L. Ortiz) and its interactions with microbial agents (J. Fabisiak), pulmonary toxicology of (nano)particles (V, Castranova,A. Shvedova). Basedon our results, mechanism-based interventions, such as specific antioxidants, new means to control iron content (using non-toxic chelators) as well as biotechnological approaches (phosphatidylserine liposomes and/or apoptotic cells down-regulating inflammatory response) may be developed to decrease toxicity of (iron-containing)SWCNT.
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