Plasminogen activator inhibitor (PAI)-1 is an inhibitor of fibrinolysis, the physiological process involved in blood clot degradation. Systemic release of PAI-1 has been associated with ischemic cardiovascular disease and poor prognosis of acute lung injury. We evaluated the induction of PAI-1 in the lung and systemic circulation of C57BL/6J mice exposed to high dose (40 ug) purified single walled carbon nanotubes (SWCNT, CNI, Inc.) or multi walled CNT (MWCNT, provided by Prof. Endo, Shinshu University, Japan) by pharyngeal aspiration. CNTs were dispersed by sonication in a dispersion solution (DS) containing mouse serum albumin and DSPC. Mice were sacrificed 4hr post-exposure and lung tissue, bronchoalveolar lavage (BAL), and blood were collected for biochemical and gene expression assessment. CNT exposure caused increased PAI-1 (~5-fold) gene expression in the lung while no increase was found in the whole blood. PAI-1 protein levels were significantly increased in the lungs of both CNT-treated groups (3.57+/-0.42 ng/ml DS; 7.45+/-0.68* SWCNT; 8.16+/-0.89* MWCNT, *p<0.05). A similar trend was demonstrated for the plasma PAI-1 protein levels (1.95+/-0.19 ng/ml DS; 2.36+/-0.57 SWCNT; 2.84+/-0.38 MWCNT) as well as plasma PAI-1 activity (0.33+/-0.10 DS; 0.64+/-0.16 SWCNT; 0.80+/-0.16* MWCNT, *p<0.05). The PAI-1 activation was accompanied by induction of lung inflammation including increased influx of neutrophils in the BAL, increased BAL LDH and albumin and elevated lung tissue gene expression of numerous inflammatory genes such as (IL- 1â, MIP-2, MCP-1, and IL-6). Furthermore, acute CNT exposure induced MIP-2 and IL-1â gene expression in the blood cells from the systemic circulation. All these effects were more prominent and consistent in mice exposed to MWCNT compared to the mice exposed to SWCNT. In conclusion, CNT-induced acute lung inflammation was associated with a systemic response which may lead to disturbances in the coagulation cascade and vascular endothelial function.
The Toxicologist. Society of Toxicology 47th Annual Meeting and ToxExpo, March 16-20, 2008, Seattle, Washington