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ORIGINAL RESEARCH ARTICLE

Effects of Pulmonary Exposure to Carbon Nanotubes on Lung and Systemic Inflammation with Coagulatory Disturbance Induced by Lipopolysaccharide in Mice

Ken-ichiro Inoue^*,1, Hirohisa Takano^*, Eiko Koike^*, Rie Yanagisawa^*, Miho Sakurai^*, Sadatomo Tasaka, Akitoshi Ishizaka and Akinori Shimada

^* Environmental Health Sciences Division, National Institute for Environmental Studies, Ibaraki 305-8506, Japan; Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo 106-8582, Japan; and Department of Veterinary Pathology, Faculty of Agriculture, Tottori University, Tottori 680-0945, Japan

To whom requests for reprints should be addressed at ¹ Environmental Health Sciences Division, National Institute for Environmental Studies, 16–2 Onogawa, Tsukuba 305-8506, Japan. E-mail: inoue.kenichirou{at}nies.go.jp

Despite intensive research as to the pathogenesis of lipopolysaccharide (LPS)-related inflammation with coagulatory disturbance, their exacerbating factors have not been well explored. This study examined the effects of pulmonary exposure to two types of nano-sized materials (carbon nano-tubes: CNT [single-wall: SWCNT, and multi-wall: MWCNT]) on lung inflammation and consequent systemic inflammation with coagulatory disturbance induced by pulmonary exposure to LPS in mice and their cellular mechanisms in vitro. ICR male mice were divided into 6 experimental groups that intra-tracheally received the vehicle, two types of CNT (4 mg/kg), LPS (33 µ g/kg), or LPS plus either type of CNT. Twenty-four hours after treatment, both types of CNT alone induced lung inflammation with enhanced lung expression of proinflammatory cytokines, but did not synergistically exacerbate lung inflammation elicited by LPS. SWCNT significantly induced/ enhanced pulmonary permeability and hyperfibrinogenemia and reduced activated protein C in the absence or presence of LPS, whereas MWCNT did moderately. Both CNT moderately, but not significantly, elevated circulatory levels of proinflammatory cytokines and chemokines. In the presence of LPS, CNT tended to elevate the levels of the mediators with an overall trend, which was more prominent with SWCNT than with MWCNT. In vitro study showed that both CNT amplified LPS-induced cytokine production from peripheral blood monocytes. These results suggest that CNT can facilitate systemic inflammation with coagulatory disturbance, at least in part, via the activation of mononuclear cells, which is accompanied by moderate enhancement of acute lung inflammation related to LPS.

Key Words: carbon nanotubes • lipopolysaccharide • lung inflammation • systemic inflammation • coagulatory disturbance