Pulmonary inflammation after intraperitoneal administration of ultrafine titanium dioxide (TiO2) at rest or in lungs primed with lipopolysaccharide.
Nanoparticles are widely used in nanomedicines, including for targeted delivery of pharmacological, therapeutic, and diagnostic agents. Since nanoparticles might translocate across cellular barriers from the circulation into targeted organs, it is important to obtain information concerning the pathophysiologic effects of these particles through systemic migration. In the present study, acute pulmonary responses were examined after intraperitoneal (ip) administration of ultrafine titanium dioxide (TiO(2), 40 mg/kg) in mice at rest or in lungs primed with lipopolysaccharide (LPS, ip, 5 mg/kg). Ultrafine TiO(2) exposure increased neutrophil influx, protein levels in bronchoalveolar lavage (BAL) fluid, and reactive oxygen species (ROS) activity of BAL cells 4 h after exposure. Concomitantly, the levels of proinflammatory mediators, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and macrophage inflammatory protein (MIP)-2 in BAL fluid and mRNA expression of TNF-alpha and IL-1beta in lung tissue were elevated post ultrafine TiO(2) exposure. Ultrafine TiO(2) exposure resulted in significant activation of inflammatory signaling molecules, such as c-Src and p38 MAP kinase, in lung tissue and alveolar macrophages, and the nuclear factor (NF)-kappaB pathway in pulmonary tissue. Furthermore, ultrafine TiO(2) additively enhanced these inflammatory parameters and this signaling pathway in lungs primed with lipopolysaccharide (LPS). Contrary to this trend, a synergistic effect was found for TNF-alpha at the level of protein and mRNA expression. These results suggest that ultrafine TiO(2) (P25) induces acute lung inflammation after ip administration, and exhibits additive or synergistic effects with LPS, at least partly, via activation of oxidant-dependent inflammatory signaling and the NF-kappaB pathway, leading to increased production of proinflammatory mediators.
Department of Physiology, School of Medicine, Ewha Woman's University, Seoul, South Korea.
Changsuk
C
Moon
Hyun-Jeong
HJ
Park
Youn-Hee
YH
Choi
Eun-Mi
EM
Park
Vincent
V
Castranova
Jihee Lee
JL
Kang
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054426:Chemokine CXCL2 / Q000378:metabolism; D004357:Drug Synergism; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D052638:Particulate Matter / Q000008:administration & dosage / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012146:Rest; D014025:Titanium / Q000008:administration & dosage / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D054426:Chemokine CXCL2; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D052638:Particulate Matter; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C009495:titanium dioxide; D014025:Titanium