Recently, it has been demonstrated that ultrafine particles (UFPs) are able to translocate from the lung into the systemic circulation. Precise mechanisms of the anatomical translocation (crossing the air-blood barrier) of inhaled UFPs at the alveolar wall are not fully understood. In this study, we examined the translocation pathway of the intratracheally instilled ultrafine carbon black (UFCB) from the lung into the blood circulation in mouse. Electron microscopy demonstrated accumulation of intratracheally instilled UFCB in the large-sized gaps developing between the cytoplasmic processes of the alveolar epithelial cells, possibly as a result of shrinkage of cytoplasm, by receiving stimulus/signals generated and released following UFCB attachment on the alveolar epithelial cells. Occasional penetration of the accumulated UFCB into the alveolar basement membrane, exposing to the air space, was observed at the gap. These results suggest that inhaled UFPs may, in part, pass the air-blood barrier through the large-sized gap formed between the alveolar epithelial cells.

To study the acute and subacute lung toxicity of low dose of ultrafine colloidal silica particles (UFCSs), mice were intratracheally instilled with 0, 0.3, 3, 10, 30 or 100 μg of UFCSs. Cellular and biochemical parameters in bronchoalveolar lavage fluid (BALF), histological alteration and the body weight were determined at 3 days after instillation. Exposure to 30 or 100 μg of UFCSs produced moderate to severe pulmonary inflammation and tissue injury. To investigate the time response, mice were instilled with 30 μg of UFCSs and sacrificed at intervals from 1 to 30 days postexposure. UFCSs induced moderate pulmonary inflammation and injury on BALF indices at acute period; however, these changes gradually regressed until recovery during the experiment. Concomitant histopathological and laminin immunohistochemical findings generally correlated to BALF data. TUNEL analyses in UFCSs-treated animals showed a significant increase of the apoptotic index in lung parenchyma at all observation times. 8-OHdG expression occurred in lung epithelial cells and activated macrophages, which correlated to lung lesions in UFCSs-treated mice. These findings suggest that instillation of a small dose of UFCSs causes transient acute moderate lung inflammation and tissue damage. Oxidative stress and apoptosis may underlie the lung tissue injury induction.

To compare the pulmonary toxicity between ultrafine colloidal silica particles (UFCSs) and fine colloidal silica particles (FCSs), mice were intratracheally instilled with 3 mg of 14 nm UFCSs and 230 nm FCSs and pathologically examined from 30 minutes to 24 hour postexposure. Histopathologically, lungs exposed to both sizes of particles showed bronchiolar degeneration and necrosis, neutrophilic inflammation in alveoli with alveolar type II cell swelling and particle-laden alveolar macrophage accumulation. UFCSs, however, induced extensive alveolar hemorrhage compared to FCSs from 30 minutes onwards. UFCSs also caused more severe bronchiolar epithelial cell necrosis and neutrophil influx in alveoli than FCSs at 12 and 24 hours postexposure. Laminin positive immunolabellings in basement membranes of bronchioles and alveoli of UFCSs treated animals was weaker than those of FCSs-treated animals in all observation times. Electron microscopy demonstrated UFCSs and FCSs on bronchiolar and alveolar wall surface as well as in the cytoplasm of alveolar epithelial cells, alveolar macrophages and neutrophils. Type I alveolar epithelial cell erosion with basement membrane damage in UFCSs treated animals was more severe than those in FCSs-treated animals. At 12 and 24 hours postexposure, bronchiolar epithelial cells in UFCSs-treated animals showed more intense vacuolation and necrosis compared to FCSs-treated animals. These findings suggest that UFCSs have greater ability to induce lung inflammation and tissue damages than FCSs.

Infection with the gastric pathogen Helicobacter pylori ( H. pylori) causes chronic gastritis, peptic ulcer, and gastric adenocarcinoma. These diseases are associated with production of reactive oxygen species (ROS) from infiltrated macrophages and neutrophiles in inflammatory sites. Metallothionein (MT) is a low-molecular-weight, cysteine-rich protein that can act not only as a metal-binding protein, but also as a ROS scavenger. In the present study, we examined the role of MT in the protection against H. pylori-induced gastric injury using MT-null mice. Female MT-null and wild-type mice were challenged with H. pylori SS1 strain, and then histological changes were evaluated with the updated Sydney grading system at 17 and 21 wk after challenge. Although the colonization efficiency of H. pylori was essentially the same for MT-null and wild-type mice, the scores of activity of inflammatory cells were significantly higher in MT-null mice than in wild-type mice at 17 wk after challenge. Histopathological examination revealed erosive lesions accompanied by infiltration of inflammatory cells in the infected MT-null mice but not in wild-type mice. Furthermore, activation of NF-κB and expression of NF-κB-mediated chemokines such as macrophage inflammatory protein-1α and monocytes chemoattractant protein-1 in gastric cells were markedly higher in MT-null mice than in wild-type mice. These results suggest that MT in the gastric mucosa might play an important role in the protection against H. pylori-induced gastric ulceration.

The objective of this study was to investigate acute lung toxicity caused by Asian sand dust. Simulated Asian sand dust collected from the Tennger desert in China (CJ-2 particles) and Asian sand dust collected from the atmosphere in Japan (Tottori particles) were used. Saline suspensions of 50, 200, 800, and 3,000 µg Asian sand dust were intratracheally instilled to ICR mice. Localized accumulation of the dust particles was observed in the bronchioles and the alveoli of the lung tissues; acute inflammatory changes characterized by infiltration of macrophages and neutrophils were observed around the particles. Degenerated alveolar walls and bronchial epithelial cells, as well as a weakened positive immunolabeling for laminin, were observed to be associated with particle attachment. Positive immunolabelings for interleukin-6, tumor necrosis factor-α inducible nitric oxide synthase, and dimeric copper- and zinc-containing superoxide dismutase were observed mainly in the inflammatory cells in the lesions; these findings were not observed in the controls or in areas lacking lesions. These results suggest that Asian sand dust particles caused damage to the lung tissue through a direct physical effect. In addition, secondary released cytokines and oxidative stress generated in the lesion may be involved in the development of the acute lung toxicity.