Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice.

Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs.

CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure.

BACKGROUND: Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear. METHODS: We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH. RESULTS: We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen. CONCLUSIONS: We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.

Nasal nitric oxide is dependent on sinus obstruction in allergic rhinitis.

OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate the associations between nasal nitric oxide and nasal symptoms, sinus opacification, and markers of allergic inflammation in allergic and in nonallergic rhinitis while taking into account the effect of sinus obstruction. STUDY DESIGN: We studied 175 young adult subjects divided into three groups: 1) allergic rhinitis, 2) nonallergic rhinitis, and 3) controls. METHODS: We measured nasal nitric oxide using the breath-holding method and exhaled nitric oxide and scored semiquantitatively nasal computed tomography scans for opacification and obstruction. We also assessed the visual analogue scores of nasal symptoms, eosinophil count, and interleukin-13 mRNA levels in nasal biopsies. RESULTS: The level of nasal nitric oxide correlated with exhaled nitric oxide (r = 0.377, P < .001). In allergic rhinitis, nasal nitric oxide was elevated when compared to the controls, and an inverse correlation existed between the nasal nitric oxide level and sinus ostial obstruction (r = -0.272, P = .013). In nonallergic rhinitis, the level of nasal nitric oxide was similar to that of the controls. In allergic rhinitis, nasal nitric oxide correlated positively with the opacification score (r = 0.250, P = .033) and the nasal eosinophil count (r = 0.293, P = .030) of patients without a marked sinus ostial obstruction. CONCLUSIONS: Sinus ostial obstruction lowers the level of nasal nitric oxide and reduces its value as an indicator of allergic mucosal inflammation. A high nasal nitric oxide level may be a useful marker of eosinophilic inflammation in the nasal cavity and indicate the absence of marked sinus ostial obstruction. LEVEL OF EVIDENCE: 3b.