High levels of ambient air pollution are associated with exacerbation of asthma and respiratory morbidity, yet little is known concerning the mechanisms of inflammation and toxicity by components of inhaled particulate matter (PM). Brief inhalation of PM(2.5) (particles of an aerodynamic diameter of < 2.5 microns) (300 microg/m(3) air for 6 h followed by a period of 24 h in clean air) by either C3H/HeJ or C57/BL6 mice caused significant (P

Only a fraction of subjects exposed to asbestos develop malignant mesothelioma (MM), suggesting that additional factors may render some individuals more susceptible. We tested the hypothesis that asbestos and Simian virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a costimulatory effect in inducing ERK1͞2 phosphorylation and activator protein-1 (AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and primary human mesothelial cells (HM). Ap-1 activity caused the expression and activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to cell invasion. Experiments using siRNA and chemical inhibitors confirmed the specificity of these results. The same effects were observed in HM and SHM. Experiments in hamsters showed strong cocarcinogenesis between asbestos and SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40. Our results indicate that mineral fibers and viruses can be cocarcinogens and suggest that lower amounts of asbestos may be sufficient to cause MM in individuals infected with SV40.activator protein-1 ͉ ERK1͞2 ͉ matrix metalloprotease ͉ environmental carcinogenesis ͉ viral oncology M alignant mesothelioma (MM) is a malignancy of the mesothelial cells that form the serosal membranes that cover the chest and abdominal cavities. Median survival is Ϸ12 months, and MM causes 2,000-3,000 deaths per year in the USA and Ϸ1,000 deaths per year in the U.K (1). The continuing increase in the incidence of MM has been associated to the widespread use of asbestos in the past century. The mechanisms of asbestos carcinogenesis have been linked to the extracellular response regulated kinase ERK1͞2 and activator protein-1 (AP-1) pathways (2), to the activation of proinflammatory cytokines and NFB (3), and to the production of reactive mutagenic oxygen species by nearby lung macrophages exposed to asbestos (4).Only a fraction (Ϸ5%) of subjects exposed to high levels of asbestos develop MM. This finding suggests that additional factors, such as SV40 infection and genetic predisposition, may render some individuals more susceptible to asbestos carcinogenicity (1, 5). SV40 is a monkey DNA virus that induces MM in hamsters (6). Following this observation, numerous laboratories have detected SV40 in MM biopsies although the prevalence of SV40 varied in different studies from Ϸ6% to 60%, and some studies did not detect SV40 (7-11). SV40 contaminated human polio vaccines worldwide from 1955 until Ϸ1961. Epidemiological studies comparing cohorts born before or after 1961 detected an increased relative risk of 3 for MM in pre-1961 cohorts that included many individuals vaccinated with contaminated polio vaccines (12). However, the overall epidemiological evidence was considered inconclusive because of differences in ages among the cohorts studied and because it was uncertain that cohorts born after 1961 we...