Asbestos-Induced Mesothelioma.

Malignant mesothelioma is a rare form of cancer, in which the cancer cells are found in the sac lining the chest (pleura) or abdomen (peritoneum). This lethal disease is associated with asbestos and has vast economic and legal implications. As the disease takes approximately twenty years to manifest itself in humans, a wave of diagnoses is expected in the near future. In the United States alone, an estimated 3,500 - 4,000 patients are diagnosed with mesothelioma annually, and it is estimated that over the next 35 years, more than 250,000 people in Western Europe will be diagnosed with the disease. Malignant Mesothelioma, edited by internationally recognized experts in the field, is a comprehensive text that relates science, pathology, clinical aspects and therapy for mesothelioma under one cover. The book integrates the newest research and advances in its discussions of the disease, covering such topics as carcinogenesis, epidemiology, benchwork, endoscopy, multimodality approaches and treatment. It includes discussions on novel approaches to mesothelioma, such as gene therapy, vaccination strategies and immunotherapy, as well as discussions on the legal and economic aspects of the disease. Over 200 illustrations round out the text. An invaluable reference for the medical oncologist, thoracic surgeon, radiation oncologist, pulmonologist, and benchworker interested in the disease

Src-dependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos

Crocidolite asbestos elicits oxidative stress and cell proliferation, but the signaling cascades linked to these outcomes are unclear. To determine the role of mitogen-activated protein kinases (MAPK) in asbestos-induced cell signaling, we evaluated the effects of crocidolite asbestos, EGF and H2O2, on MAPK activation in murine lung epithelial cells (C10 line). In contrast to rapid and transient activation of extracellular signal-regulated kinase 5 (ERK5) by EGF or H2O2, asbestos caused protracted oxidant-dependent ERK5 activation that was inhibited by an Src kinase inhibitor (PP2), but not by an inhibitor of epidermal growth factor receptor (EGFR) phosphorylation (AG1478). ERK1/2 activation by asbestos was inhibited by either PP2 or AG1478. To confirm the involvement of Src in ERK1/2 and ERK5 activation, a dominant-negative Src construct was used. These experiments showed that Src was essential for ERK1/2 and also ERK5 phosphorylation by asbestos. Time frame studies indicated immediate activation of Src by asbestos fibers, whereas EGFR phosphorylation occurred subsequently. Data suggest that asbestos causes activation of ERK5 through an EGFR-independent pathway, whereas ERK1/2 activation is dependent on Src through a mechanism involving phosphorylation of the EGFR. Furthermore, Src, ERK1/2 and ERK5 activation are essential for cell proliferation by asbestos. The use of a dominant-negative ERK5 construct caused selective downregulation of c-jun expression, whereas inhibition of Src by PP2 or MEK1 by PD98059 caused decreases in c-fos, fra-1 and c-jun expression in asbestos-exposed C10 cells. These observations may have broad relevance to cell proliferation by carcinogenic mineral fibers and oxidants

Myeloperoxidase modulates lung epithelial responses to pro-inflammatory agents.

During extensive inflammation, neutrophils undergo secondary necrosis causing myeloperoxidase (MPO) release which may damage resident lung cells. Recent observations suggest that MPO has pro-inflammatory properties, independent of its enzymatic activityHoHHHimportant role in thas. The aims of this study were to characterize MPO internalization by lung epithelial cells and to investigate the effect of MPO on oxidative stress, DNA damage and cytokine production by lung epithelial cells.Human alveolar and bronchial epithelial cells were stimulated with MPO with or without priming the cells with pro-inflammatory stimuli. MPO protein was detected in cell cytoplasm. Expression of heme-oxygenase (HO)-1 and DNA strand breakage were determined. The production of interleukin (IL)-8 and 6 were measured.Analyses of MPO stimulated cells demonstrated MPO presence in the cells. HO-1 expression was increased after MPO stimulation and increased further when cells were primed before MPO stimulation. MPO exposure also induced DNA strand breakage. Interestingly, MPO inhibited IL-8 production in bronchial, but not alveolar epithelium.In conclusion, alveolar and bronchial epithelial cells can internalize MPO. Stimulation with MPO increases HO-1 expression and DNA strand breakage, suggesting cell damaging capacity of MPO. In addition, MPO inhibited IL-8 production by bronchial epithelial cells, indicating a negative feedback loop for neutrophil recruitment

Silica induces NLRP3 inflammasome activation in human lung epithelial cells

ABSTRACT: BACKGROUND: In myeloid cells the inflammasome plays a crucial innate immune defenses against pathogen- and danger-associated patterns crystalline silica. Respirable mineral particles impinge upon the lung causing irreversible damage, sustained inflammation and silicosis. In we investigated lung epithelial cells as a target for silica-induced activation. METHODS: A human bronchial epithelial cell line (BEAS-2B) normal human bronchial epithelial cells (NHBE) were exposed to toxic but nonlethal doses of crystalline silica over time to perform functional characterization of NLRP3, caspase-1, IL-1beta, bFGF and HMGB1. RT-PCR, caspase-1 enzyme activity assay, Western blot techniques, cytokine-specific ELISA and fibroblast (MRC-5 cells) proliferation performed. RESULTS: We were able to show transcriptional and upregulation of the components of the NLRP3 intracellular platform, as activation of caspase-1. NLRP3 activation led to maturation of pro-IL- secreted IL-1beta, and a significant increase in the unconventional the alarmins bFGF and HMGB1. Moreover, release of bFGF and HMGB1 was dependent on particle uptake. Small interfering RNA experiments using revealed the pivotal role of the inflammasome in diminished release of pro-inflammatory cytokines, danger molecules and growth factors, and proliferation. CONCLUSION: Our novel data indicate the presence and activation of the NLRP3 inflammasome by crystalline silica in human lung epithelial cells, which prolongs an inflammatory signal and affects proliferation, mediating a cadre of lung diseases

Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells

Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathological presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis vs. silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBE). Observations were confirmed in an immortal human bronchial epithelial cell line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials