Pathophysiology

mesothelium consists of a single layer of flattened to cuboidal cells

The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.

Pleural contamination with asbestos or other mineral fibres, has been shown to induce carcinogenesis. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers)[2]. Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres. It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localized lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumor.

Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibres remain unclear despite the demonstration of its oncogenic capabilities. However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibres has not yet been achieved. In general, asbestos fibres are thought to exert their carcinogenic effects via direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.
critical to the pathogenesis of mesothelioma Studies involving intrapleural or intraperitoneal inoculation of rats and mice with different types of asbestos fibre established that long, thin fibres caused a higher incidence of mesothelioma than did short fibres and that cells phagocytose and accumulate longer fibres more effectively than shorter fibres. Similarly, incubation of Syrian hamster cells with fibrerglass which had an average length of 9.5m resulted in cell transformation with an efficiency identical to crocidolite. Grinding these fibres to approximately 2.2m reduced the transforming ability 10- to 20-fold while further reduction to <1m completely eliminated the transforming ability of the fibreglass particles.

Analysis of the interactions between asbestos fibres and DNA has shown that phagocytosed fibres are able to make contact with chromosomes, often adhering to the chromatin fibres or becoming entangled within the chromosome. This contact between the asbestos fibre and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.



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