The Multitopic Blog

The epithelial lining of the serous cavities of the body which is formed by a layer of flattened cuboidal cells and includes the peritoneal, pericardial and pleural cavities constitutes the mesothelium. When asbestos fibres are deposited in the parenchyma of the lung, they may penetrate the visceral pleura from where the fibres are carried to the pleural surface, thus leading to malignanat mesothelial plaques being formed. How peritoneal mesothelioma develops is still unknown, though there have been suggestions that the asbestos fibres may be transported to the abdomen and associated organs from the lungs through the lymphatic system. Asbestos fibres may also be deposited in the gut after the intake of sputum contaminated by asbestos fibres.

Contamination of the pleural cavity by asbestos and other mineral fibres has been known to lead to cancer. Among asbestos fibres, there are certain kinds which can be more potent to the human body. Long and thin fibres such as blue asbestos and amphibole fibres are more potent carcinogens as compared to what are known as “feathery fibres” such as chrysotile or white asbestos fibres. However in the recent past, studies have show that since smaller particles remain suspended in the air whereby they are inhaled and find their way into the lungs more easily, they are by far more dangerous that the longer variety. Dr. Alan Fein who is chief of pulmonary and critical-care medicine at the North Shore Long Island Jewish Health System, said following the World Trade Center attacks that due to the asbestos exposure to many patients from the collapsed buildings; a lot could be learnt about the various aspects of asbestos.

Some scientists believe that the transport of fibres to the pleura is critical to the pathogenesis of mesothelioma. This observation is backed by the increase of macrophages and other cells of the immune system in localized lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats that were experimented upon.

During experiments it has been found that asbestos could be a carcinogen with the development of mesothelioma that occurs in the stages of initiation and promotion. The molecular mechanisms that cause normal mesothelial cell into malignant ones by asbestos fibres are still unknown even though its oncogenic capabilities are known. The complete in vitro change of normal mesothelial cells into malignant ones subsequent to asbestos exposure has not yet been achieved. It is believed that asbestos fibres directly interact with the cells of the mesothelium along with the other effects of interaction with inflammatory cells.

It has been shown through observing the reactions between asbestos fibres and DNA that phagocysted fibres make contact with chromosomes, getting attached to chromatin fibres or becoming entangled with the chromosome. Such interaction between the asbestos fibres and the chromosomes can cause severe abnormalities, the most common being the monosomy of chromosome 22 and the structural change of 1p,3p,9p and 6q chromosome arms.

Some gene abnormalities in mesothelioma cell lines are deletion of Neurofibromatosis type 2 at 22q12, P16^INK4A, P14^ARF which are tumor suppressor genes.

Asbestos is also known to control the entry of DNA into target cells and the entry of this foreign DNA may lead to complications, mutations and oncogenesis in the following ways including-

Inactivation of tumor suppressor genes

Activation of oncogenes

Activation of proto-oncogenes due to incorporation of foreign DNA

Activation of DNA repair enzymes which may be likely to cause errors

Activation of telomerase

Prevention of apoptosis

Asbestos fibres also have in the past altered the function and secretory properties of macrophages thereby creating conditions which lead to the development of mesothelioma. After asbestos phagocytosis an increased amount of hydroxyl radicals which could also be routine bi-products of cellular anaerobic metabolism. These free radicals are also clastogenic and membrane-active agents which are believed to promote asbestos carcinogenicity. These oxidants are capable of participating in the oncogenic process by directly and indirectly coming into contact with DNA, modifying membrane-related cellular events, including oncogene activation and disturbance of cellular antioxidant defences.

Asbestos in some cases may have immunosuppressive properties like chrysotile fibres are known to reduce the in vitro spread of phytohemagglutin-stimulated peripheral blood lymphytes, reduce natural killer cell lysis and decrease lymphokine-activated killer cell viability and recovery. Also, genetic changes in asbestos-activated macrophages could cause the release of deadly mesothelial cell mitogens such as platelet-derived growth factor and transforming growth factor- ? which may lead to the chronic stimulation and spread of mesothelial cells after injury due to asbestos fibres.

Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-? (TGF-?) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.