Pathophysiology
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 cause cancer. Long thin asbestos fibers (blue asbestos,
amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile
or white asbestos fibers).[4] However, there is now evidence that
smaller particles may be more dangerous than the larger fibers.[1][2]
They remain suspended in the air where they can be inhaled, and may
penetrate more easily and deeper into the lungs. "We probably will find
out a lot more about the health aspects of asbestos from [the World
Trade Center attack], unfortunately," said Dr. Alan Fein, chief of
pulmonary and critical-care medicine at North Shore-Long Island Jewish
Health System. Dr. Fein has treated several patients for "World Trade
Center syndrome" or respiratory ailments from brief exposures of only a
day or two near the collapsed buildings.[3]
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 localised 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 tumour.
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 act through direct physical interactions with the cells of
the mesothelium in conjunction with indirect effects following
interaction with inflammatory cells such as macrophages.
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.
Common gene abnormalities in mesothelioma cell lines include deletion of
the tumor suppressor genes:
Neurofibromatosis type 2 at 22q12
P16INK4A
P14ARF
Asbestos has also been shown to mediate the entry of foreign DNA into
target cells. Incorporation of this foreign DNA may lead to mutations
and oncogenesis by several possible mechanisms:
Inactivation of tumor suppressor genes
Activation of oncogenes
Activation of proto-oncogenes due to incorporation of foreign DNA
containing a promoter region
Activation of DNA repair enzymes, which may be prone to error
Activation of telomerase
Prevention of apoptosis
Asbestos fibres have been shown to alter the function and secretory
properties of macrophages, ultimately creating conditions which favour
the development of mesothelioma. Following asbestos phagocytosis,
macrophages generate increased amounts of hydroxyl radicals, which are
normal by-products of cellular anaerobic metabolism. However, these free
radicals are also known clastogenic and membrane-active agents thought
to promote asbestos carcinogenicity. These oxidants can participate in
the oncogenic process by directly and indirectly interacting with DNA,
modifying membrane-associated cellular events, including oncogene
activation and perturbation of cellular antioxidant defences.
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-β (TGF-β) which in turn, may induce the
chronic stimulation and proliferation of mesothelial cells after injury
by asbestos fibres.
|
