Role of Reactive Oxygen and Nitrogen Species in Asbestos Bioreactivity

An important unresolved issue is whether asbestos fiber carcinogenicity is through direct effects of asbestos on mesothelial cells or through indirect mechanisms involving oxidative stress. A ramification of interaction of long (>5mm) fibers with cells is frustrated phagocytosis and a prolonged oxidative burst (Fig. 2.1).

The increased durability and high iron content of the amphiboles crocidolite and amosite also may contribute to their higher carcinogenic potential through oxidants catalyzed by iron or surface reactions occurring on the fiber. Iron-rich durable fibers such as crocidolite, which contain as much as 36% iron by weight, also may have increased reactivity because of the oxidation state of iron, i.e., increases in ferrous iron, aiding in its chelation. The cytotoxicity of crocidolite fibers in human lung carcinoma cells is directly linked to iron mobilization and is followed by increased ferritin synthesis, a perpetual feedback system for uptake of iron by cells.

Studies on animal models and cell cultures have confirmed that asbestos fibers generate ROS and RNS, and these effects may be potentiated by the inflammation associated with fiber exposures. Asbestos also activates redox-sensitive transcription factors such as nuclear factor kappa B (NF-kB) and activator protein-1 (AP-1), which lead to increased cell survival, inflammation, and, paradoxically, the upregulation of antioxidant enzymes such as manganese superoxide dismutase. This enzyme is also overexpressed in asbestos-related mesotheliomas, rendering them highly resistant to oxidative stress in comparison to normal mesothelial cells. Moreover, its overexpression prevents cell injury by asbestos. In human pleural mesothelial cells in vitro, crocidolite asbestos causes oxidative stress and DNA single-strand breaks, but these are not exacerbated by pretreatment with inhibitors of antioxidant enzymes.

Other studies have demonstrated overexpression of enzymes related to oxidative stress, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (NOS-2), and endothelial nitric oxide synthase (eNOS) in malignant mesotheliomas (47). Thioredoxin, a small redoxactive protein reduced by the selenoprotein thioredoxin reductase and reduced nicotinamide adenine dinucleotide phosphate (NADPH), is associated in other models of cancer with cell growth and differentiation and is also overexpressed in mesothelioma cells. This protein might be a factor governing the poor prognosis of mesotheliomas and their reduced responsiveness to conventional therapies. Overexpression of gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione-associated pathways, could also play an important role in the primary drug resistance of mesotheliomas. Catalytically active 5-lipooxygenase could also be involved in the regulation of proliferation and survival in mesotheliomas via a vascular endothelial growth factor (VEGF)-related circuit.