Role of Reactive Oxygen and Nitrogen Species (ROS/RNS) in Asbestos Bioreactivity
An important unresolved issue is whether asbestos fiber carcinogenic-ity is through direct effects of asbestos on mesothelial cells or through indirect mechanisms involving oxidative stress (31,32). A ramification of interaction of long (>5mm) fibers with cells is frustrated phagocyto-sis and a prolonged oxidative burst (Fig. 2.1) (33).
The increased durability and high iron content of the amphiboles cro-cidolite and amosite also may contribute to their higher carcinogenic potential through oxidants catalyzed by iron or surface reactions occur-ring on the fiber. Iron-rich durable fibers such as crocidolite, which contain as much as 36% iron by weight, also may have increased reac-tivity because of the oxidation state of iron, i.e., increases in ferrous iron, aiding in its chelation (34). The cytotoxicity of crocidolite fibers in
The increased durability and high iron content of the amphiboles cro-cidolite and amosite also may contribute to their higher carcinogenic potential through oxidants catalyzed by iron or surface reactions occur-ring on the fiber. Iron-rich durable fibers such as crocidolite, which contain as much as 36% iron by weight, also may have increased reac-tivity because of the oxidation state of iron, i.e., increases in ferrous iron, aiding in its chelation (34). The cytotoxicity of crocidolite fibers in
Figure 2.1. Scanning electron microscopy showing phagocytosis of long asbestos fibers by alveolar macrophages.
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 (35,36).
Studies on animal models and cell cultures have confirmed that asbestos fibers generate ROS and RNS (19,32,37), and these effects may be potentiated by the inflammation associated with fiber exposures (38). Asbestos also activates redox-sensitive transcription factors such
as nuclear factor kappa B (NF-kB) (39) and activator protein-1 (AP-1) (40), which lead to increased cell survival, inflammation, and, para-doxically, the upregulation of antioxidant enzymes such as manganese superoxide dismutase (38). This enzyme is also overexpressed in
asbestos-related mesotheliomas (41,42), rendering them highly resis-tant to oxidative stress in comparison to normal mesothelial cells.
Moreover, its overexpression prevents cell injury by asbestos (43). In human pleural mesothelial cells in vitro, crocidolite asbestos causes oxidative stress and DNA single-strand breaks (44), 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) (45,46), and endothelial nitric oxide synthase (eNOS) in malignant mesotheliomas (47). Thioredoxin, a small redox-
active 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 differen-tiation 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 (48). Over-expression of gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione-associated pathways, could also play an im-
portant role in the primary drug resistance of mesotheliomas (49).
Catalytically active 5-lipooxygenase could also be involved in the reg-ulation of proliferation and survival in mesotheliomas via a vascular endothelial growth factor (VEGF)-related circuit (50).
Studies on animal models and cell cultures have confirmed that asbestos fibers generate ROS and RNS (19,32,37), and these effects may be potentiated by the inflammation associated with fiber exposures (38). Asbestos also activates redox-sensitive transcription factors such
as nuclear factor kappa B (NF-kB) (39) and activator protein-1 (AP-1) (40), which lead to increased cell survival, inflammation, and, para-doxically, the upregulation of antioxidant enzymes such as manganese superoxide dismutase (38). This enzyme is also overexpressed in
asbestos-related mesotheliomas (41,42), rendering them highly resis-tant to oxidative stress in comparison to normal mesothelial cells.
Moreover, its overexpression prevents cell injury by asbestos (43). In human pleural mesothelial cells in vitro, crocidolite asbestos causes oxidative stress and DNA single-strand breaks (44), 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) (45,46), and endothelial nitric oxide synthase (eNOS) in malignant mesotheliomas (47). Thioredoxin, a small redox-
active 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 differen-tiation 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 (48). Over-expression of gamma-glutamylcysteine synthetase, a rate-limiting enzyme in glutathione-associated pathways, could also play an im-
portant role in the primary drug resistance of mesotheliomas (49).
Catalytically active 5-lipooxygenase could also be involved in the reg-ulation of proliferation and survival in mesotheliomas via a vascular endothelial growth factor (VEGF)-related circuit (50).
No comments:
Post a Comment