Pathobiological Responses

Once fibers and particles land on the airway and alveolar surfaces, the epithelial lining cells quickly respond. In the conducting airways, the mucociliary escalator rapidly transports the inhaled materials to the mouth where they can be swallowed or expectorated. This fast clearance compartment clears the great majority of inhaled particles within the first 24 hours post exposure, while the slow clearance compartment at the alveolar level retains a smaller proportion of the asbestos and silica (2). 

there are the multiple fibers or crystals that have deposited on an alveolar epithelial surface (Fig. 1). Lipid peroxidation could ensue (as discussed above) but may be blunted by the alveolar lining layer, which is known to have a strong buffering effect on particle toxicity (16,19). Within the first hour after a particle lands on the Type I epithelium, this cell type responds by actively surrounding and actually phagocytizing the fibers or crystals (Fig. 2) (4,7). These cells 

This may be the best juncture for a description of the two diseases, asbestosis and silicosis, to diverge. While the end product of exposure (i.e., diffuse scarring of the lung at the alveolar level) is the same, the basic cellular and molecular mechanisms that mediate the diseases, apparently, are not. There are a number of details available as inhaled asbestos fibers are followed through the sequence that leads to interstitial fibrosis. Fewer such details are reported for silicosis, but it is clear that this disease is immune mediated and will be described accordingly. 

A consequence of asbestos-induced cell injury is a prominent increase in the number of cells proliferating in several anatomic compartments. The alveolar epithelium was dramatically affected, with the percent of dividing cells increasing up to 40-fold after three consecutive days of exposure (29,30). Surprisingly, the airway epithelium in this model also exhibited significant increases in dividing cells (31). The increase was not expected because there was no apparent injury to this epithelial population. However, other excellent models of 

The microscopic nodular pattern of sihcosis that results in these clinical features is more difficult to understand than the pattern of asbestosis. As described above, the lesions of asbestosis develop just as one would predict from the deposition pattern of the fibers. While it is clear that initial deposition of sihca crystals is essenhaUy the same as fibers, there is an airway component of the disease that is not understood on the basis of this deposition pattern. Thus, fibrosis of the alveolar waUs could proceed through the rapid generation of oxygen radicals that are highly cytotoxic to epithehal cells and responding macrophages, and then there would be an influx of chronic inflammatory cells like the lymphocyte populations described above. However, sihca crystals are found embedded along the airway walls. They must be taken up by epithehal 

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Allen JR, Norback DH. 1976. Pathobiological responses of primates to polychlorinated biphenyl exposure. In Proceedings of the National Conference on Polychlorinated Biphenyls, EPA... 

When animals or humans are exposed to aerosohzed fibers or particles, some proportion of the inhaled materials will be deposited in the nasal passages and upper airways. Other particles reach the conducting airways, including the terminal bronchioles, and part of the disease process is manifested there. Finally, a proportion of the asbestos fibers or silica crystals is deposited on the alveolar epithelium. With every breath that contains particles, more are deposited along the respiratory tract, thus triggering a series of pathobiological responses. AU the diseases caused by asbestos and silica are dose responsive, i.e., the more particles inhaled, the more likely it is that the disease will develop and the more advanced the disease will finally appear (2). 

About 10-20% of all transmembrane proteins that are targeted to the ER and subsequently enter the secretory pathway are subject to post-translational modification with glycosylphosphatidyl-inositol (GPI). Proteins bearing the GPI anchor are involved in signal transduction, immune response, cancer cell invasion, and metastasis and the pathobiology of trypanosomal parasites. The structure of the GPI anchor has been analyzed for mammals, protozoa, and yeast. The general structure of the glycolipid structure is shown in Scheme 4. 

Since oxidative stress is related to the risk of chronic diseases, lower levels of oxidative stress are considered consistent with lower risk of these diseases. A few studies have also measured biochemical and pathobiological markers of cancer in patients after lycopene intervention (Kucuk et al., 2001). However, the levels of lycopene used in these studies were based on preliminary studies investigating the absorption and oxidative stress status in healthy and at risk for cancer patients. Dose-response studies have not been undertaken. 

Exposure to pathobiological stressors causes the formation or release of mediators other than cytokines and ROS. These include stress-induced hormones and nitric oxide (NO). Stress responses stimulate the hypothalamic-pituitary axis causing the release of adrenocorticotropin, thereby elevating glucocorticoid levels. Glucocorti-... 

Jones DH, Lewis DH, Eurell TE, et al. 1979. Alteration of the immune response of channel catfish (ictalurus punctatus) by polychlorinated biphenyls. In Symposium on pathobiology of environmental pollutants Animal models and wildlife as monitors. Washington, DC National Academy of Sciences, 385-386. 

Tumor necrosis factor-a is an endotoxin (LPS)-inducible cytokine that plays an important role in the inflammatory processes. TNF-a is implicated in the pathobiology of many human diseases such as septic shock, cancer, rheumatoid arthritis, and AIDS. Inhibition of elevated TNF-a levels has been proposed as a strategy for alleviating the progression of these diseases. Eicosanoids derived from AA (20 4n-6), such as leukotrienes and thromboxanes, have been implicated in the inflammatory responses. In this study, the roles of eicosanoids on the inhibition of LPS-induced TNF-a production by n-3 PUFA were investigated in human monocytic THP-1 cells. The n-3 PUFA, EPA and DHA, decreased the production of TNF-a to the greatest extent among various... 

Asbestos particles therefore initiate an inflammatory response mediated via the pleural mesothelial cell release of chemokines in the pleural space (55-57). Chemokines play an important role in the pathogenesis of asbestos-induced pleural effusions. Typically, patients with asbestos-induced pleural effusions have recurring episodes of fluid formation which may resolve spontaneously. These repeated episodes are presumed to be due to new asbestos fibers activating pleural mesothelial cells. Whether chemokines such as IL-8 that are present in such high quantities in asbestos-induced pleural disease play any role in mesothelial cell transformation into mesothelioma remains unclear. The association of asbestosis and mesothelioma has been well described, but the origin and pathobiology of the disease remain clouded. 

Makala, L.H., Suzuki, N., and Nagasawa, H. 2002-2003. Peyer s patches Organized lymphoid structures for the induction of mucosal immune responses in the intestine. Pathobiology. 70 55-68. 

Many aspects of atherogenesis are only partially understood. The sequences of hormonally and humorally induced cellular responses, the relative importance of distinct secretory products, and the wide range of genetic features are not well delineated. Only intensive research in the field of the molecular biology of the arterial wall will help to develop a more fundamental understanding of the pathobiology of atherosclerosis [107]. 

The effects of o>-3 polyunsaturated fatty acids on platelet, neutrophil, and monocyte functions, membrane fluidity, serum lipids, and both prostanoid and leukotriene formation are aspects of a fundamental modulation of complex interactions between different cellular systems [16] and may be potentially important in the pathobiology of atherosclerosis [36, 106, 107]. Moreover, recent investigations indicated that other substances in addition to polyunsaturated fatty acids may be responsible for the antithrombotic properties of marine flsh [3], a point which has to be evaluated in the future. 

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