Air Pollution, the Automobile, and Public Health (1988) / Chapter Skim
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Biochemical and Cellular Interrelationships in the Development of Ozone-Induced Pulmonary Fibrosis
Biochemical and Cellular Interrelationships in the Development of Ozone-Induced Pulmonary Fibrosis
Pages 415-440
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From page 415... ...
LAST University of California, Davis Difficulties in Relating Ozone Exposure to Lung Disease / 416 Response to Fibrogenic Insult / 417 Acute Lung Injury and Edema / 417 Transition from Pulmonary Edema to Cellular Inflammation / 418 The Middle Phase / 420 Lung Fibrosis / 425 Models of Exposure / 427 Experimental Approaches / 427 Chronic Exposure / 429 Progression of Lung Injury After Cessation of Exposure / 430 Synergistic Interactions / 430 Determination of Human Risk / 431 Identification of Susceptible Populations / 432 Summary 1 433 Summary of Research Recommendations / 434 Air Pollution, the Automobile' and Public Health.
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From page 416... ...
Animal hygiene in those experiments was not always adequate to prevent outbreaks of pneumonia and other confounding disease. It may be that the human disease analogous to that caused by O3 is not chronic lung fibrosis but acute forms of pulmonary fibrosis such as the adult respiratory distress syndrome.
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Acute Lung Injury and Edema The earliest quantifiable response of the lung to many types of injury, including exposure to 03, is pulmonary edema. At high levels of injury, this response is easy to quantify; the animal is sacrificed and the lung weighed.
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Transition from Pulmonary Edema to Cellular Inflammation The first lung cells to encounter inhaled or intratracheally instilled fibrogenic agents are the epithelial cells lining the respiratory tract. Oxidant gases such as nitrogen diox
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Such mediators could include products from fibrin, fibronectin, albumin, prostaglandins, leukotrienes, and a vast array of poorly characterized chemoattractants and other factors. Present concepts of the critical sequence of events in lung injury suggest that the response of the lung to cellular damage and/or to pulmonary edema is the movement of alveolar macrophages and (perhaps)
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From page 420... ...
, or indirectly as a result of phagocytotic activity by alveolar macrophages or neutrophils. These cells release free radicals such as superoxide and hydroxyl during increased metabolism which is often termed "oxidative burst." Evidence for the role of free radicals in lung damage includes a wide variety of observations.
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Studies of the linkages between epithelial cell damage and repair and changes in populations of pulmonary macrophages and interstitial cells should be undertaken in whole animals. Pulmonary Alveolar Macrophages.
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Mediators possibly released by damaged lung epithelial cells or derived from damaged matrix components, which maintain and amplify lung injury after acute cellular or organ damage, should be characterized. Macrophage secretion of effecter cell chemoattractants appears to be increased in fibrosis.
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Elias and coworkers (1985) found that supernatants from normal human alveolar macrophages inhibit growth of log-phase fibroblasts.
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However, hyperopia in the presence of lung macrophages increased collagen synthesis about the same extent as did bleomycin. There is also evidence that bleomycin affects fibroblast proliferation.
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Examination of factors released by inflammatory cells that modulate collagen synthesis or fibroblast proliferation, especially in response to 03, might help to define the mechanisms underlying the transition from the damaged, inflamed lung to the fibrotic lung. Lung Fibrosis Lung fibrosis, as defined clinically, refers to interstitial fibrosis as is seen in the later stages of idiopathic pulmonary fibrosis (also called cryptogenic fibrosing alveolitis in the literature of the United Kingdom)
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Clark and coworkers (1980) found that fibroblasts exposed to bleomycin in vitro not only had increased collagen synthesis rates, but also synthesized more type I collagen when compared with controls.
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Assays analogous to the quantification of lung collagen synthesis rate can be used to measure elastin synthesis in lungs of rats or other laboratory animals exposed to O3 (Dubick et al.
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1979~. The terminal bronchiolar and proximal alveolar duct region is an area in which a fibroblastic response to O3 would be expected since several studies have demonstrated O3-induced epithelial cell injury and proliferation, as well as a moderate inflammatory response, in this location (Stephens et al.
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Such new methods may allow us to distinguish collagen synthesis associated with normal lung repair from abnormal deposition of collagen associated with fibrosis, and to distinguish be tween reversible and irreversible events in lung collagen metabolism. These methods may also be made very sensitive; they remain to be validated for this purpose.
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A six-week postexposure "recovery period" breathing filtered air exacerbated the increase in lung collagen content appreciated immediately after cessation of exposure. This result suggests that not only are these effects irreversible, at least in this time frame, but that they are also progressive.
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From page 431... ...
Furthermore, responses in this and other assays in rats exposed to 0.2 ppm O3 for 8 hr/night and in rats exposed continuously have been similar. That is, the increase in lung collagen synthesis rate is not contingent upon continuous exposure of rats to O3, but may occur under an intermittent exposure regimen that models human diurnal exposures as well.
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From page 432... ...
The potential adverse health effects of air pollution that constitute the major concern, however, are chronic effects from intermittent, long-term, low-level exposures: cancer, emphysema, pulmonary fibrosis, and chronic obstructive lung disease. Controlled human exposures are of absolutely no value for assessing these types of risks.
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From page 433... ...
These models have certain features in common with the continuing changes observed in lungs of rats and monkeys exposed to O3 followed by periods where they breathe only filtered pure air. Rats exposed to O3 in combination with various acidic aerosols, which by themselves apparently cause no lung damage at the concentrations tested, have suffered enhanced acute lung damage.
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Recommendlation 6 Basic research in cell culture systems should be performed to examine the biochemical basis of cell-cell communication and the molecular nature of various mediators, released by leukocytes and macrophages from damaged lungs, that enhance or prolong the cellular inflammatory response. MEDIUM PRIORITY Recommendation 7 Mediators possibly released by damaged lung epithelial cells or derived from damaged matrix components (arachidonic acid
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, which maintain and amplify lung injury after acute cellular or organ damage should be characterized. Recommendation 8 Examination of factors released by inflammatory cells that modulate collagen synthesis or fibroblast proliferation, especially in response to 03, might help to define the mechanisms under lying the transition from the damaged, inflamed lung to the fibrotic lung.
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1983. Lactate dehydrogenase isoenzymes in hamster lung ravage fluid after lung injury, Toxicol.
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1983. Potentiation of butylated hydroxytoluene-induced acute lung damage by oxygen.
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1984. The regulation of lung fibroblast proliferation by alveolar macrophages in experimental silicosis, Am.
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1982. Role of alveolar macrophages in asbestosis: modulation of neutrophil migration to the lung after acute asbestos exposure, Thorax 37:803-809.
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1984. Neutrophil chemotactic activity generation by alveolar macrophages after bleomycin injury, Am.
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