Biologic Markers in Pulmonary Toxicology (1989) / Chapter Skim
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3 Markers of Physiologic Effects in Intact Organisms
3 Markers of Physiologic Effects in Intact Organisms
Pages 43-82
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From page 43... ...
Although all these tests yield markers of lung response, only a few thought most likely to have potential for detecting responses of populations to environmental exposures are discussed in detail. The second category includes markers of increased airway reactivity, both to specific environmental agents and to standardized physical or pharmacologic bronchial provocation.
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From page 44... ...
That is based on knowledge of correlations among measured values related to function, subjective perception of ill health, clinical lung disease, and impairment of physical performance. MARKERS IN PULMONARY TOXICOLOGY RESPIRATORY FUNCTION The respiratory functions of the lung include mechanisms involved in ventilation, gas distribution,alveolar-capillary gas exchange, and perfusion.
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From page 45... ...
and %FVC in 1 second Peak aspiratory flow Mean midexpiratory flow Flows at selected absolute lung volumes or portions of FVC Breathing mechanics Dynamic lung mechanics Dynamic lung compliancea Total pulmonary resistance Airway resistance and conductance, and specific airway resistance and conductance Oscillation mechanics (respiratory system impedance, composed of compliance, resistance, and inertanceJa Static-quasistatic lung compliancea Intrapulmona~y gas distribution Single-breath gas washouts Multiple-breath gas washout Imaging of radiolabeled gas and particlesa Particle bolus distributions Alveolar-capillary gas transfer Blood gases, pH, and alveolar-arterial gas tension differences Oxygen and carbon dioxide exchange at rest Diffusing capacity for carbon monoxides Gas exchange during exercises Multiple-gas evaluation of ventilation-perfusion relationships Evaluation of respiratory control . aDiscussed In this report.
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From page 46... ...
The interpretation of those measures as biologic markers of risk is only partly MARKERS IN PULMONARY TOXICOLOGY 5 4 2 1 o B ~ Normal Normal ~ CAO 25 35 45 55 YEARS 65 75 understood. When asthmatic subjects are exposed at rest to SO2 at 0.25-0.5 ppm, some undergo significant reductions in FIVE (Sheppard et al., 1980~.
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From page 47... ...
. Classical measures of dynamic lung mechanics are often useful in evaluating clinical lung disease, but by themselves have low potential as sensitive markers of lung response to environmental exposures.
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From page 48... ...
It provides indexes of lung compliance, as well as resistance; thus, it has potential for adding to the spectrum of information obtained in population studies. Tests of oscillation mechanics are in use for measuring the integrated compliance and resistance of an entire lung, but its potential as a marker is primarily in describing mechanical properties of specific regions of the respiratory system.
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From page 49... ...
Static-Quasistatic Lung Pressure-Volume Analysis Lung compliance measured during breathing is usually lower than the actual compliance of lung tissue, because of the lack of time for tissue relaxation and because of differences in compliance among lung units. Measurement of static or quasistatic compliance avoids such frequency dependence by plotting transpulmonary pressure against lung volume during a single, slow exhalation.
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From page 50... ...
Equipment for performing the test is available commercially, and several equations have been developed for predicting normal values of SBNW parameters (Gold, 1982~. Although the SBNW test continues to be included in lists of tests sensitive to small-airway disease, its usefulness as a marker of responses to environmental exposures has not been clearly demonstrated.
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From page 51... ...
~ 1981 a,b) found significant correlations between abnormal values of washout slope and closing volume in human subjects and small-airway disease in excised lung tissue.
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From page 52... ...
and alveolar dimensions; it is of particular use for assessing changes in diameter, such as those associated with obstructive lung disease. Conducting-airway obstruction can also be detected with conventional pulmonary function tests, but the latter might be less sensitive than the probe procedures in detecting early changes.
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From page 53... ...
That results in magnification of the differences in particle recovery after a single breath. The test is able to screen reproducibly for airway constriction and might also indicate the extent of such concentration; variability in both normal subjects and those with chronic obstructive airway disease was 5-10%.
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From page 54... ...
The types of detectors used are the same as those used in measuring particle clearance and are discussed in MARKERS IN PULMONARY TOXICOLOGY might alter amounts present and lead to false conclusions as to regional deposi tion. In addition, 24-hour retention var ies widely in normal people and even more in smokers and people with lung disease.
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From page 55... ...
Gas Exchange During Exercise A major problem in using respiratory function tests at rest to detect subtle
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From page 56... ...
Characteristics that can be measured during exercise and their interpretive usefulness have been listed and discussed at length (Wasserman et al., 1987~. The anaerobic threshold and relationships between heart rate and oxygen uptake appear to have good overall sensitivity to gas exchange and cardiovascular inefficiencies.
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From page 57... ...
Thn.ce results suggest that exercise testing can greatly improve the detection of subtle gas-exchange abnormalities, in addition to providing considerable discrimination among the factors that cause the abnormalities. In summary, exercise testing appears to have one of the strongest potentials among respiratory function assays as a sensitive marker of pulmonary injury associated with environmental exposures.
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From page 58... ...
Methods of Assessment In the laboratory, airway reactivity testing is divided into two general categories, depending on the choice of nonspecific versus specific agents. In both, the increased bronchoconstrictor response is assessed with pulmonary function tests.
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From page 59... ...
Nonspecific airway hyperreactivity testing has proved to be highly useful for assessing airway responses to low concentrations of environmental air pollutants. Even after the return to baseline lung function on removal from acute nitrogen dioxide (Bauer et al., 1986)
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From page 60... ...
Airway Hyperreactivity as a Marker Population-based studies that examine the effect of bronchial hyperreactivity on the rate of decline of pulmonary function in asymptomatic subjects are prerequisites to understanding airway reactivity as a risk factor. Several lines of evidence suggest that airway hyperreactivity is important in the development of chronic lung disease.
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From page 61... ...
Efforts are needed to determine whether transient but recurrent episodes of airway hyperreactivity, such as follow pollutant exposure or viral respiratory tract infection, also serve as a risk factor for progressive lung disease. Similar issues emerge in examining the relationship between airway hyperreactivity and occupational asthma.
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From page 62... ...
Evidence is accumulating that dysfunction of bronchial clearance plays a role in the pathogenesis of chronic bronchitis; mucus transport is impaired in people who have the disease (Wanner, 1977~. Cigarette-smokers and persons with chronic obstructive pulmonary disease show a wider variation in clearance rates than do nonsmoking healthy people (Albert et al., 1973; Gongora et al., 1981~.
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From page 63... ...
Alveolar clearance rates appear to be reduced in people with chronic obstructive lung disease and in cigarettesmokers (Cohen et al., 1979; Bohning et al., 1982~; that suggests some relation between altered defense and disease development. Clearance dysfunction has also been shown in animals that have viral infection (Cresia et al., 1973~.
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From page 64... ...
Alterations in nasal or tracheal transport rates have been used as markers of disease or of response to inhaled pollutants, because they are easier to measure than is whole-lung clearance (Sackner et al., 1978; Wolff et al., 1981; Majima et al., 1983; Stanley et al., 1985~. However, findings in the upper respiratory tract or trachea cannot be extrapolated to the lower lung and might not be adequate indexes of overall respiratory tract effect.
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From page 65... ...
For example, an apparent increase in clearance rate after pollutant exposure could be due to a proximal shift in deposition of the tracer aerosol, rather than to an effect on the clearance system itself. That could be a special problem in the comparison of different groups; e.g., subjects with chronic obstructive lung disease tend to have greater central airway deposition of a given tracer aerosol than healthy subjects (Lippmann et al., 1980~.
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From page 66... ...
can provide information on the amount of fibrosis in lung tissue (Cohen, 1975~. One technique used for whole-lung clear A[4RKERS IN PULMONARY TOXICOLOGY ance in both humans and experimental animals allows visualization of tracer particle distribution without the need for radiolabeled aerosols.
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From page 67... ...
, which reflects the magnitude and direction of active ion transport and the passive ion permeabilities of cellular and paracellular pathways; PD differs by site in the respiratory tract (Knowles et al., 1981~. Some sites might be better than others for assessing effects of pollutant exposure.
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From page 68... ...
The marker must be able to distinguish lung injury from the normal changes in a noninjured lung, such as an increase in lung volume, an increase in blood flow, or an increase AL4RKERS IN PULMONARY TOXICOLOGY in interstitial fluid volume due entirely to high lung vascular pressures. · It must not be transformed in the lung.
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From page 69... ...
Alveolar Epithelial Barrier The layer of epithelial cells lining the airspaces of the lungs forms a tight barrier that greatly restricts the movement of most solutes. It is not clear what happens when lung injury causes an increase in the permeability of the barrier, but two responses are possible: enzymes gain access to the lung tissue and cause increased tissue damage; and solutes and fluid pass more easily from the interstitial spaces and vascular spaces resulting in either an alteration in the composition of the liquid lining of the airspaces or alveolar edema.
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From page 70... ...
In anesthetized sheep, the albumin clearance rate measured with nuclear imaging increases in the presence of lung injury, but is unaffected by changes in lung volume or by lung edema due to increased lung vascular pressures (Figures 3-3, 3-4, 3-5~. However, the process of labeling and aerosolizing the albumin could cause the formation of macroaggregates, which complicate interpretation of the data.
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From page 71... ...
In addition to that barrier function, pulmonary vascular endothelium performs such functions as the removal or metabolism of endogenous and exogenous circulating agents and the synthesis of biologically active substances (e.g., prostacyclin and factor VIII antigen) that help to maintain vascular homeostasis.
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From page 72... ...
Loss of Endothelial Barrier Function A major role of endothelium is to prevent loss of fluid from vessel lumina. Endothelial cell injury is usually manifested clinically as evidence of pulmonary edema.
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From page 73... ...
They have provided much important information on vascular leak in laboratory animal studies, but not directly in humans. Loss of barrier functions is also reflected in an increase in extravascular lung water.
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From page 74... ...
Thus, they can measure extravas cular lung water accumulation, which is in fact the entity of interest, inasmuch as the abnormal accumulation of extravas cular water represents breakdown in en dothelial cell barrier function. In addi tion, gas rebreathing techniques have been used to estimate lung tissue volume and pulmonary capillary blood volume.
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From page 75... ...
The abnormal accumulation of excess lung water represents not only a failure of endothelial barrier function, but also a failure of various other mechanisms (the most important of which is lymphatic function) that the lung can use to maintain normal water homeostasis.
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From page 76... ...
Research during the last several years has led to the identification of several non-barrier functions of pulmonary endothelium. From the standpoint of increasing our knowledge of mechanisms of lung injury, there is a need to understand better both barrier and nonbarrier functions of endothelium, to attain the capacity to assess them, and to determine how nonbarrier functions of endothelium are correlated with barrier properties.
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From page 77... ...
A number of studies have suggested that pulmonary metabolic functions may provide sensitive markers of endothelial injury. For example, exposure to the herbicide paraquat results in pulmonary lesions in humans and experimental animals.
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From page 78... ...
The data suggest that, under some circumstances, pulmonary metabolic function can provide a sensitive index of injury to pulmonary endothelium. As with several other potential markers of lung injury, the use of pulmonary metabolic function to assess endothelial injury in the lung requires further development and validation before it can be considered useful.
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From page 79... ...
The focus of this category was the suitability of the assay for use in studies of large populations of people, as might be required for evaluating effects of some environmental exposures. Considerations included adaptability of equipment for mobile use, length and nature of subject interaction (i.e., degree of cooperation required)
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From page 80... ...
Metabolic lung function was chosen as an example of a biologic property under development as a potential marker of lung injury. That choice was intended not to imply that it is expected to be more useful than other potential markers, but rather to illustrate the challenges that must be met in assessing injury to the pulmonary circulation.
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From page 81... ...
PHYSIOLOGYIN INTACT ORGANISMS in this section, and a tabular summary of their characteristics was thought to be a useful adjunct to the more detailed information in the text. Such tabulation is difficult, because no system of characteristics or rating codes fits all the measurements well.
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