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6 Markers of Cellular and Biochemical Response
Pages 105-132

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From page 105...
... It focuses particularly on the analysis of respiratory tract fluids. SOURCES OF RESPIRATORY TRACT MARKERS Although this report deals with several possible sources of biologic markers, the introduction of sampling techniques peculiar to the lung and upper respiratory tract has improved understanding of the lung in normal and diseased states.
From page 106...
... When the total volume of instilled ravage fluid was 240 ml, the relative proportions of neutrophils and lymphocytes decreased from the first 120 ml to the second 120 ml in normal subjects. In patients with interstitial lung disease and presumably inflammatory cells in the alveoli, the percentages of lymphocytes and neutrophils increased in the second 120 ml (Dohn and Baughman,1985~.
From page 108...
... Eosinophils seem not to appear in BAL fluid until the late phase of a reaction; BAL fluid from patients without a late-phase reaction does not contain eosinophils. That difference supports the current concept that what causes the early phase of the asthmatic response is the release of histamine from mast cells, whereas the late phase is mediated by inflammatory cells (Booij-Noord et al., 1971)
From page 109...
... Recovery of ravage fluid in total-lung ravage in control animals is approximately 75% for the first ravage and 100% for later ravages (Henderson, 1988b)
From page 110...
... Other potential markers of inflammatory response that could be measured in BAL fluid include additional factors released by phagocytic and epithelial cells, such as growth factors, arachidonate metabolites, and interleukin I, which are beginning to be used in toxicology (Seltzer et al., 1986; Henderson et al., 1 985a; Koren et al., 1989~. In larger animals, such as dogs and nonhuman primates, BAL-fluid analysis offers a means of following the course of a pulmonary condition sequentially in the same animal.
From page 111...
... Nasal Lavage The nose is the primary portal of entry of inspired air, and one of its major roles 111 is to protect the lower respiratory tract from inhaled pollutants. For example, 100% of SO2 drawn into the nose, 20-80% of O3, and 73% of NO2 are trapped there under normal conditions (Vaughan et al., 1969~.
From page 112...
... Markers in nasal-ravage fluid that have been studied include increase in total protein, associated with cell damage and permeability change (Lorin et al., 1972; Marom et al., 1984~; increases in concentrations of albumin and immunoglobulin G associated with increased vascular permeability (Butler et al., 1970; Rossen et al., 1971; Brandtzaeg, 1984~; histamine and prostaglandin D2, released from mast cells in response to an allergic reaction (Naclerio et al., 1983; Eggleston et al., 1984~; increases in concentrations of sulfidopeptide leukotrienes and kininogens, after an allergic response (Creticos et al., 1984; Baumgarten et al., AL9R=RS IN PULMONARY TOXICOLOGY 1985; Togias et al., 1986~; and increases in concentrations of immunoglobulin E in hay fever (Miadonna et al., 1983; Small etal.,1985~.
From page 113...
... POTENTIAL MARKERS IN RESPIRATORY TRACT FLUIDS Both the cellular and acellular contents of nasal, bronchial, and bronchoalveolar ravages can provide markers of response to environmental exposures, as shown in Table 6-2. In the following sections, the cellular and the acellular supernatant fractions of these fluids and their potential for use as biologic markers are discussed in more detail.
From page 114...
... 114 AL4R=RS IN PULMONARY TOXICOLOGY TABLE ~2 Techniques for Detecting Markers of Inflammatory and Immune Response Technique Advantages Disadvantages Bronchoalveolar Relatively safe; material Variable concentration of ravage obtained from lung (com- return fluid constituents; partmentalization) ; large expenshe; obtaining of normal quantities of cells and controls in large numbers fluid available; repeatable; difficult; sample can be inter large area of lung sampled stitial, alveolar, or bronchial; invasive Nasal ravage Suitable for large studies; Yields few cells; might not safe; repeatable; establish- reflect lower respiratory tract ment of reproducible base- response; response short-lived; line values possible; in- timing of sampling after expo expensive; affords both sure critical; requires patient cellular and fluid analysis; cooperation and understanding quick return to baseline; no anesthesia needed Blood and urine Inexpensive; safe; repeat- Often does not reflect collection able; large sample avail- respiratory tract response; able; widespread patient risk of exposure of investigator acceptance Measurement of Sensitive for inflammatory Leukocyte influx a non cellular influx and immune responses; easily specific response and might measured by established be transient methods; presence of in creased numbers of some leukocyte types is assoc iated with specific pul monary responses Phenotyping Specific; reproducible Expensive; pathophysiologic relevance of specific marker must be established; might re quire large number of cells Measurement of Probably important mediators Expensive; difficult with cur arachidonic acid of respiratory tract injury rent methods; importance cur metabolites, easily measured in respire- rently unknown; nonspecific; cytokines, and tory secretions; relatively samples sometimes cannot be enzymes inexpensive; sensitive stored in bulk for later analysis Examination of Sensitive; relatively spe- Measurement difficult; ex mast cell cific for inflammation pensive In vitro assay Measures antigen-specific Cumbersome; expensive; re response; risk low, well quires extrapolation to established whole-body response; relevant antigens unavailable Skin test Measures antigen-specific Some associated risk; sensi whole-body response; has tivity and specificity often been used in large popula- poor; relevant antigens una tion studies vailable Intrabronchial Measures antigen-specific Use still limited; some as test tissue response sociated risk; expensive
From page 115...
... Release of factors Y Y P N Release of o~yradicals Y P P N Change in cell surface Y P P N Mast cells Influx Y Y P N Release of factors Y Y P N Eosinophils Influx Y Y Y Y Release of factors P Y N N Biochemical changes Arachidonic acid metabolites Urine N Y N N Nasal wash Y N N N BAL Y Y N N Histamine Blood N Y N N Nasal wash Y Y P - N BAL Y Y N N En~ymes, fluid Blood Y Y N N Nasal wash Y Y N N BAL Y Y P N Enzymes, cell-associated Nasal wash P P N N BAL N Y N N Functional changes Antigen-toxin challenge Skin Y Y Y Y Nasal wash Y Y P N Aerosol Y Y Y P Intrabronchial Y Y N N Rast N Y Y N In Vitro Lymphocyte Blood Y Y Y N BAL Y Y P N Monocyte-Macrophage Blood Y Y Y N BAL Y Y N N ay = yes (well documented) ; P = preliminary data; N = not done yet.
From page 116...
... AMs from normal subjects and persons with lung disease might differ in their response to stimuli that increase I1- 1 secretion (Eden and Turino,1986~. · Interferon.
From page 117...
... It has recently been shown that T cells in the lower respiratory tract of patients with active sarcoidosis proliferate spontaneously (Pinkston et al., 1983) and release 11-2 (Hunninghake et al., 1983~.
From page 118...
... Lung T cells of patients with active sarcoidosis are characterized by an increased number of Th cells (Hunninghake and Crystal, 1981b; Semenzato et al., 1982~. In patients with active disease, the ratio of Th to Ts cells can be as high as 20:1 in both the lung and the hilar lymph nodes (Semenzato et al., 1982; Thomas and Hunninghake, 1987~; in normal subjects, the ratio is approximately 1.6:1.
From page 119...
... Eosinophil influx into ravage fluid has been seen 6-48 hours after allergen challenge in sensitized asthmatics (se Monchy et al., 1985; Metzger et al., 1987~. Mast Cells Mast cells are found in the walls of alveoli and airways, usually between the basement membrane and epithelial membrane 119 in normal humans.
From page 120...
... , and hydroxyl radical (OH.) can be generated in the lower respiratory tract through the action of PMNs and AMs involved in local inflammatory reactions or through the direct effects on lung tissue of inhaling oxygen-rich air or toxic substances (s~h as paraquat)
From page 121...
... Taken together, those studies suggest that antioxidant components of alveolar lining fluid provide a first line of defense against oxidants in the lower respiratory tract. Arachidonic Acid Metabolites The synthesis and function of arachidonic acid metabolites remain the focus of extensive investigation (Gordon et al., 1988; Regal, 1988~.
From page 122...
... A cigarette-smoke- induced lesion in phospholipid hydrolysis is most consistent with the findings. Inasmuch as arachidonic acid metabolites are involved in the regulation of immune and inflammatory responses and bronchiolar and vascular smooth muscle reactivities in the lung, it was concluded that the defect observed in smokers' AM can play a role in the pathogenesis of cigarette-smokeinduced diseases.
From page 123...
... Results of that study, the first to demonstrate in viva release of arachidonic acid metabolites in the lung in response to inhalation of cotton dust extract, strongly suggest that the metabolites are responsible for the bronchoconstriction seen in the acute byssinotic reaction in humans. Further studies that establish the presence of those metabolites at sites of lung injury are needed, for their role in the pathogenesis of lung injury to be understood.
From page 124...
... , many of which are known to have profound effects on pulmonary cells and tissues. Three well-known examples of such products are oxygen radicals, arachidonic acid metabolites, and growth factors for fibroblasts.
From page 125...
... The lung is prone to oxidant stress with a variety of sources, and it has been suggested that a reactive oxygen species plays a role in the development of acute lung injury and the etiology of chronic lung disease (Johnson et al., 1981~. As described previously, oxidants can be generated in the lower respiratory tract via the action of PMNs and AMs involved in local inflammatory reactions.
From page 126...
... Those observations lend support to the hypothesis that lung damage during hyperopia is mediated by increased production of oxygen radicals. In conclusion, reactive oxygen species in the lung can be generated by multiple and diverse processes and appear to play a role in the onset of acute lung injury and possibly in the development of chronic lung disease.
From page 127...
... The use of molecular markers, defined here as alterations in DNA or RNA, to identify cellular responses or responsiveness to environmental toxicants theoretically can provide informa tion useful in determining the magnitude of exposure, the effects of exposure on human health, and the mechanisms of response. This section discusses some general considerations in the use of molecular markers, defines some general types of molecular markers, identifies specific markers for potential use in pulmonary toxicology or the study of carcinogenesis, and identifies subjects for research that could lead to the identification of new molecular markers.
From page 128...
... Potential molecular markers can be divided into several categories, including those based on genetics (modifications of DNA bases, changes in DNA sequence or structure, and changes in extent or pattern of gene expression) and those based on their ability to detect toxicant exposure, effect, or susceptibility or their ability to identify the toxicant involved.
From page 129...
... Changes in DNA sequence or structure could be a source of exposure-related molecular markers. Structural damage to DNA, such as double-strand or singlestrand breaks, can be detected with filter elusion assays and alkaline or neutral elusion (Bradley et al., 1982~.
From page 130...
... A gene- and exposure-specific response could therefore be followed with molecular markers if specific (identified) genes were overexpressed after exposure to particular toxicants, if molecular probes for the genes were available (i.e., if the genes had been isolated and molecularly cloned)
From page 131...
... Theoretically, exfoliated tumor cells could be identified and characterized from ravage fluid with in situ hybridization, if tumor-specific oncogene changes were established. In addition, toxicant-specific oncogene activation could be characterized in developing lung tumors.
From page 132...
... The development and use of molecular markers to identify cellular responses or responsiveness to environmental toxicants and to characterize pulmonary-disease will be important in increasing understanding of the mechanisms involved in the development of pulmonary disease and in its prevention and treatment.


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