Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 441
Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions JOANNE L. WRIGHT University of British Columbia Lung Anatomy and Defense Mechanisms / 442 Airway Cells / 442 Alveoli / 443 Deposition of Particulates / 443 Pathologic Conditions: Concepts and Quantification / 443 Emphysema / 443 Small Airways Disease / 446 Mucus Hypersecretion / 446 Animal Models of Human Disease / 446 Emphysema / 448 Small Airways Disease / 449 Emphysema and Small Airways Disease: Relations to Vehicular Emissions / 449 Lung Disease Produced in Animals by Vehicular Emissions / 449 Animal Exposure to Diesel Exhaust / 454 Summary / 454 Summary of Research Recommendations: Discussion / 455 Pathogenesis of Pulmonary Disease / 455 Pathobiology / 457 Animal Studies / 457 Human Studies / 458 Summary of Research Recommendations: Priorities / 458 In Vitro Experiments / 458 In Vivo Experiments / 459 Human Studies / 460 Air Pollution, the Automobile, and Public Health. ~ 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 441
OCR for page 442
442 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions The ability of gasoline and diesel engine emissions to cause pulmonary disease in humans depends not only on the character and components of emissions but also on the structure of the lung and the adequacy of its defense mechanisms. This defense system can be modulated by other factors such as age, general health, or the presence of specific lung diseases. To understand the effects of emissions, it is necessary to understand the mechanisms of damage and their relationship, if any, with such lesions as emphysema or small airways disease. In this chapter, lung struc- ture is described as it pertains to disease processes, and then methods of diagnosis and mechanisms thought to be involved in the production of pulmonary diseases are outlined. The lesions of emphysema and small airways disease produced by tobacco smoke inhalation in humans are similar to those that appear in animals experimentally exposed to emissions. To investigate the effects of emissions on human lungs it is necessary to use animal models. A review of similarities and disparities between ani- mal models and humans is followed by a discussion of similarities between human lung disease and diseases produced by ma- nipulation of animal models. Finally, a summary description of the lesions that have been identified in animals . . . . exposer . to emissions or emission compo- nents is followed by a discussion of areas in which knowledge is lacking and recom- mendations for further experiments. Lung Anatomy and Defense Mechanisms Lung anatomy has been elegantly described by Nagaishi et al. (1972~. Grossly, the lung is divided into lobes and segments. The smallest structures are the secondary lob- ules, consisting of lung tissue confined by lobular septa. Embedded within the lung tissue is supported by cartilage rings or plates, whereas the more distal airways are mus- cular. There are approximately 13 divisions from the trachea to the membranous bron- chioles, characterized by a complete wall formed of fibromuscular tissue. At approx- imately the eighteenth generation, respira- tory bronchioles are identified. These air- ways are alveolated; that is, they have alveoli budding from the wall. The mem- branous and respiratory bronchioles less than 2 mm in internal diameter have been termed "the small airways." The respira- tory bronchioles branch and form alveolar ducts which in turn divide to form alveolar sacs and finally alveoli. The airway branch- ing patterns are well described by Horsfield (1976), and are reviewed by Schlesinger in this volume. Airway Cells The mucus-secreting cells and ciliated epi thelial cells are the most important cellular structures in lung defense mechanisms (Gail and Lenfant 1983~. The epithelial mu cous cells and serous cells secrete some of the components of airway mucus, but the major source of mucus is the submucosal mucoserous glands. The ciliated epithelial cells, which occur from the trachea to the respiratory bronchioles, contribute to the mucociliary transport system. These air way components are known to react to, and be damaged by, inhaled particles and gases. In addition to epithelial cells, macro phages and polymorphonuclear neutrophils contribute to lung defenses. Neutrophils originate in the blood and migrate onto airway surfaces. Macrophages originate as blood monocytes and enter the pulmonary interstitium where they mature. A contin ually renewing population of matured cells migrate onto pulmonary surfaces. Under conditions of inflammation, the numbers and functional capacities of cell types in crease. (For a more detailed discussion of cellular components and their products see Last, this volume.) the bronchial tree, a complex structure formed of approximately 15 million ~ Recommendation 1. In vitro cell exper branches. The more proximal airways are iments should be directed to basic cell
OCR for page 443
Joanne L. Wright 443 biology wherein pollutant constituents are introduced to cell cultures of epithelial and/or inflammatory cells. Alveoli There are two types of alveolar epithelial cells. Type I are attenuated cells covering 93 percent of the alveolar surface. They are highly susceptible to injury and their death is followed by proliferation of type II cells which then differentiate into type I cells. Type II cells are responsible for the synthe- sis of the phospholipid and protein compo- nents of surfactant. These cells are thought to play a role in initiation of fibrotic repair reactions in the lung. The lung matrix is composed of colla- gen, elastin, glycosaminoglycans, and fi- bronectin (Turing 1985~. Collagen and elastin provide the tissue structural ele- ments and together form what have been loosely termed the lung "scleroproteins." Types I and III are the most common of the multiple subtypes of collagen. The balance of these two types appears to be important in lung repair reactions. The other sub- stances appear to induce and modulate the responses of the matrix to injury. Elastin is formed as a soluble protein which is secreted into the extracellular space. The soluble elastin is converted into mature elastic fiber by a cross-linking proc- ess that is mediated by the enzyme lysine oxidase. The signal that stimulates elastin synthesis is unknown. Elastin degradation releases peptides which can be measured in the plasma, urine, or broncho-alveolar lav- age fluid. a Recommendation 2. Studies should be undertaken to ascertain whether the pep- tides present in body fluids can be measured accurately, and whether the measured pa- rameters do, in fact, relate to the degrada . . t1on anc . repair process. Deposition of Particulates Deposition in the lung of the particulate components of inhaled material depends on the mean diameter of the particles and the distribution of particle diameters. There are a number of experimental techniques for measuring deposition (Brain and Valberg 1979~. Particles less than 1 ,um in diameter may reach the alveoli, but particles less than 5 ,um in diameter are deposited in the airways by processes of sedimentation and inertial impaction. A large fraction of the particles emitted by gasoline and diesel engines is less than 5 ,um in diameter. The main defense mechanism in the air- ways is the mucociliary escalator. In the alveoli, it is the macrophage. The balance between particle deposition and action of the defenses can be altered by pathological changes in the airways or in the lung pa- renchyma. These changes affect the mech- anisms of deposition and clearance. (For a review of deposition and clearance, see Schlesinger, this volume.) Pathologic Conditions: Concepts and Quantification The definitions and pathophysiological concepts of emphysema and small airways disease have been formulated primarily in the context of their relationship to tobacco smoke. It has been postulated that tobacco smoke produces three separate but highly interrelated pathologic conditions: emphy- sema, small airways disease, and mucus hypersecretion. Furthermore, because to- bacco smoke is the only source of air pollu- tion where there is a large data base, it is often used as a model for studying the effects of inhaled pollutants such as auto- motive emissions. Emphysema Emphysema has been defined as a condi- tion of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Destruction is defined as nonuniformity in the pattern of respiratory airspace enlargement, so that the orderly appearance of the acinus and its compo- nents is disturbed and may be lost (Snider et al. 1985~.
OCR for page 444
444 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions There are three anatomic subtypes of emphysema, of which two-panacinar and . . . . centrlaclnar emphysema- are pertinent to this discussion. In panacinar emphysema, all components of the acinus are equally involved, whereas in centriacinar emphy- sema, destruction is centered around the respiratory bronchiole. Panacinar Emphysema. Panacinar em- physema has been observed in humans with a-1-proteinase inhibitor C-1-PI defi- ciency. Use of papain, pancreatic, neutro- phil, or bacterial elastase in animal models has produced anatomic lung destruction identical to panacinar emphysema in hu- mans (Snider et al. 1985~. The realization of these facts led to a theory of proteolysis/an- tiproteolysis imbalance as a pathogenic fac- tor in pulmonary emphysema. This theory has immediate bearing on the question of effects of auto emissions on the lungs. For instance, what are the effects of emissions on a population with altered levels of c-1-PI? And what are the effects on a-1-PI of direct emissions that alter the balance of proteinase and antiproteinase? In relation to proteinase, researchers have shown that cigarette smokers have an in- creased number of neutrophils, both in the peripheral blood (Sparrow et al. 1984) and within the lung, as seen by broncho-alve- olar ravage (Hunninghake and Crystal 1983~. Smoke is chemotactic (that is, an attractant) for macrophages and neutro- phils, and the neutrophilic response can be amplified by macrophage-secreted chemo- tactic factors and stimulated by a comple- ment that has been activated by cigarette smoke. The idea that these neutrophils show increased enzymatic activity is more controversial. Although elastase-like activity has been found in the ravage of smokers, it was metallo-enzyme in type, implicating the pulmonary macrophage as its source. This is not surprising, since macrophages in the lumens of respiratory bronchioles are a prominent feature in young healthy ciga- rette smokers (Niewoehner et al. 1974~. This response may reflect early disease, and may be important in the pathogenesis of emphysema. Recommendation 3. Cell damage and its relation to inflammation should be stud- ied through further research on exposure- related increases in neutrophils and macro- phages, including collagen and elastin biomechanics, and the dose/time relation- ship between exposure and neutrophil and macrophage increase. There are several proteinase inhibitors in the respiratory tract, including low molec- ular weight (MOO) bronchial mucus inhib- itor, a-2-macroglobulin, and a-1-PI. It was thought that `~-1-PI was the most impor- tant inhibitor, but this may not be entirely true Janoff 1985~. This is certainly an area that needs further investigation in regard to smoking as well as to the effects of emis- sions. Cigarette smoke has been shown to oxidize a methionyl residue on cY-1-PI, thus rendering it essentially inactive. This method of inactivation may be important with regard to emissions, since nitrogen dioxide (NO2) is able to inactivate cr-1-PI in an in vitro situation, presumably through an oxidative mechanism. Recommendation 4. The relation of oxidants to the proteinase/antiproteinase balance should be studied. Centriacinar Emphysema. There are two morphologically similar subtypes of cen- triacinar emphysema, both applicable to this discussion. Exposure to coal dusts re- sults in the dilatation of respiratory bron- chioles with abundant collections of dust particles. Whatever the pathophysiological mechanism involved in this lesion, it is conceivable that it may be related to, or amplified by, exposure to the emissions from the machinery used in mining or processing. In recent years, the bulk of investigation has been directed toward the proteinase/antiproteinase hypothesis for the causation of the second subtype of centriacinar emphysema found in people who smoke cigarettes. Quantification of Pulmonary Destruction. Indirect methods of quantifying pulmonary destruction include pulmonary function tests and radiographic examinations. Both
OCR for page 445
Joanne L. Wright 445 methods can detect abnormalities in estab- lished disease but neither is particularly useful in the identification of early disease. Direct methods of estimation and/or quantification of lung parenchymal de- struction can be performed on several lev- els. Most accurate are the methods based on analysis oftissue parameters. However, these methods can only be applied to experimental animal models and human autopsy or surgi- cal resection material, and the resulting data represent a single point in a cross-sectional study. These methods are not applicable to case-control longitudinal studies. Recommendation 5. Pulmonary me- chanics should be assessed on excised lung specimens obtained from human autopsies or surgical specimens and results related to data collected from live subjects. Morpho- logical examinations of human lung tissues could duplicate methods used to investigate effects of tobacco smoke. Gross and subgross methods involve ei- ther whole lung slices or Gough sections in which the degree of destruction is ranked by comparison with a standard grading panel (Thurlbeck et al. 1970~. These methods are only truly applicable to inflated human lungs and are by their very nature imprecise. Since gross estimation of emphysema requires a fully established lesion, methods in which the earliest phases of disease can be defined and quantified must be considered. Measurements of tissue using micros- copy include calculation of mean linear intercept (Dunnill 1962), destructive index (Saetta et al. 1985a), and analysis of alveolar attachments (Saetta et al. 1985b). These measurements are more precise than those obtained by gross and subgross methods, and they reflect airspace enlargement (mean linear intercept), or alveolar destruction (destructive index, alveolar attachments). They can be performed on human and animal tissues alike. A minor disadvantage is that the methodology requires lungs in- flated to a standard pressure. Measurements of destructive index and alveolar attachments show relatively good separations of smoking and nonsmoking populations. Since mean linear intercept reflects dilatation of the airspace rather than destruction per se, it is affected by aging. However, it may be more sensitive than other methods to scleroprotein alteration, and it should not be abandoned. An image analysis system can perform detailed measurements of alveolar surface area and surface density to provide infor- mation relating both to alveolar space dila- tation and destruction. This is a labor- intensive technique, however, and it does not yield data of greater value or accuracy than the techniques mentioned previously. Transmission or scanning electron mi- croscopy techniques are applicable to assess substructural alteration such as changes of cell types, nuclear and/or cytologic alter- ations, and collagen and elastin structural changes. Such techniques may identify ex- tremely early lesions in the microstructure. Disadvantages include the potential for sampling error because of the small sample size, and the necessity for special fixation and preparation. Potential advantages in- clude applications for biopsy technique and use in longitudinal studies. ~ Recommendation 6. Examination should be made of epithelial cells, collagen, and elastin by electron microscopy to docu- ment possible progression of emission-re- lated disease during a recovery period after direct exposure ceases. Biochemical techniques can be direct, using portions of lung, or indirect, using ravage fluid or urine. These techniques can be used to assay hydroxyproline and fibro- nectin and lung tissue collagen types. Mea- surements of by-products of elastin turn- over are more exciting, because of their potential use in longitudinal studies. Uri- nary desmosine correlates well with lung destruction in an animal model, but its applications in human investigations have been less promising Janoff 1985~. How- ever, elastin peptides in human blood have been shown to separate nonsmokers from smokers, and measurements of lysyl oxi- dase as an indicator of elastin synthesis have shown that cigarette smoke inhibits elastin repair after initial damage with instilled elastase Janoffl985~.
OCR for page 446
446 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions Small Airways Disease The concept of small airways disease as a major cause of airflow obstruction in ciga- rette smokers arose from early work show- ing that peripheral airways resistance was markedly increased in patients with chronic obstructive pulmonary disease (Hog" et al. 19681. This was initially thought to be due to abnormalities in airways of less than 2-mm internal diameter and was associated with inflammation and fibrosis of airway walls as well as with epithelial changes (Cosio et al. 1977~. These initial reports were followed by pathological description and semiquantita- tive analysis of airways in the lungs of patients with varying smoking histories, degrees of emphysema, and abnormalities of pulmonary function (Cosio et al. 1980; Wright et al. 1984~. The most important components of small airways disease now appear to be an inflammatory response and a fibrotic repair reaction. The broncho-alveolar ravage fluid of smokers shows greater numbers of poly- morphonuclear neutrophils and macro- phages. Some of these cells must represent an airway inflammatory response. The pathological abnormalities of inflammation and fibrosis relate to perturbations of the pulmonary function tests, including flow rates and elastic recoil. Pathological parameters in the small air- ways can be assessed by semiquantitative grading schemes or by direct morphomet- ric analysis. The grading methodology is subjective but easy to perform and has the advantage of being usable on noninflated lungs (Wright et al. 19851. In this method, various degrees of abnormality are defined and displayed as a poster format (figure 1~. The test-case airways are compared to these standards, and grade score is assessed. This method isolates individual parameters such as inflammation and fibrosis while also giv- ing an overall estimation of abnormality. Morphometric analysis is more precise but requires standard inflation pressures of fixation and some technical expertise. This method allows the investigator to measure directly the airway diameter and wall thick- nesses, and in addition, to quantify the types and numbers of inflammatory cells in the airway walls and lumens. Small airways disease can be assessed indirectly with specialized pulmonary func- tion tests including nitrogen wash-out curve and forced expiratory flow of 25-75 liters/sec (FEF2~75~. It would be difficult to detect minor degrees of injury in this fash- ion, but the tests would be suitable for longitudinal studies (Buist et al. 1984~. Fur- thermore, the tests could be used to docu- ment established disease. ~ Recommendation 7. Some of the more detailed pulmonary function tests should be used to identify progressive dysfunction. Mucus Hypersecretion Cigarette smoking increases the size of the bronchial mucous glands (Reid 1960) and the proportion of glands in the bronchial wall and also causes goblet cell metaplasia (Mitchell et al. 19761. The Reid index mea- sures the thickness of the bronchial mucous glands compared to the thickness of the bronchial wall measured from perichon- drium to basement membrane. This thick- ness correlates with the presence of chronic bronchitis (Reid 19601. The proportion of mucous glands in the bronchial wall can be estimated either by a point-counting tech- nique or by direct measurement of the areas. Although these changes are associated with chronic cough and sputum production (a process formerly referred to as chronic bronchitis) with their attendant nonesthetic qualities and psychological disabilities, they have not been associated with airflow ob- struction (Fletcher et al. 1976) and physical disabilities. Since mucus hypersecretion ap- pears to be a nonspecific response to an irritant, and since this does not produce pulmonary function abnormalities, it will not be considered further. A ni m al M odels of H u m an Disease It is important to ascertain whether lung disease produced in animals by manipula- tions such as the instillation or inhalation of
OCR for page 447
Joanne L. Wright 447 : ~ :21 ~0 _, ~At, ~.. ~ ~ ~ ~ ~ :~: ~ ~ I Figure 1. Type of poster format applicable in the semiquantitative grading technique for assessing pathological parameters in the small airways: top, normal respiratory (A) and membranous bronchioles (MB) (B); middle, grade III intralu- menal macrophages in the respiratory bronchioles (RB) (C) and grade III intramural inflammation in the membranous bronchioles (D) (In the MB, the grading is based on overall cellularity rather than the inflammatory cell types.); bottom, grade III fibrosis of both the RB (E) and MB (F). (Adapted with permission from Wright et al. 1985. Arch. Pathol. Lab. Med. 109:16~165. Copynght 1985 American Medical Association.) various materials is similar to human dis- ease. Animal models have been used exten- sively to test specific hypotheses related to the pathogenesis of emphysema and small . . airways c .lsease. Comparisons of animal and human lung structure have concentrated on two areas: airway structure and airway surface epithe- lial cells and glands. The casts of the tra- cheobronchial trees of humans have a dis- tinctive, almost spherical shape with a relatively symmetrical branching pattern. In contrast, most other mammals have elongated casts with tapered monopodial airways and small lateral branches. Small airways and terminal units in spe- cies other than rodents are similar to human lung structure. In rodents, the respiratory bronchiole is either absent or very short. This may be significant since the respira- tory bronchiole appears to be a target area for injury after inhalation of dusts and fumes. Various mammalian species, including humans, have different cell populations in the normal surface epithelium, and even within an individual species there are changes dependent upon maturation. There are also species variations in the total vol- ume of submucosal glands as well as in their distribution within the airways. In addition, differences in the histochemical staining of the epithelial cells and glands indicate different mucus secretions among the species.
OCR for page 448
448 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions Emphysema Elastin/Collagen Destruction. Elastin/col- lagen destruction in animal models has been studied primarily by using inflamma- tory cell increases, elastase administration, or reduction of ct-1-PI to test the relation- ships between proteinases and antiprotein- ases. Administration of elastases, either pancreatic or leukocytic (endogenous or exogenous), has produced airspace destruc- tion morphologically similar to panacinar emphysema Janoff 1985~. Electron microscopy of enzyme-induced emphysema shows elastic fiber disruption, with beading and irregularity of the fibers (Kuhn et al. 1976~. Biochemical analysis of elastase-instilled lungs has shown a rapid and marked decrease in total elastin content with a lesser decrease in collagen (Karlinsky et al. 1983~. After a postexposure recovery period, however, lung elastin content re- turned to normal limits. Alterations in physiological parameters show a dose/response effect (Raub et al. 1982), and age at exposure appears impor- tant since the effects of elastase have been shown to be greater in younger animals (Goldstein 1982~. Administration of ciga- rette smoke to animals previously given elastase has augmented destruction (Hoidal and Niewoehner 1983~. Chronic adminis- tration of the oxidant chloramine-T to in- terfere with the function of a-1-PI pro- duces similar results. Cigarette smoke itself, in high doses, has been shown to produce enlargement of airspaces and ab- normalities in pulmonary function (Huber et al. 1981; Heckman and Dalbey 1982~. These studies have also described, but not quantified, changes in the small airway walls. ~ Recommendation 8. Research should be undertaken on the elastin and collagen degradation/repair balance to determine whether repair is affected by pollutants, and if so, by what mechanism. Studies should map the time course of collagen and elastin degradation and repair, relating data to type and concentration of exposure as well as ascertaining the possibility of alteration or repair by pollutants or other oxidants. Elastin/Collagen Formation. Lysyl oxi- dase, a copper-requiring enzyme that me- diates the conversion of lysine to the elastin-specific cross-links desmosine and isodesmosine, is involved in the process of elastin/collagen formation. Elastin synthe- sis occurs rapidly after elastase-induced em- physema, and there is an associated increase in lysyl oxidase activity Janoff 1985~. De- creased lysyl oxidase activity results in poorly formed elastin and in lung lesions morphologically and physiologically iden- tical to panlobular emphysema in the blotchy mouse (Snider et al. 1985~. Recommendation 9. Pollutant interfer- ence.with lysyl oxidase and impairment of elastin resynthesis should be investigated as a possible destructive mechanism. Dietary insuff~ciencies have also pro- duced pulmonary abnormalities. Protein/ calorie starvation produces enlargement of the airspaces, but physiological alterations are different from those seen in human emphysema Janoff 1985~. When exposed to cigarette smoke, exper- imental animals with elastase-induced em- physema show a greater degree of lung de- struction. These data, in conjunction with in vitro studies showing that cigarette smoke can inhibit the activity of lysyl oxidase Janoff 1985), suggest that interference with elastin synthesis contributes to the alteration of the lung structure as seen in emphysema. Administration of cadmium chloride to experimental animals produces inflamma- tion and a granulation tissue response fol- lowed by airspace enlargement. Adminis- tration of the lathyrogen beta amino propionitrile (BAPN) appears to limit the fibrosis (Niewoehner and Hoidal 1982~. The mechanism for disease is unclear in this model, but it appears to involve some balance between destruction and repair re- action with ultimate fibrosis. The physiological requirements for the diagnosis of emphysema in humans are very controversial. Since these physiologi- cal requirements have not yet been estab- lished, only the morphology of human and animal emphysema can be compared. This comparison itself may be diff~cult, since the
OCR for page 449
Joanne L. Wright lungs of the various species are not identi- cal. Although physiological abnormalities are often found in animal models, the pres- ence or absence of emphysema is deter- mined by whether airspace enlargement can be documented. Within these limits, instillation or inha- lation of elastase is an excellent model for panacinar emphysema; however, there is no workable model for centriacinar emphy- sema at the present time. Some animal ma- nipulations produce airspace enlargement as well as fibrosis. Although these manipula- tions cannot be used as models for emphy- sema, they are appropriate to assess condi- tions where the balance of lung destruction and fibrogenic reaction are important. Recommendation 10. Research should be undertaken on the balance between fi- brosis and destruction and its relation to particulates/oxidants. Small Airways Disease Two studies utilizing acid inhalation in either acute or a short-term exposure cor- relate airways inflammation with airways dysfunction (Baile et al. 1982; Peters and Hyatt 1986~. This model suggests that any inhaled substance that results in an inflam- matory response is capable of causing air- flow obstruction. These data are similar to those obtained from human studies of the association between inflammation and air- flow obstruction in cigarette smokers. Use of an acid nebulization technique in a dog model allowed researchers to ascer- tain whether acute airway inflammation could be detected by pulmonary function tests. Inhalation of a weak hydrochloric solution was associated with discernable inflammation in the airways and with ab- normalities in the tests for small airway function (Baile et al. 1982~. The acid inhalation technique was also used with a semiquantitative grading tech- nique to evaluate the airways. Researchers found inflammation and fibrosis of the car- tilaginous as well as the noncartilaginous airways. These changes correlated with de- creased dynamic compliance and increased slope of phase III of the nitrogen wash-out 449 curve, as well as with a decrease in flow rates (Peters and Hyatt 1986~. Emphysema and Small Airways Disease: Relations to Vehicular · ~ Emlsslons Data on pathophysiology of disease due to cigarette smoking can help document the presence of disease and the progression from early to well-developed disease and provide information on the mechanisms of disease. Recent reports suggest key physi- ological alterations relevant to production of disease in animals. The exhaust from diesel engines contains most of the pollutants present in the emis- sions of gasoline engines, but differs in that it has a large particulate component. When possible, studies involving effects of diesel emissions are treated separately. . Lung Disease Produced in Animals by Vehicular Emissions . It is important first to ascertain whether lung diseases produced in animals by inha- lation of vehicular emissions are similar to human diseases suspected to be caused by emissions. A comparison of the physiolog- ical responses of NO2-induced disease in several animal models to those of human emphysema (figure 2) showed that the an- imals had similar shifts in flow/volume and pressure/volume curves as well as in lung volumes (Mauderly 1984~. The author con- cluded that animals provide data applicable to humans. When he compared acute re- sponses to NO2, the magnitude of the effects was different, but all subjects showed irritant effects at various doses. An earlier study examined the morphol- ogy of normal and experimentally induced emphysema in animals and compared these data to those on emphysema in horses and in humans (figure 3~. Dilatation of airspaces occurred in all species. Papain or continu- ous NO2 exposure with peak increases or followed by intermittent exposure, caused similar lung destruction in all of the rodent models (Port et al. 1977~. The morphology
OCR for page 450
450 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions - . _ 400 _ 300 - IL ~ 200 6 ~ 4 _ \\ rs Rabbit ,1~`-_ u ~N 100 80 60 40 FVC (%) 20 0 r--__ ! Normal \ Human on, r an | | \ Dog t1: 1.5 .0 ns c 12C 1nC an 6a 2c 0 ~ 100 80 60 40 20 0 FVC (%) / ~ \\ Figure 2. Companson of flow-volume curves in normal and emphysematous subjects, including humans, dogs, rabbits, and rats. Flow rates of all species were reduced to a similar extent by emphysema. Maximum Expiratory Flow (MEF); Forced Vital Capacity (FVC). (Adapted with permission from Mauderly 1984, and Hemisphere Publishing Corp.) of emphysema in rodents differs from that in horses and humans, but the models are certainly applicable for research on patho- physiological relationships. Evidence of Emphysema and/or Small Air- ways Disease. Several studies have pro- vided evidence of emphysema and/or small airways disease by demonstrating changes in physiological as well as morphological parameters after the administration of var- ious concentrations of NO2 (Freeman et al. 1968; Freeman et al. 1972; Kleinerman and Niewoehner 1973; Coffin and Stokinger 1977; Evans and Freeman 1980~. NO2 appears to exert its major damage on the bronchioles and alveolar ducts, and this seems related to a concentration gradi- ent (Menzel 1980~. Loss of cilia is a subtle airway change which occurs early in acute experiments (Evans 1984), and is seen after long-term exposures as low as 0.3 ppm (Nakajima et al. 1980~. Not surprisingly, these structural abnormalities are associated with delayed mucociliary clearance (Gior- dano and Morrow 1972~. Bronchiolar epithelial cell damage from NO2 appears to be repaired by proliferation of nonciliated epithelial cells cells that act as the progenitors for both ciliated and nonciliated cells. Type I damage is repaired by type II cell proliferation (Evans 1984~. Physiological Charges. Pulmonary func- tion tests in animals exposed to NO2 con
OCR for page 451
Joanne L. Wright -~ (_j ~ ~ _ :, Figure 3. Comparison of the light microscopic findings from (A) NO2-exposed rat, (B) papain~xposed hamster, (C) NO2-exposed mouse, (D) emphysematous hu- man, and (E, F) emphysematous horse. All lungs show dilatation of the airspaces. (Reproduced with permission from Port et al. 1977, and Hemisphere Publishing Corp.) sistently indicate airflow obstruction. A large portion of this obstruction appears to be due to airway disease and is potentially reversible (Kleinerman and Niewoehner 1973; Kleinerman et al. 1976~. An early study concluded that the pulmonary func- tion changes in the rabbit model were due to bronchiolitis (Davidson et al. 1967~. In other studies of bronchiolar abnormal- ities related to exposure to NO2, research- ers have found massively enlarged collagen fibrils underlying bronchioles and associ- ated with thickened basement membranes in rats (Stephens et al. 1971), and increased thickness of the basement membrane with increased collagen in the interstitium in squirrel monkeys (Bils 1976~. In the latter 451 study, basement membrane thickness and collagen in the interstitium increased even during recovery. In contrast, a study by Buell (1970) indicated that the morpholog- ical parameters of collagen and elastin de- naturation following exposure to NO2 were no longer present after a 7-day recov- ery period. Biochemical Changes. Biochemical find- ings in animal exposure studies suggest that the degradation or repair of collagen and elastin do not necessarily occur at the same time and that they can therefore be individ- ually influenced by exogenous or endoge- nous factors (Hacker et al. 1976; Kleiner- man 1979~. Hydroxylysine in either urine or ravage
OCR for page 454
454 Relation of Pulmonarv Emohvsema Small Airways Disease to Vehicular Emissions pollutants produced pulmonary injury and loss of pulmonary function which contin- ues following termination of exposure. They further suggest that "due to the ubiq- uitous nature of nitrogen and sulfur oxides and auto exhaust (per se and photochemi- cally reacted) in the ambient air of urban communities, the chronic cardiopulmon- ary changes . . . denote serious potential health hazards to the populace of certain communities." This statement underscores the importance of these multidisciplinary studies, and stresses the value of chronic studies. Animal Exposure to Diesel Exhaust In studies involving the administration of diesel exhaust to animals, researchers have found abnormalities that appear to be fo- cused on the centriacinar space (Wiester et al. 1980; Barnhart et al. 1981; Vostal et al. 1981; Plopper et al. 1983~. Several of these investigators have noted small foci of fi- brosis in relation to large clusters of mac- rophages (Wiester et al. 1980; Vostal et al. 1981~. Some (Barnhart et al. 1981) have localized these changes to the bronchioles. Others have found the bronchiolar fibrosis to be progressive, even after a 6-month recovery period; they also found a trend toward increases in total lung collagen, with a twofold increase in newly synthe- sized collagen (Hyde et al. 1985~. Pulmonary function testing in diesel-ex- posed animals has produced conflicting re- sults. Studies (Pepelko 1981) have shown dose-dependent decreases in vital capacity (VC) and diffusing capacity for carbon monoxide (DLCO) associated with loss of elastic recoil pressure in hamsters. Cat models have shown decreases in VC and Deco accompanied by decreased maximum expiratory flow, but also accompanied by a decrease in total lung capacity (TLC). This suggests a combination restrictive/obstruc- t~ve pattern. A rat model showed evidence of de- creased compliance, reduced DI no, and in- homogeneity of airways emptying, with- out evidence of airflow obstruction (Mauderly et al. 1983~. A progressive in- crease in hydroxyproline peptides as well as in total lung collagen appeared to be a function of increasing time as well as in- creasing exhaust concentrations. Tracheal muscle histamine dose/response curves documented in rats exposed to diesel exhaust and/or coal dust for 2 years dem- onstrate an additive effect from coal dust and diesel exhaust (Fedan et al. 1985~. These data may reflect a role of the immune system. A shortcoming of this study is the lack of any morphological, physiological, or biochemical data relating to the lungs of these animals. There is also evidence of nonspecific dysfunction in exposed animals, with de- creased spontaneous forced locomotor ac- tivity (Pepelko 1981~. Data from the same laboratory suggest that exposure during the first week of life affected adult learning abilities. ~ Recommendation 17. Studies should be undertaken to determine whether the ef- fects of diesel exhaust are different from the effects of gasoline exhaust in regard to disease progression, the effects of age at exposure, and additional applied stress. Summary It is apparent that exposure to gasoline or diesel emissions or their components has the potential to produce disease. Animal models of emphysema and small airways disease, with some exceptions, are very similar to the same diseases in humans. Most histopathological, morphometric, and electron microscopic data on effects of emissions and their components have been derived from animal models which provide evidence of alveolar wall destruction with loss of surface area, and of abnormalities of the airways. Investigations of lung disease and tobacco smoke have utilized fairly so- phisticated measurements, and these meth- ods can be, and in some areas have been, easily utilized in emission protocols. Sim- ple histological descriptions are no longer justified. The pulmonary disease produced in ex
OCR for page 455
loanne L. Wright perimental animal models by vehicular emissions appears to involve, as a first step, inflammation and destruction at the level of the respiratory bronchioles. The lesions produced by exposure to emissions may destroy the alveolar parenchyma and result in emphysema. Lesions may also act on the airways to produce fibrosis and subsequent airway narrowing and airflow obstruction. These morphological reactions to emis- sions are very similar to those produced by cigarette smoke, leading to speculation that pulmonary disease caused by emissions in- volves the same mechanisms as disease induced by cigarette smoke. The hamster model of Hoidal and Nie- woehner (1982) suggests that the particu- late component of smoke is important, not only in inducing inflammation in the bron- chioles, but also in activating macrophages. NO2 itself results in macrophage accumu- lation, but in that case, the chemotactic stimulus may be the injured epithelial cells. If both of these mechanisms are functional, one would suspect that the addition of particulates would amplify the inflamma- tory response, perhaps making diesel ex- haust dangerous. Indeed, this could be ex- pected to happen with the addition of any other injurious agent perhaps some of the other components of gasoline exhaust, for instance. Vehicular emissions and their compo- nents, like cigarette smoke, have oxidant properties. Therefore emissions can injure the lung through direct damage to the cell membrane as well as through inactivation of the antiproteolytic system. With inacti- vation of antiproteinase as well as an in- crease in the source of proteinases, the proteolysis/antiproteolysis balance might be tipped, resulting in lung destruction. Other data suggest that the antioxidants selenium and vitamins C and E may be important in lung defense. Furthermore, emissions produce an inflammatory re- sponse involving neutrophils as well as macrophages, with evidence for collagen and elastin degradation and repair. Finally, there is good correlation of disease (em- physema and airway fibrosis and inflam- mation) with abnormalities of pulmonary . tunctlon. 455 Summary of Research Recommendations: Discussion There are two main questions to ask about the relation of pulmonary disease to vehic- ular emissions. Although both questions are studied in relation to cigarette smoke, data are still sparse. First, does significant disease occur, and if so, what is it? This is difficult to determine in a human population, as data on cigarette smoking have shown. Second, what is the cellular basis of this disease? Other questions appropriate to the study of pulmonary disease in relation to vehicu- lar emissions are: What is the role of the proteolysis/antiproteolysis balance in pol- lutant exposure? What agent induces a re- sponse by the inflammatory cells, and does it have one or multiple components? What roles do the particulates and the immune system play? What is the role of the anti- proteinases, and are they affected by the oxidants in pollutants and which oxidants are more Important? Pathogenesis of Pulmonary Disease The similarity of damage caused by vehic- ular emission exposure to damage caused by cigarette smoke has implicated the pro- teolysis/antiproteolysis balance in the pathogenesis of pulmonary disease. Mea- surement of elastase and antiproteinases in ravage fluids has been useful in investigat- ing damage related to tobacco smoke and to the adult respiratory distress syndrome, and the feasibility of using this procedure to analyze proteolysis/antiproteolysis imbal- ance is an important subject for further research (Recommendation 2~. The inflammatory cells stimulated by cigarette smoke are a source of proteinases and represent a possible mechanism for lung destruction. In addition, since ciga- rette smoke, acting as an oxidant, is able to inhibit cz-1-PI by binding to a methionine residue, it is possible that the oxidants in emissions can act in a similar fashion. This in itself would not be harmful unless pro- teolytic factors (that is, neutrophil and macrophage enzymes) were also increased, either by increasing the amount of enzyme
OCR for page 456
456 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions per cell, or by increasing the number of cells. Both of these facts are true for ciga- rette smokers, but it is not clear which component of smoke is responsible (Rec- ommendation 4~. Some information sug- gests that gasoline and diesel exhaust expo- sure increase neutrophils as well as macrophages. This suggestion needs tur- ther clarification relative to dose and time as well as to collagen and elastin biomecha- nics (Recommendation 3~. The elastin and collagen degradation/re- pair balance is another mechanism whose operation elicits such questions as: Is repair affected by pollutants, and if so, by which component and by what mechanism? The same primary agent can produce fibrosis as well as destruction (Niewoehner and Hoidal 1982~. That study was directed at cadmium, but it is very tempting to sup- pose that model would be applicable to disease produced by emissions. Further work on this hypothesis could use the lathyrogen BAPN. ~ hIS manipulation would allow assessment of any destructive potential. Collagen can be subtyped, and it is im- portant to determine whether any subtype in particular is affected. Hydroxyproline or hydroxylysine from ravage can also be quantified and may be indicators of lung injury and repair. Fibronectin, which may prove important in both degradation and repair, can be quantified as well. Measure- ment of collagen subtypes or hydroxy- proline would allow mapping of the dose response and the time course of the fibrotic response (Recommendation 8~. Initial data have suggested that in the early stages of emission injury, collagen and elastin degrade, but in different time frames. Studies should map the time course of degradation and repair and determine whether repair could be altered by pollut- ants or other oxidants such as cigarette smoke. These data should be further quan- tified and related to type and concentration of exposure. Other studies should attempt to quantify degradation products such as elastin, pep- tides, urinary desmosine, and hydroxyly- sine for use in long-term animal and human Investigations (Recommendation 11~. Hi. . . . . Cigarette smoke is thought to impair elastin resynthesis by interfering with lysyl oxidase. It is not known if this results from air pollutant exposure, but it could be an important mechanism underlying any destruction that occurs (Recommendation 9~. r How could these data relate to the cen triacinar versus panacinar locations of de struction in the lung? In c'-1-PI deficiency or elastase administration the imbalance is a generalized event. In cigarette smoke-in duced emphysema, the imbalance is local ized in the area of the proteinase excess the respiratory bronchiole. This localiza tion might be expected to occur also during pollutant-induced lung destruction, where the respiratory bronchioles do appear to be abnormal, and there is an inflammatory infiltrate of macrophages. What is the balance between fibrosis and destruction, and is this related to particu lates rather than oxidants (Recommenda tion 10~? This has been suggested by work on diesel exhaust (Mauderly et al. 1986) which shows that there is focal fibrosis in the alveoli as well as in the bronchiolar wall. There may be some differences in the effects of gasoline and diesel emissions. Such possible differences should be investi gated in regard to disease progression, ef fects of age at exposure, and additional applied stress (Recommendation 17~. Destruction of alveolar parenchyma has not been a universal finding; indeed, foci of alveolar fibrosis have been described (Mau derly et al. 1986~. Perhaps if there is no imbalance of the proteolytic system, and there is particle stimulation of the intersti tial cells, there will be fibrosis. But if there is imbalance of proteolysis, the collagen/ elastin repair mechanism is hampered, and destruction results. Although there is evidence for dose de pendency of injury, this should be further quantified and related to the lower doses (Recommendation 13~. Determining which . . . . . emission components are most Injurious and the degree of synergism between com ponents active in the causation of disease is also important (Recommendation 14~. Some data suggest progression of disease even after the insult has been discontinued.
OCR for page 457
Joanne L. Wright 457 Such progression should be fully docu- mented. Experiments could count and type inflammatory cells in ravage or in tissue. With electron microscopy, examinations for early abnormalities in collagen, elastin, and epithelial cells (Recommendation 6) could be extended to analyze the repair reaction and to identify agents that amplify or ameliorate the response. The data ob- tained would help to clarify whether dam- age was related to the oxidant components of the emissions. Abundant evidence suggests abnormali- ties of airflow and lung volumes in animals exposed to emissions. Although measure- ments of lung volume, compliance, and resistance are important, their normal range varies widely, so it is important to analyze indicators of flow such as the pres- sure/volume curve, as well as flow/volume curves and tests such as the nitrogen wash- out curve indicating inhomogeneity of air- flow. Mauderly's group (1984) has used these techniques to great advantage in their experimental models and have been able to identify subtle changes in pulmonary func- tion. Pathobialogy In vitro cell experiments should be directed to basic cell biology. Such studies might focus on introducing pollutant constitu- ents, gaseous as well as particulate, to cell cultures of epithelial and/or inflammatory cells (Recommendation 1~. Epithelial cells could then be examined for damage and production of inflammatory cell chemotac- tic factors. The inflammatory cells could also be examined for evidence of activation with production of oxygen radicals. To obtain obvious abnormalities, a dose range should initially be broad, with some con- centrations fairly high. These experiments should measure biochemical parameters in- cluding a-1-PI and elastase in ravage fluid, elastin, desmosine, collagen type, and lysyl oxidase in lung tissue. These data would suggest which components of pollutants are important and whether combinations have greater effects than single exposures. They could also form the basis for short- and long-term animal experiments. Animal Studies Short-term animal experiments should be designed to determine the pathobiology of disease related to emissions (Recommenda- tion 12~. Since age at exposure may be a factor in disease, research should document abnormalities produced by exposure begin- ning at various points in the lifespans of animals studied. Researchers should ana- lyze the effects of additional stress such as diesel particulates, cigarette smoke, infec- tion, and nutritional deficiencies on the production of pulmonary disease (Recom- mendation 16~. The influence of particle size and compo- sition as well as the gaseous components of the emissions need analysis. Brain and Val- berg (1979), as well as others, have shown that there are multiple factors, including age and health of the experimental subject, that influence the deposition and subse- quent management of a particulate aerosol. These workers have also described various methods to assess deposition, and these factors should be investigated. Other necessary data include those on morphological abnormalities at multiple points over a long-term exposure, particu- larly at the lower doses. The animal model chosen should therefore have a long life- span. Long-term animal studies should be multidisciplinary and should include phys- iological, morphological, and biochemical analyses (Recommendation 15~. Study hypotheses should be related to the pa- thophysiology of disease and directed toward a low concentration range of emis- sions including single or multiple compo- nents. Long-term experiments could an- swer the question of severity of disease or tolerance to emissions in relation to expo- sure at an early age. Since there are some data suggesting disease progression very similar to the postexposure progression of elastase-in- duced emphysema, it is important to ana- lyze a recovery period as well as several . . points c curing exposure. Sacrifice at various time points would provide information relating collagen and elastin breakdown and repair to parenchy- mal destruction and production of airway
OCR for page 458
458 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions abnormalities. These data would be corre- lated with lung function. If proven helpful in the short term, biochemical estimations of elastin products would be useful to mon- itor disease without the necessity for sacri- fice. Similarly, certain types of pulmonary function could be performed on a routine basis without sacrifice, following the gen- eral procedure of Mauderly (1984~. These methods would allow a longitudinal study and avoid potential artifact produced by tracheostomy. Data from such long-term animal exper- iments would provide a basis for long- term epidemiologic studies on humans. They would help to develop a scheme to suggest important variables and allow for appropriate testing and analysis of human data. The data obtained from such experi- ments could also be important in assess- ment of early disease and of the transition between health and disease in a pollutant- exposed population. Although this list of recommendations treats the areas of histopathology, bio- chemistry, and physiology separately, re- searchers performing animal experiments should collect these data and correlate them. In particular, the data provided by the groups of dog model (beagle) studies at the University of California at Davis have evinced the need for study of the mecha- nisms of pulmonary disease. This can only be accomplished by carefully planned mul . . . .. . tic 1sclpllnary stuc lest Human Studies Physiological and morphological investiga- tions form a major tool for human studies. Although there are some difficulties in per- forming the more specialized physiological tests in a community or workplace envi- ronment, these difficulties are not insur- mountable, and the additional data pro- vided are extremely valuable. These specialized tests can certainly be performed in the short-term-exposure laboratory set- ting (Recommendation 7~. Researchers performing structural/func- tional correlations on human autopsies can perform lung mechanics on excised speci- mens and relate results to data collected on the live subject. Morphological examinations for human exposures could also be per- formed on autopsy and surgical specimens, duplicating the methods used for tobacco smoke investigations (Recommendation 5~. Summary of Research Recommendations: Priorities The research recommendations are resummarized here by exper- imental technique rather than by subject area, for the purpose of focusing on a research program. In the following listing, the needed experiments are ranked from high to low priority within each category. In Vitro Experiments HIGH PRIORITY Recommendation 1 Pollutant constituents should be introduced to cell cultures of epithelial and/or inflammatory cells. MEDIUM PRIORITY Recommendation 3 Cell damage and its relation to inflammation should be studied through further research on exposure-related increases in neutro phils and macrophages, including collagen and elastin biomechan ics, and the dose/time relationship between exposure and neutro phil and macrophage increase.
OCR for page 459
Joanne L. Wright 459 Recommendation 8 Research should be undertaken on the elastin and collagen degradation/repair balance to determine whether repair is affected by pollutants, and if so, by what mechanism. Studies should map the time course of collagen and elastin degradation and repair, relating data to type and concentration of exposure as well as ascertaining the possibility of alteration or repair by pollutants or other oxidants. LOW PRIORITY Recommendation 4 The relation of oxidants to the proteinase/antiproteinase balance should be studied. In Vito Experiments HIGH PRIORITY' Recommendation 2 Studies should be undertaken to ascertain whether the peptides present in body fluids can be measured accurately, and whether the measured parameters do, in fact, relate to the degradation and repair process. Recommendation 12 Experiments should be performed to determine the pathobiol ogy of emissions-related diseases by measuring biochemical param eters in lung tissue and by counting and typing inflammatory cells . . in avage or tissue. Recommendation 15 Long-term, multidisciplinary animal studies should be designed to document abnormalities produced by exposure to emissions at various points in the lifespans of subjects. MEDIUM PRIORITY Recommendation 9 Pollutant interference with lysyl oxidase and impairment of elastin resynthesis should be investigated. Recommendation 10 Research should be undertaken on the balance between fibrosis and destruction and their relation to particulates/oxidants. Recommendation 11 Degradation products such as elastin, peptides, urinary des ~ ~ ~ , mosine, and hydroxylysine should be quantified. Recommendation 13 Dose dependency should be quantified and extrapolated to lower doses. . LOW PRIORITY Recommendations Epithelial cells, collagen, and elastin should be examined by electron microscopy to document possible progression of emis * Experiments are meant to be short term unless explicitly stated otherwise. ,.
OCR for page 460
460 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions sion-related disease after the cessation of direct exposure, in both short-term and long-term studies. Recommendation 14 The degree of synergism between components and their relative importance in causing disease should be investigated. Recommendation 16 Experiments should be conducted to analyze the effects of nutrition, stress, infection, exercise, and co-contaminants such as diesel particulates and cigarette smoke on pulmonary disease. Recommendation 17 Short-term and long-term studies should be undertaken to determine whether the effects of diesel exhaust are different from the effects of gasoline exhaust in regard to disease progression, the effects of age at exposure, and additional applied stress. Human Studies HIGH PRIORITY Recommendation 5 Pulmonary mechanics should be assessed on excised lung spec imens obtained from human autopsies and results related to data collected from live subjects. Morphological examinations of hu man autopsies could duplicate methods used to investigate the effects of tobacco smoke. Recommendation 7 Some of the more detailed pulmonary function tests should be used to identify progressive dysfunction. References Arner, E. C., and Rhoades, R. A. 1973. Long-term nitrogen dioxide exposure, Arch. Environ. Health 26:156-160. Baile, E. M., Wright, J. L., Pare, P. D., and Hogg, J. C. 1982. The effect of acute small airway inflam- mation on pulmonary function in dogs, Am. Rev. Respir. Dis. 126:298-301. Barnhart, M. I., Salley, S. O., Chen, S.-T., and Puro, H. 1981. Morphometric ultrastructural analysis of alveolar lungs of guinea pigs chronically exposed by inhalation to diesel exhaust (DE), Develop. Toxicol. Environ. Sci. 10:183-200. Bils, R. F. 1976. The connective tissues and alveolar walls in the lungs of normal and oxidant-exposed squirrel monkeys, J. Cell Biol. 70:318. Brain, J. D., and Valberg, P. A. 1979. Deposition of aerosol in the respiratory tract, Am. Rev. Respir. Dis. 120: 1325-1373. Buell, G. C. 1970. Biochemical parameters in inhala- tion carcinogenesis, In: Inhalation Carcinogenesis Correspondence should be addressed to J. L. Wright, Pulmonary Research Laboratory, St Paul's Hospital, 1081 Burrard St., Vancouver, British Columbia, Can ada V6Z 1Y6. (M. G. Hanna, P. Nettesheim, and J. R. Gilbert, eds.), pp. 209-225, USAEC Division of Technical Information, Oak Ridge, Tenn. Buist, S., Vollmer, W., end Johnson, L. 1984. Does the single breath N2 test identify the susceptible individual? Chest 85:10S. Cabral-Anderson, L. J., Evans, M. J., and Freeman, G. 1977. Effects of NO2 on the lungs of aging rats. I: Morphology, Exp. Mol. Pathol. 27:35~365. Coff~n, D. L., and Stokinger, H. E. 1977. Biological effects, In: Air Pollution. Vol. II: The EfJects of Air Pollution (A. C. Stern, ed.), Academic Press, New York, N.Y. Cosio, M., Ghezzo, H., Hogg, J. C., Corbin, R., Loveland, M., Dosman, J., and Macklem, P. T. 1977. The relations between structural changes in small airways and pulmonary function tests, N. Engl. J. Med. 298:1277-1281. Cosio, M. G., Hale, K. A., and Niewoehner, D. E. 1980. Morphologic and morphometric effects of prolonged cigarette smoking on the small airways, Am. Rev. Respir. Dis. 122:265-271. Davidson, J. T., Lillington, G. A., Haydon, G. B., and Wasserman, K. 1967. Physiologic changes in the lungs of rabbits continuously exposed to nitro- gen dioxide, Am. Rev. Respir. Dis. 95:790-796. Dunnill, M. S. 1962. Quantitative methods in the study of pulmonary pathology, Thorax 17:320-328.
OCR for page 461
Joanne L. Wright Evans, M. J. 1984. Oxidant gases, Environ. Health Perspect. 55:85-95. Evans, M. J., and Freeman, G. 1980. Morphological and pathological effects of NO2 on the rat lung, In: Nitrogen Oxides and Their Effects on Health (S. D. Lee, ed.), pp. 24~264, Ann Arbor Science Publish- ers, Ann Arbor, Mich. Evans, M. J., Cabral, L. J., Stephens, R. J., and Freeman, G. 1973. Cell division of alveolar macro- phages in rat lung following exposure to NO2, Am. J. Pathol. 70:199-208. Evans, M. J., Cabral-Anderson, L. J., and Freeman, G. 1977. Effects of NO2 on the lungs of aging rats. II: Cell proliferation, Exp. Mol. Pathol. 27:366-376. Fedan,J. S., Frazer, D. G., Moorman, W. J., Attfield, M. D., Franczak, M. S., Kosten, C. J., Cahill, J. F., Lewis, T. R., and Green, F. H. Y. 1985. Effects of a two-year inhalation exposure of rats to coal dust and/or diesel exhaust on tension responses of iso- lated airway smooth muscle, Am. Rev. Respir. Dis. 131 :651-655. Fletcher, B. L., and Tappel, A. L. 1973. Protective effects of dietary alpha-tocopherol in rats exposed to toxic levels of ozone and nitrogen dioxide, Environ. Res. 6:165-175. Fletcher, C., Peto, R., Tinken, C., and Speizer, F. E. 1976. The Natural History of Chronic Bronchitis and Emphysema, pp. 7~105, Oxford University Press, New York, N.Y. Freeman, G., Crane, S. C., Stephens, R. J., and Furiosi, N. J. 1968. Pathogenesis of the nitrogen dioxid~induced lesion in the rat lung: a review and presentation of new observations, Am. Rev. Respir. Dis. 98:429-443. Freeman, G., Crane, S. C., Furiosi, N. J., Stephens, R. J., Evans, M. J., and Moore, W. D. 1972. Covert reduction in ventilatory surface in rats during pro- longed exposure to subacute nitrogen dioxide, Am. Rev. Respir. Dis. 106:56~579. Furiosi, N. J., Crane, S. C., and Freeman, G. 1973. Mixed sodium chloride aerosol and nitrogen diox- ide in air, Arch. Environ. Health 27:405008. Gail, D. B. and Lenfant, C. J. M. 1983. Cells of the lung: biology and clinical implications, Am. Rev. Respir. Dis. 127:36~387. Gardner, D. E., Coffin, D. L., Pinigin, M. A., and Sidorenko, G. I. 1977. Role of time as a factor in the toxicity of chemical compounds in intermittent and continuous exposures. Part I: Effects of continuous exposure, J. Toxicol. Environ. Health 3:811-820. Gardner, D. E., Miller, F. J., Blommer, E. J., and Coffin, D. L. 1979. Influence of exposure mode on the toxicity of NO2, Environ. Health Perspect. 30:2~29. Gillespie, J. R., Berry, J. B., White, L. L., and Lindsay, P. 1980. Effects of pulmonary function of low-level nitrogen dioxide exposure, In: Nitrogen Oxides and Their E.~ects on Health (S. D. Lee, ed.), pp. 231-241, Ann Arbor Science Publishers, Ann Arbor, Mich. Giordano, A. M., and Morrow, P. E. 1972. Chronic low-level nitrogen dioxide exposure and mucocil- iary clearance, Arch. Environ. Health 25:44~449. Goldstein, R. H. 1982. Response of the aging hamster 461 lung to elastase injury, Am. Rev. Respir. Dis. 125:295-298. Gregory, R. E., Pickrell, J. A., Hahn, F. F., and Hobbs, C. H. 1983. Pulmonary effects of intermit- tent subacute exposure to low-level nitrogen diox- ide,J. Toxicol. Environ. Health 11:405-414. Hacker, A. D., El Sayed, N., Mustafa, M. G., Ospital, J. J., and Lee, S. D. 1976. Effects of short-term nitrogen dioxide exposure on lung col- lagen synthesis, Am. Rev. Respir. Dis. 113:107. Hammond, E. C., Kirman, D., and Garfinkel, I. 1970. Effects of cigarette smoking on dogs, Arch. Environ. Health 21:74~753. Heckman, C. A., and Dalbey, W. E. 1982. Pathogen- esis of lesions induced in rat lung by chronic tobacco smoke inhalation, J. Nat. Cancer Inst. 69:117-129. Hogg, J. C., Macklem, P. T., and Thurlbeck, W. M. 1968. Site and nature of airway obstruction in chronic obstructive lung disease, N. Engl. J. Med. 278:1355-1360. Hoidal, J. R., and Niewoehner, D. E. 1982. Lung phagocyte recruitment and metabolic alterations induced by cigarette smoke in humans and in ham- sters, Am. Rev. Respir. Dis. 126:548-552. Hoidal, J. R., and Niewoehner, D. E. 1983. Cigarette smoke inhalation potentiates elastase-induced em- physema in hamsters, Am. Rev. Respir. Dis. 127:478-481. Horsfield, K. 1976. Lung morphology, Recent Adv. Respir. Med. 1:12~154. Huber, G. L., Davies, P., Zwilling, G. R., Pochay, V. E., Hinds, W. C., Hicholas, V. K., Mahajan, V. K., Hayashi, M., and First, M. W. 1981. A morphological and physiologic bioassay for quan- tifying alterations in the lung following experimen- tal chronic inhalation of tobacco smoke, Bull. Eur. Physiopathol. Respir. 17:269-327. Hunninghake, G. W., and Crystal, R. G. 1983. Cig- arette smoking and lung destruction: accumulation of neutrophils in the centri-lobular form of hyper- trophic emphysema and its relation to chronic bron- chitis, Thorax 12:219-235. Hyde, D., Orthoefer, J., Dungworth, D., Tyler, W., Carter, R., and Lum, H. 1978. Morphometric and morphologic evaluation of pulmonary lesions in beagle dogs chronically exposed to high ambient levels of air pollutants, Lab. Invest. 38:455~69. Hyde, D. M., Plopper, C. G., Weir, A. J., Murname, R. D., Warren, D. L., Last, J. A., and Pepelko, W. E. 1985. Peribronchiolar fibrosis in lungs of cats chronically exposed to diesel exhaust, Lab. Invest. 52:192-206. Janoff, A. 1985. Elastases and emphysema: current assessment of the proteinase-antiproteinase hypoth- esis, Am. Rev. Respir. Dis. 132:417033. Karlinsky, J., Fredette, J., Davidovits, G., Catanese, A., Snider, R., Faris, B., Snider, G. L., and Franz- blau, C. 1983. The balance of lung connective tissue elements in elastase-induced emphysema, J. Lab. Clin. Med. 102:151-162. Kelley, J., Hemenway, D., and Evans, J. N. 1986. Hydroxylysine as a marker of lung injury in nitro- gen dioxide exposure, Am. Rev. Respir. Dis. 133:A86.
OCR for page 462
462 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions Kleinerman, J. 1979. Effects of nitrogen dioxide on elastin and collagen contents of lung, Arch. Environ. Health 34:22~232. Kleinerman, J., and Niewoehner, D. 1973. Physiolog- ical, pathological and morphometric studies of long term nitrogen dioxide exposures and recovery in hamsters, Am. Rev. Respir. Dis. 107:1081. Kleinerman, J., Rynbrandt, R., and Sorensen, J. 1976. Chronic obstructive airways disease in cats pro- duced by NO2, Am. Rev. Respir. Dis. 113:107. Kuhn, C., Shiu-Yeh, Y., Chraplyvy, M., Linder, H. E., and Senior, R. 1976. The induction of emphysema with elastase, Lab. Invest. 34:372-380. Lam, C., Kattan, M., Collins, A., and Kleinerman, J. 1983. Long-term sequelae of bronchiolitis induced by nitrogen dioxide in hamsters, Am. Rev. Respir. Dis. 129:1020-1023. Lewis, T. R., Moorman, W. J., Yang, Y.-Y., and Stara, J. F. 1974. Long-term exposure to auto exhaust and other pollutant mixtures: effects on pulmonary function in the beagle, Arch. Environ. Health 29:102-106. Mauderly, J. L. 1984. Respiratory function responses of animals and man to oxidant gases and to pulmo- nary emphysema, J. Toxicol. Environ. Health 13:345-361. Mauderly, J. L., Benson, J. M., Bice, D. E., Carpen- ter, R. L., Evans, M. J., Henderson, R. F., Jones, R. K., McClellan, R. O., Pickrell, J. A., Redman, H. C., Shami, S. G., and Wolff, R. F. 1983. Inhalation Toxicology Research Institute Annual Report, pp. 305-316, LMF-107 Inhalation Toxicol- ogy Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M. Mauderly, J. L., Bice, D. E., Gillett, N. A., Hender- son, R. F., and Wolff, R. K. 1986. Differences in the responses of developing and adult rats to inhaled diesel exhaust, Am. Rev. Respir. Dis. 133:A84. Menzel, D. B. 1980. Pharmacological mechanisms in the toxicity of nitrogen dioxide and its relation to obstructive respiratory disease, In: Nitrogen Oxides and Their Elects on Health (S. D. Lee, ed.), pp. 199-216, Ann Arbor Science Publishers, Ann Ar- bor, Mich. Mitchell, R. S., Stanford, R. E., Johnson, J. M., Silvers, G. W., Dart, G., George, M. S. 1976. The morphologic features of the bronchi, bronchioles and alveoli in chronic airways obstruction: a clinic pathological study, Am. Rev. Respir. Dis. 114:137- 145. Mustafa, M. G., Faeder, E. J., and Lee, S. D. 1980. Biochemical effects of nitrogen dioxide on animal lungs, In: Nitrogen Oxides and Their Effects on Health (S. D. Lee, ed.), pp. 161-171, Ann Arbor Science Publishers, Ann Arbor, Mich. Mustafa, M. G., El Sayed, N. M., von Dohlen, F. M., Hassett, C. M., Postlethwait, E. M., Quinn, C. L., Graham, J. A., and Gardner, D. E. 1984. A comparison of biochemical effects of nitrogen diox- ide, ozone, and their combination in mouse lung, Toxicol. Appl. Pharmacol. 72:82-90. Nagaishi, C., Nagasawa, N., Yamashita, M., Okada, Y., and Inoba, N. 1972. Functional Anatomy and Histology of the Lung, University Park Press, Baltimore, Md. Nakajima, T., Oda, H., Kusumoto, S., and Nogami, H. 1980. Biological effects of nitrogen dioxide and nitric oxide, In: Nitrogen Oxides and Their E~ects on Health (S. D. Lee, ed.), pp. 121-139, Ann Arbor Science Publishers, Ann Arbor, Mich. Niewoehner, D. E., and Hoidal, J. R. 1982. Lung fibrosis and emphysema: divergent responses to a common injury, Science 217:359-360. Niewoehner, D. E., Kleinerman, J., and Rice, D. P. 1974. Pathologic changes in the peripheral airways of young cigarette smokers, N. Engl. J. Med. 291 :755-758. Orthoefer, J. G., Bhatnagar, R. S., Rahman, A., Yang, Y. Y., Lee, S. D., and Stara, J. F. 1976. Collagen and prolyl hydroxylase levels in lungs of beagles exposed to air pollutants, Environ. Res. 12:299-305. Pepelko, W. E. 1981. EPA studies on the toxicological effects of inhaled diesel engine emissions, Develop. Toxicol. Environ. Sci. 10:121-142. Peters, S. G., and Hyatt, R. E. 1986. A canine model of bronchial injury induced by nitric acid, Am. Rev. Respir. Dis. 133:1049-1054. Plopper, C. G., Hyde, D. M., Weir, A. J. 1983. Centriacinar alterations in lungs of cats chronically exposed to diesel exhaust, Lab. Invest. 49:391-399. Port, C. D., Ketels, K. V., Coffm, D. L., and Kane, P. 1977. A comparative study of experimental and spontaneous emphysema, J Toxicol. Environ. Health 2:589004. Raub, J. A., Mercer, R. R., Miller, F. J., Graham, J. A., O'Neil, J. J. 1982. Dose response of elastase- induced emphysema in hamsters, Am. Rev. Respir. Dis. 125:432035. Reid, L. 1960. Measurement of the bronchial mucous gland layer: a diagnostic yardstick in chronic bron- chitis, Thorax 15:132-141. Rynbrandt, D., and Kleinerman, J. 1977. Nitrogen dioxide and pulmonary proteolytic enzymes: effect on lung tissue and macrophages, Arch. Environ. Health 32:16~172. Saetta, M., Shiner, R. J., Angus, G. E., Kim, W. D., Wang, N.-S., King, M., Ghezzo, H., and Cosio, M. G. 1985a. Destructive index: a measurement of lung parenchymal destruction in smokers, Am. Rev. Respir. Dis. 131:76~769. Saetta, M., Ghezzo, H., Kim, W. D., King, M., Angus, G. E., Wang, N.-S., and Cosio, M. G. 1985b. Loss of alveolar attachments in smokers: a morphometric correlate of lung function impair- ment, Am. Rev. Respir. Dis. 132:890900. Selgrade, M. K., Mole, M. L., Miller, F. J., Hatch, G. E., Gardner, D. E., and Hu, P. C. 1981. Effect of NO2 inhalation and vitamin C deficiency on protein and lipid accumulation in the lung, Environ. Res. 6:422037. Snider, G. L., Kleinerman, J., Thurlbeck, W. M., and Bengali, Z. H. 1985. The definition of emphysema: report of a National Heart, Lung, and Blood Insti- tute, Division of Lung Diseases workshop, Am. Rev. Respir. Dis. 132:182-185. Sparrow, D., Glynn, R. J., Cohen, M., and Weiss,
OCR for page 463
Joanne L. Wright 463 S. T. 1984. The relationship of the peripheral leu- kocyte count and cigarette smoking to pulmonary function among adult men, Chest 86:38~386. Stara, J. F., Dungworth, D. L., Orthoefer, J. G., and Tyler, W. S. 1980. Long-Term Effects of Air Pol- lutants: In Canine Species, series no. 8, Environ- mental Protection Agency, Office of Research and Development, EPA-600/8-80-014, Cincinnati, Ohio. Stephens, R. J., Freeman, G., and Evans, M. J. 1971. Ultrastructural changes in connective tissue in lungs of rats exposed to NO2, Arch. Intern. Med. 127:87~883. Thurlbeck, W., Dunnil, M. S., and Hurtung, W. 1970. A comparison of other methods of measuring emphysema, Human. Pathol. 1:215-226. Turino, G. M. 1985. The lung parenchyma-a dy- namic matrix, Am. Rev. Respir. Dis. 132:1324-1334. Vaughan, T. R., Jr., Jennelle, L. F., and Lewis, T. R. 1969. Long-term exposure to low levels of air pollutants: effects on pulmonary function in the beagle, Arch. Environ. Health 19:45-50. Vostal, J. J., White, H. J., Strom, K. A., Siak, J.-S., Chen, K.-C., and Dziedzic, D. 1981. Response of the pulmonary defense system to diesel particulate exposure: toxicological effects of emissions from diesel engines, Develop. Toxicol. Environ. Sci. 10:201-221. Wiester, M. J., Iltis, R., and Moore, W. 1980. Altered function and histology in guinea pigs after inhala- tion of diesel exhaust, Environ. Res. 22:285-297. Wright, J. L., Lawson, L. M., Pare, P. D., Kennedy, S., Wiggs, B., and Hogg, J. C. 1984. The detection of small airways disease, Am. Rev. Respir. Dis. 129:989-994. Wright, J. L., Cosio, M., Wiggs, B., and Hogg, J. C. 1985. A morphologic grading scheme for membra- nous and respiratory bronchioles, Arch. Pathol. Lab. Med. 109:16~165.
OCR for page 464
Representative terms from entire chapter: