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The Inorganic Dust Pneumoconioses Richard P. Stankus and John E. Salvaggio

The association between inhalation of inorganic dust and the development of lung disease has been known for centuries. Silicosis, perhaps the oldest and most common of these pulmonary disorders, results from the inhalation of free crystalline silica. Asbestosis is a chronic fibrotic lung disease initiated by prolonged inhalation of asbestos fibers, and coal workers' pneumoconiosis and berylliosis can occur after inhalation of coal dust and beryllium compounds, respectively. Together, these diseases represent the major clinical expressions of a group of pulmonary disorders labeled the inorganic dust pneumoconioses. This review describes the radiographic, physiologic, and immunologic findings associated with these interstitial fibrotic lung diseases and proposes a role for abnormalities of immune regulation in disease pathogenesis.

Silicosis Classic silicosis (in contrast to acute or accelerated forms) reflects the pulmonary inflammatory response to prolonged and extensive exposure to respirable free silica (uncombined forms of silicon dioxide in contrast to silicates, which contain cations). Because of the ubiquity of silicon dioxide in the earth's crust, workers in many occupations frequently come in contact with free silica. In several occupations (mining, sandblasting, foundry work, and abrasive processing), the risk for developing disease is readily apparent; however, half of those at risk are employed in manufacturing where the dust hazard may go unrecognized.1 Although the spectrum of disease is broad, silicosis has been divided between simple and complicated forms, which represent wellestablished chest radiographic categories and provide a rational basis with which to compare and contrast host immunologic responses and to formulate theories of pathogenesis (Table 1). The diagnosis of simple silicosis is based on chest radiographic changes of small, rounded opacities, usually less than 5 mm in diameter, which occur predominantly in the upper lung zones and are associated with a history of significant silica exposure (Fig. 1). Histologically, these radiographic opacities

From the Clinical Immunology Section, Department of Medicine, Tulane University Medical School, New Orleans, Louisiana. Send correspondence and requests for reprints to Richard P. Stankus, PhD, MD, Clinical Immunology Section, Department of Medicine, Tulane University Medical School, 1700 Perdido Street, New Orleans, LA 70112. © 1985 Elsevier Science Publishing Co., Inc. 52 Vanderbflt Ave., New York, NY 10017

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Table 1. Clinical Characteristics of Silicosis Radiologiccategory Simple silicosis

Complicated silicosis

Signs and symptoms

Pathology

Usually none, but may be associated with occupationallyinduced bronchitis Initially, chroniccough and progressive dyspnea; restriction of lung volumes, weight loss, respiratory cachexia, and cor pulmonale may develop

Fibrotic nodules locatednear respiratory bronchioles Large (>1 cm) conglomerate masses in upper lung zones

represent the silicotic nodule---the hallmark of silicosis. Although often straightforward in terms of diagnosis, this form of silicosis must be differentiated from sarcoidosis, which also has a tendency to produce widespread nodulation, especially in the upper lung zones. Pulmonary function studies in simple silicosis are often normal. No functional measurement or combination of measurements is specific for silicosis. The primary risk associated with simple silicosis is mycobacterial infection and progression to complicated disease or progressive massive fibrosis. Complicated silicosis is characterized by radiographic opacities greater than 1 cm in diameter that usually occur within the upper lobes and often are associated with lobar contraction, elevation of the lung roots, and the development of emphysematous changes at the bases (Figs. 2 and 3). Lymph nodes may calcify, producing an eggshell appearance. Massive disease (progressive massive fibrosis) with contraction of the upper lobes is frequently associated with thickening of the pleura. Complicated cases often show mixed patterns

Figure 1. Chest radiographic changes of simple silicosis demonstrating diffuse nodular infiltrates (<1 cm diameter) predominantly in the upper lung zones.

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Figure 2. Chest radiographic changes of complicated silicosis demonstrating upper lobe nodular infiltrates (>1 cm diameter).

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Figure 3. Chest radiographic changes of complicated silicosis demonstrating large perihilar nodular infiltrates.

of ventilatory impairment, with reduced diffusing capacities and exerciseinduced hypoxemia. Lung compliance may be reduced with advanced stages, demonstrating severe restrictive impairments. There is no specific therapy, and progression of silicosis is to be expected despite termination of exposure. A growing body of literature supports t h e association of silicosis with regulatory abnormalities of host immunologic responses. This significant relationship is exemplified by the increased prevalence of collagen vascular disease (scleroderma, rheumatoid arthritis, systemic lupus erythematosus) in subjects with silicosis. Although a substantial number of immunologic alterations have been documented in both experimental and human silicosis, many nonhuman observations lack apparent clinical relevance. Accordingly, the following discussion will reference human observations and selected animal models that parallel human disease. Both simple and complicated forms of human silicosis are associated with humoral and cellular peripheral blood abnormalities. Antinuclear antibodies, rheumatoid factors, hypergammaglobulinemia, immune complexes, i n creased levels of serum angiotensin converting enzyme, and elevated factor B levels occur with increased frequency in subjects with silicosis. 2"3Alterations in peripheral blood T lymphocyte subsets (T-helper, T-suppressor) and lymphocyte response to phytohemagglutinin (PHA) have also been observed in subjects with both simple and complicated disease. 3 In several studies attempting to associate these changes with disease severity and/or the probability of its progression, no significant correlation has been observed b e t w e e n the presence of antinuclear antibodies, rheumatoid factors, serum immunoglobulin concentration, or immune complex formation and radiographic changes or decline in pulmonary functions tests. 2Similarly, in recent comparison stud-

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R. P. Stankus and J. E. Salvaggio ies of two groups of patients, one with simple silicosis and one with complicated pulmonary changes, no significant differences were noted in T lymphocyte subpopulations or lymphocyte response to mitogen stimulation. 3 Although these observations are disappointing from the standpoint of defining predictive serologic "markers" of disease severity, it is premature to label the associated serologic, immunologic changes as epiphenomena. Rather, these alterations reveal that silica exposure is associated with very early changes in cell populations and their products---alterations that persist as silicosis progresses. In a preliminary study, Schuyler and coworkers examined the population of ceils retrieved from segmental bronchopulmonary lavage of six subjects with complicated silicosis. 4 Increased numbers of type II pneumocytes were present in lavage fluid from silicotic subjects. However, no obvious differences in pulmonary macrophage adherence, phagocytosis, or bactericidal activity were found when cells from subjects with silicosis were compared with cells obtained from a control population. Although h u m a n studies have largely assessed peripheral blood alterations in silicosis, several well-controlled animal models of experimental disease have characterized local bronchopulmonary humoral and cellular changes. Analysis of bronchoalveolar lavage fluid obtained from rabbits exposed to silica via the respiratory tract route confirmed increased levels of IgG and secretory IgA, along with both elevated pulmonary macrophage concentrations of the lysosomal enzymes, beta-glucuronidase and acid phosphatase, and increased pulmonary macrophage adherence. 5 Significantly, elevations in lavage fluid beta-glucuronidase activity persisted for as long as 28 months following silica exposure, supporting the role of macrophage enzyme release in disease pathogenesis. 6Similar changes were not observed in a group of appropriate controls, including a group exposed to a commercial silica substitute. Although local pulmonary alterations were observed in all silica-exposed animals, peripheral blood changes were not a consistent finding. This result stresses the importance of defining "local" bronchopulmonary responses in unraveling the pathogenesis of many immunologically mediated pulmonary diseases. The above observations, in addition to relevant in vitro studies, provide the basis for theories of immunopathogenesis in human silicosis. The development of silicosis depends on the inhalation of respirable particles of free silica that are less than 10 ~m in diameter. The resultant effect on macrophage release of hydrolytic enzymes is strongly dependent on the nature, structure, and surface activity of the dust inhaled. Etching of crystalline tridymite (silicon dioxide with hexagonal crystals) with hydrofluoric acid significantly enhances macrophage death and release of lysosomal enzymes, in comparison with the effect of unetched tridymite. 7 Cytotoxicity, however, does not appear to be a prerequisite for enzyme release, as vitreous silica does not lead to macrophage death following in vitro exposure, but does allow significant secretion of lysosomal and nonlysosomal enzymes. 8 The initial pulmonary reaction following experimental silica exposure is soon followed by a substantial influx of cells from the peripheral blood to the lungs. Miller et al. 9 demonstrated macrophage chemotactic factors derived

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from the silica-exposed bronchopulmonary macrophages of guinea pigs. The increased number of pulmonary macrophages observed after exposure to silica presumably reflects several mechanisms of cell recruitment. Macrophage hydrolases have been shown to cleave complement components, resulting in production of chemotactic factors for both macrophages and polymorphonuclear cells (PMNs).1° The pulmonary immigration of PMNs may represent an important stage in disease pathogenesis. Conceivably, release of toxic oxidation products (hydrogen peroxide, hydroxyl radical, and superoxide anion) may alter macrophage and lymphocyte cell populations 11 and directly affect tissue fibroblasts.12 In addition to macrophages and PMNs, pulmonary lymphocytes represent an important component of the reaction to silica. As discussed earlier, there are increased levels of secretory IgA and IgG in bronchial lavage fluid obtained from silica-exposed rabbitsd This local response is in agreement with enhancement of antibody responses observed in a number of animal models following exposure to silica and antigen 1~-1s and correlates well with the increased serum levels of IgG, IgA, and IgM documented in human silicosis. 2 Enhanced production of immunoglobulin is also associated with an increased prevalence of autoantibodies in humans with silicosis. Both rheumatoid factors and antinuclear antibodies are significantly increased in patients with silicosis in comparison with age-matched controls. 2 Although silica-induced alterations of host humoral and cellular responses are well documented, the critical link in disease pathogenesis involves interactions of immune cells/factors with the tissue fibroblast. Burrell and Anderson 16 demonstrated a macrophage-derived soluble factor that enhanced the content of hydroxyproline and DNA in fibroblast subcultures. Supernatant fractions from cultures of normal macrophages incubated without silica also were able to stimulate fibroblast subcultures. Richards and Wusterman 17confirmed the ability of normal or silica-exposed macrophages to stimulate production of collagen. In a related study, Johnson and Ziff TM reported enhanced accumulation of collagen following exposure of human lung fibroblasts to lymphokine-rich supernatants from mitogen-stimulated human peripheral blood mononuclear cells. In contrast, however, Korn et a1.19 demonstrated suppression of fibroblast proliferation by supernatants of both unstimulated and mitogen-stimulated cultures of mononuclear cells. Finally, a recent report has documented a fibroblast proliferation factor generated by silica-exposed human macrophages that is identical to interleukin-1. 2° In summary, silicosis represents a fibrotic lung disease with protean manifestations of humoral and cellular immune alterations. Although the exact pathway of disease expression is as yet undefined, the interaction of several distinct immune cell types and factors presumably modify fibroblast synthesis and secretion of collagen, with resultant interstitial pulmonary fibrosis. Asbestosis Asbestosis is a chronic fibrotic lung disease initiated by prolonged inhalation of asbestos dust. Asbestos minerals are fibrous silicates of which chrysotile (white asbestos), crocidolite (blue asbestos), and amosite (brown asbestos)

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are the most important commercial fibers. Because all are thermal resistant, asbestos has been employed in numerous industries in the last half century. The most important factors in the development of asbestosis are the duration of exposure and the amount of dust to which the individual is exposed. Occupations that involve an increased risk of asbestosis include asbestos milling, mining, and handling. Also at risk are workers in shipyard, automotive, textile, insulation, cement, paper, construction, demolition industries. Indirect nonoccupational exposure of family members of asbestos workers and persons who reside near a mine has also been associated with asbestosis and mesothelioma. 21 Clinically, the symptoms and signs of asbestosis are similar to those of other interstitial lung diseases. The usual clinical presentation is an incidental radiographic finding in an asymptomatic patient. Symptoms usually occur after 20 years of exposure. Dyspnea on exertion is the most common early symptom, but cough and a feeling of tightness in the chest may also develop. Physical findings include dubbing of the fingers and lung crepitafions. Radiographic findings, primarily in the lower lung fields, include pleural changes (thickening and calcified plaques). Parenchymal changes consist of reticulonodulation and a honeycomb pattern. Pulmonary function impairment usually reflects a restrictive ventilatory defect, with a reduction in compliance and gas transfer. Thus, a diagnosis of asbestosis depends on a history of exposure to asbestos, supported by associated signs or symptoms of any interstitial fibrotic pulmonary disease. There is no specific treatment for asbestosis, and the disease may progress even after cessation of exposure. Like silicosis, asbestosis and asbestos exposure are associated with abnormalities in both the humoral and cellular components of the immune response. Significant cutaneous anergy to recall antigens SK-SD, C a n d i d a albicans, 22 and tuberctflin PPD23 has been demonstrated in patients with asbestosis, together with a decrease in the percentage and absolute number of circulating T lymphocytes. 2. Results of studies of lymphocyte transformation in patients with asbestosis have varied. A significant reduction in lymphocyte transformation to phytohemagglutinin has been reported by several authors. 22 In contrast, Campbell et al. zs reported a significant increase in the lymphocyte response to phytohemagglutinin and pokeweed mitogen in smokers with asbestosis, whereas nonsmokers with asbestosis showed a normal lymphocyte response to pokeweed mitogen. Assays of cytotoxic effector cell function (K cells) in patients with asbestosis have also revealed conflicting results. Kagan et al. z2 reported a significant reduction in phytohemagglutinin-induced lymphoid cell-mediated toxicity, whereas Campbell and associates 25 failed to demonstrate any significant abnormality in either smokers or nonsmokers with asbestosis. An increased prevalence of antinuclear antibodies and rheumatoid factor, in addition to cold lymphocytotoxins, has been reported in patients with asbestosis. 26However, the presence of antinuclear antibodies and rheumatoid factor has not consistently correlated with severity of disease, and a specific antinuclear factor has not been demonstrated in asbestosis.2Z Recently, asbestos-exposed individuals were found to have significant hypergammaglobulinemia, lymphopenia, and decreased numbers of all lym-

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phocyte populations (B cells, T cells, T helper/inducer cells, T suppressor/cytotoxic cells) w h e n compared with controls. These immunologic abnormalities were unrelated to the degree of chest x-ray abnormality, estimates of cumulative asbestos exposure, or results of pulmonary function tests. Apparent dysfunction of mitogen-induced lymphocyte proliferation among the exposed population was no longer detectable when values were corrected for effects related to age and decreased T lymphocyte numbers in cultures exposed to mitogen. 28 It is important to note that asbestos fibers can directly interact with and alter components of immune reactivity. For example, asbestos fibers activate both the alternative and classic pathways of complement. 29These fibers also generate chemotactic factor activity in normal human serum, 3° absorb serum IgGY have adjuvant-like action in animals, 31 are cytotoxic to monocytes/macrophages, 32 and stimulate collagen synthesis in vitro. ~ Undoubtedly, the effects of asbestos exposure on immune function are widespread. However, like silicosis, little is known of local bronchopulmonary alterations of humoral and cellular function in humans. Accordingly, theories of disease pathogenesis must rely on observations obtained from suitable animal models. Miller and Kagan 31 have shown that alveolar macrophages from rats exposed tO crocidolite fibers in vivo develop alterations in membrane structure. 3~ Macrophage Fc receptors for IgG are significantly increased, as are cytoplasmic processes. When alveolar macrophages from cr0cidolite-exposed rats were incubated in vitro with homologous splenocytes, there was a proliferation of mononuclear cell populations enriched for T lymphocytes, suggesting the induction by asbestos of a macrophage-associated neoantigen. This phenomenon would help explain the production of autoantibodies observed in h u m a n and animal model studies. 34 Hartmann et al. 35have recently demonstrated enhanced interleukin-1 and interleukin-2 production by alveolar macrophages and autologous splenic lymphocytes cocultured after in vivo exposure to asbestos. By using a defined rat model, the authors also demonstrated enhanced Ia expressivity on alveolar macrophages obtained from animals following both chrysotile and crocidolite asbestos exposure. 36 Histologic and ultrastructural examination of the lung suggested that the crocidolite fibers were retained within pulmonary macrophages for longer time intervals than chrysotile fibers. This observation correlated well with the persistence of increased Ia expression on alveolar macrophages for as long as 20 months after crocidolite exposure and the temporary increase in the chrysotile-exposed group. Taken together, the above observations suggest a role for changes in macrophage activity and/or its various subpopulations in the pathogenesis of asbestosis. Presumably, the release of lysosomal enzymes following phagocytosis of asbestos may cause tissue damage, leading to fibrosis. Indeed, supernatants obtained from guinea pig alveolar macrophages incubated with chrysotile asbestos significantly increased the rate of human lung fibroblast proliferation. 37 Although macrophages may play a central role in the pathogenesis of asbestosis, release of neutrophil chemotactic factor(s) from asbestos-exposed alveolar macrophages 3°has been shown to attract PMNs to the sites of asbestos deposition. Bronchoalveolar lavage studies have revealed increased numbers

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of polymorphonuclear leukocytes in lavage cell populations from patients and mice with asbestos-induced pulmonary fibrosis 3s and in guinea pigs shortly after intratracheal administration of fibers. 39 The release of toxic oxygen byproducts (hydroxyl radical, superoxide anion) by asbestos-exposed PMNs has been suggested by in vitro enhancement of PMN chemiluminescence *° and could produce tissue injury and parenchymal fibrosis. In summary, patients with asbestosis may have aberrations in both humoral and cell-mediated immunity. Although the dinical significance of these changes and their relationship to disease pathogenesis is as yet undefined, it is difficult to discount the role of altered cell populations (e.g., macrophage subpopulations) as inducers/effectors of tissue fibrosis. Coal Workers' Pneumoconiosis The inhalation of coal dust may lead to a spectrum of pulmonary disorders, including coal worker's pneumoconiosis, silicosis, and industrial bronchitis. Coal was first recognized as a fibrogenic dust in 1920, when CoUis and Gilchrist 41 reported radiographic changes in Welsh coal trimmers. Additional support for ,the concept that coal alone may cause lung disease evolved from the demonstration of pneumoconiosis in electrode workers exposed to pure carbon. 42 Coal may be found on the surface or in underground seams. All men who work in coal mines, whether on the surface or underground, are considered miners. Although the highest concentrations of coal mine dust occur at the coal face (area at which the coal is cut), all miners, including the workers who maintain the utilities, are exposed to coal dust, or silica dust, or both. 43 The prevalence rate of coal workers' pneumoconiosis is influenced by the dust levels to which the miners have been exposed in the preceding 3(}--40 years. Significantly, the majority of coal miners do not develop pneumoconiosis; data from the United States coal mines suggest a prevalence rate of 10.1%, of which 0.4% is progressive massive fibrosis. 43 Similar to silicosis, coal workers' pneumoconiosis may be subclassified as simple or complicated, according to defined chest radiographic criteria. Simple pneumoconiosis is represented by small opacities (less than 1 cm in diameter) located predominantly in the upper lung zones. Complicated pneumoconiosis, or progressive massive fibrosis, is diagnosed when there is an opacity 1 cm or more in diameter. The clinical manifestations of coal workers" pneumoconiosis depend on the severity and classification of the disease. Usually, neither objective signs nor symptoms will indicate simple pneumoconiosis. In progressive massive fibrosis, exertional dyspnea, cough, and black sputum are common. According to clinical criteria, miners with simple pneumoconiosis'usuaUy have normal lung function. Cigarette smoke is a more potent cause of ventilatory impairment than coal workers' pneumoconiosis. Simple pneumoconiosis does not usually progress in the absence of further exposure to coal dust, and the life expectancy for patients with simple pneumoconiosis is equivalent to that for miners with no radiographic evidence of disease. .4 Miners with progressive massive fibrosis, however, nearly always progress in disease severity, whether or not exposure is terminated.

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Peripheral blood humoral immunologic alterations have been demonstrated in subjects with both simple and complicated coal workers' pneumoconiosis. Soutar et al. 4s found rheumatoid factor in 2 of 32 miners with simple pneumoconiosis, compared with 9 of 77 miners with progressive massive fibrosis. Lippman and coworkers, ~ as well as Pearson et al. 47 could find no correlation between the presence of rheumatoid factor and the radiographic category of pneumoconiosis. Antinuclear antibodies also have been reported in increased frequency in sera from subjects with coal workers' pneumoconiosis. Similar to rheumatoid factor, the presence of antinuclear antibodies does not correlate with the severity of coal workers' pneumoconiosis, as judged by chest x-ray analysis. Anti-lung antibodies directed against connective tissue components have been reported in the sera of miners with coal workers' pneumoconiosis. 4s Although several tenable hypotheses may relate these autoantibodies to pulmonary pathology, the role and significance of anti-lung antibodies in the pathogenesis and progression of disease remains uncertain. Several studies have investigated the association between major histocompatibility antigens (HLA) and coal workers' pneumoconiosis. The rationale for these studies centers on the above and previously discussed observations that have failed to demonstrate significant differences in the occurrence of immunologic alterations between subjects with simple or complicated pneumoconiosis. Conceivably, HLA antigens, through associated gene products, may modify existing immunologic responses and allow disease progression. Heise and colleagues 49 found a weakly negative association between HLAA1 and coal workers' pneumoconiosis in 358 United States miners. There was no difference, however, in the prevalence of HLA-A1 between miners with simple or complicated disease. Wagner and Parke s° failed to confirm an association between HLA-A1 in 267 Welsh coal miners, but did report an increased frequency of HLA-Bw45. To date, there have been no reported human studies investigating the cellular immune response in subjects with coal workers' pneumoconiosis. Recently, however, Barkman et al. 51 demonstrated an increased uptake of gallium in the lung of workers with coal workers' pneumoconiosis. This technique, together with an "analysis of local bronchopulmonary humoral and cellular responses provided by bronchoalveolar Iavage should aid in defining the mechanism(s) of disease progression in coal workers' pneumoconiosis. Berylliosis There are two independent forms of lung disease that have been associated with beryllium inhalation. One is an acute chemical pneumonitis due to heavy exposure to metallic beryllium or any of the several beryllium salts, and the other is a chronic disease characterized b y cough and progressive dyspnea. In acute beryUiosis, the character of the pathologic lesions appears to have less relation to the duration of the disease than to the intensity of the exposure. Many alveoli are filled with an eosinophilic, granular, acellular material, and others may contain an exudate of foamy macrophages, desquamated epithelial cells, red blood cells, lymphocytes, and plasmacytes. An organizing obliterative bronchiolitis is frequently observed. Symptoms may occur within 72 hr

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of heavy exposure and include a nonproductive cough, malaise, weakness, dyspnea on exertion, cyanosis, tachypnea, and tachycardia. Bilateral basilar rales may be present on chest auscultation. Chest x-ray analysis reveals a series of changes beginning with increased linear markings and progressing to bilateral and symmetrical consolidation. Lung lesions disappear with time and rarely leave residual, permanent changes. The chronic form of berylliosis was first recognized in workers exposed to beryllium phosphor in fluorescent lights. 52Although exposure is generally in the beryllium extraction and smelting industry, metal machinery, ceramic manufacturing, and atomic research are also associated with chronic berylliosis. Inhabitants living in areas adjacent to beryllium plants are also at risk for disease. The characteristic lung pathology in chronic berylliosis reflects a diffuse interstitial infiltration of mononuclear cells, with or without noncaseating granuloma formation. Discrete nodular lesions may be present in up to 40% of cases. 53 The presence of beryllium in lung tissue, although not diagnostic of disease, represents an important confirmation of exposure. Symptoms of chronic disease are often insidious and include chronic cough and profound dyspnea on exertion. Weight loss, fatigue, anorexia, and weakness may also be present. Few physical signs are routinely found, but they may include tachycardia and clubbing. Chest roentgenographic findings reveal diffuse, fine, granular lesions in both lungs, not unlike changes seen with miliary tuberculosis. A mixture of granular, nodular, and linear shadows may also be seen in chronic disease. Pulmonary function testing reveals a reduction in diffusing capacity and a restrictive ventilatory impairment. During the inflammatory stage of berylliosis, corticosteroids have been shown to significantly alter disease activity and to produce clinical improvement. Several human studies support a role for cell-mediated immunologic mechanisms in the pathogenesis of chronic berylliosis. Persons with chronic berylliosis show cutaneous delayed hypersensitivity reactions to beryllium compounds, ~ and their peripheral blood lymphocytes undergo blast transformationss and release of macrophage inhibition factor~ after exposure to beryllium in vitro. Recently, immunologic properties of peripheral blood and bronchoalveolar lymphocytes have been studied in a subject with chronic berylliosis,s7 Lavage studies revealed a large increase in the number and proportion of bronchoalveolar T lymphocytes. Many of these T lymphocytes were activated (64% vs a control of 14%). Both peripheral blood and bronchoalveolar lymphocytes proliferated in response to beryllium salts. Collectively, these findings are similar to observations in hypersensitivity pneumonitis, and indeed, berylliosis may represent a form of this disease spectrum. Clearly, additional studies are needed to support this concept.

Summary Collectively, the pneumoconioses represent a spectrum of pulmonary diseases initiated by inorganic dust exposure. Although multiple humoral and cellular immune alterations have been demonstrated in these interstitial and commonly fibrotic lung diseases, the exact role of immune changes in disease pathogenesis presently is undefined. Insight into disease mechanisms may

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h a v e to a w a i t t h e c a r e f u l c h a r a c t e r i z a t i o n of s u i t a b l e a n i m a l m o d e l s , a l o n g w i t h a n a l y s i s o f local, h u m a n b r o n c h o p u l m o n a r y i m m u n e r e s p o n s e s t h r o u g h t h e v e h i c l e of b r o n c h o a l v e o l a r l a v a g e .

References 1. Ziskind M, Jones RN, Weill H: Silicosis. Am Rev Respir Dis 113:643-655, 1976 2. Doll NJ, Stankus RP, Hughes J: Immune complexes and autoantibodies in silicosis. J Allergy Clin Immunol 68:281-285, 1981 3. Stankus RP, deShazo RD, Doll NJ, Salvaggio JE: Immunologic markers of disease severity in human silicosis. Clin Res 31:847, 1984 4. Schuyler ME, Gaumer HR, Stankus RP, Kaimal J, Salvaggio JE: Bronchoalveolar lavage in silicosis. Lung 157:95-100, 1980 5. Stankus RP, Salvaggio JE: Bronchopulmonary humoral and cellular enhancement in experimental silicosis. J Reticuloendothel Soc 29:153-161, 1981 6. Stankus RP, Dannenberg AM, Salvaggio JE: Persistent and disease-associated lysosomal enzyme increases in experimental silicosis. J Reticuloendothel Soc (submitted for publication) 7. Comolli R: Cytotoxicity of silica and liberation of lysosomal enzymes. J Pathol Bacteriol 93:241-253, 1967 8. Kessel RWI, Monaco L, Marchisio MA: The specificity of the cytotoxic action of silica--A study in vitro. Br J Exp Pathol 44:351-364, 1963 9. Miller K, Calverly A, Kagen E: Evidence of a quartz-induced chemotactic facfdr for guinea pig alveolar macrophages. Environ Res 22:31--39, 1980 10. Snyderman R, Shin HS, Dannenberg AM: Macrophage proteinase and inflammation: The production of chemotactic activity from the fifth component Of complement by macrophage proteinase. J Immunol 109:896-898, 1972 11. Nishida Y, Tanimoto K, Akaoka h Effects of free radicals on lymphocyte response to mitogen and rosette formation. Clin Immunol Imrnunopathol 19:319-324, 1981 12. Simon R, Scoggin C, Patterson D: Hydrogen peroxide mediates the toxic effect of oxygen radicals on human fibroblasts. Chest 80:455, 1981 13. Mancino D, Bevilacqua N: Adjuvant effect of amorphous silica on the immune response to various antigens in guinea pigs. Int Arch Allergy Appl Irnmunol 53:97-103, 1977 14. Mancino D, Bevilacqua N: Persistent and boosterable IgE antibody production in mice injected with low doses of ovalbumin and silica. Int Arch Allergy Appl Immunol 57:155-158, 1978 15. Pernis B, Paronetta F: Adjuvant effect of silica (tridymite) on antibody production. Proc Soc Biol Med 110:390-392, 1962 16. Burrell R, Anderson M: The induction of fibrogenesis by silica-treated alveolar macrophages. Environ Res 6:389-394, 1973 17. Richards RJ, Wusterman FS: The effects of silica dust and alveolar macrophages on lung fibroblasts grown in vitro. Life Sci 14:355-364 1974 18. Johnson RL, Ziff M: Lymphokine stimulation of collagen accumulation. J Clin Invest 58:240-252, 1976 19. Korn JH, Halushka PV, LeRoy EC: Mononuclear cell modulation of connective tissue function. J Clin Invest 65:543-554, 1980 20. Schmidt JA, Oliver CN, Green I: Silica-stimulated macrophages release a fibroblast proliferation factor identical to interleukin-1 (IL-1). Fed Proc 41:438, 1982 21. Doll NJ, Salvaggio JE: Asbestos-caused disease: Which patients are at risk? J Respir Dis 1:36-49, 1980 22. Kagen E, Solomon A, Cochrane JC: Immunological studies of patients with asbestosis. I. Studies of cell-mediated immunity. Clin Exp Immunol 28:261-267, 1977 23. Kang KY, Sera Y, Okochi T: T-lymphocytes in asbestosis. N Engl J Med 291:735-736, 1974 24. Kagen E, Soloman A, Cochrane JC: Immunological studies of patients with asbestosis. IL Studies of circulating lymphoid cell numbers and humoral immunity. Clin Exp Immunol 28:268-275, 1977

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25. Campbell MJ, Wagner MMF, Scott MD: Sequential immunologic studies in an asbestosexposed population. II. Factors affecting lymphocyte function. Clin Exp Immuno139:176-182, 1980 26. Lange A: An epidemiological survey of immunological abnormalities in asbestos workers. I. Non-organ and organ-specific autoantibodies. Environ Res 22:162-175, 1980 27. Doll NJ, Diem JE, Jones RN, Rodriguez M, Bozelka BE, Stankus RP, Weill H, Salvaggio JE: Humoral immunological abnormalities in workers exposed to asbestos cement dust. J Allergy Clin Immunol 72:509-512, 1983 28. deShazo RD, Hendrick DJ, Diem JE, Nordberg JA, Baser Y, Bevier D, Jones RN, Barkman HW, Salvaggio JE: Immunologic aberrations in asbestos cement workers: Dissociation from asbestosis. J Allergy Clin Immunol 72:454-461, 1983 29. Hasselbacher P: Binding of immunoglobulin and activation of complement by asbestos fibers. J Allergy Clin Immunol 64:294-297, 1979 30. Schoenberger C, Hunninghake G, Gadek J: Role of alveolar macrophages in asbestosis: Modulation of neutrophil migration to the lung following asbestos exposure. Am Rev Respir Dis 121:257(S), 1980 (abstr) 31. Miller K, Kagen E: The in vitro effects of asbestos on macrophage membrane structure and population characteristics of macrophages: A scanning electron microscope study. J Reticuloendothel Soc 20:159-171, 1976 32. Kang KY, Bice D, D'Amato D: Effects of asbestos and beryllium on release of alveolar macrophage enzymes. Arch Environ Health 34:133-140, 1979 33. Richards RJ, Morris TG: Collagen and mucopolysaccharide production in growing lung fibroblasts exposed to chrysotile asbestos. Life Sci 12:441, 1973 34. Tumer-Warwick M, Parkes WR: Circulating rheumatoid and antinuclear factors in asbestos workers. Br Med J 3:492-495, 1970 35. Hartmann DP, Georgian M, Oghiso Y, Kagen E: Enhanced interleukin activity following asbestos inhalation. Clin Exp Immunol 55:643-650, 1984 36. Hartmann DP, Georgian M, Kagen E: Enhanced alveolar macrophage la antigen expression after asbestos inhalation. J Immunol 132:2693-2695, 1984 37. Bitterman P, Rennard S, Schoenberger C: Asbestos stimulates alveolar macrophages to release a factor causing human lung fibroblasts to replicate. Chest 80:38(S), 1981 (abstr) 38. Bignon J, Atassi K, Jaurand MC: Cellular and protein content analysis of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and asbestosis. Am Rev Respir Dis 117:56(S), 1978 (abstr) 39. Schoenberger C, Hunninghake G, Gadek J: Inflammation and asbestos: Characterization and maintenance of alveolitis following acute asbestos exposure. Chest 80:70(S), 1981 (abstr) 40. Doll NJ, Stankus RP, Goldbach S: The in vitro effects of asbestos fibers on polymorphonuclear leukocyte function. Int Arch Allergy App1 Immunol 68:17-21, 1982 41. Collis EL, Gilchrist JC: Effect of dust on coal trimmers. J Ind Hygiene 10:101-110, 1928 42. Watson AJ, Black J, Doig AT: Pneumoconiosis in carbon electrode workers. Br J Med 16:275-285, 1959 43. Morgan WKC, Lapp NL: Respiratory disease in coal miners. Am Rev Respir Dis 113:531-559, 1976 44. Cochrane AL: Relation between radiographic categories of pneumoconiosis and expectation of life. Br Med J 2:532-534, 1973 45. Soutar CA, Turner-Warwick M, Parkes WR: Circulating antinuclear antibody and rheumatoid factor in coal pneumoconiosis. Br J Med 3:145-152, 1974 46. Lippman M, Eckert HL, Hahon N: Circulating antinuclear and rheumatoid factor in coal miners. Ann Intern Med 79:807--811, 1973 47. Pearson DJ, Mentnech MS, Elliot JA: Serologic changes in pneumoconiosis and progressive massive fibrosis of coal workers. Am Rev Respir Dis 124:696-699, 1981 48. Burrell R: Immunologic aspects of coal workers' pneumoconiosis. Ann NY Acad Sci 200:94-105, 1972 49. Heise ER, Mentnech MS, Olenchock SA: HLA-A1 and coal-workers' pneumoconiosis. Am Rev Respir Dis 119:903-908, 1979

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