Faculty Bibliography

Tropical pulmonary eosinophilia (TPE) presents as an acute syndrome with dyspnea, fluffy infiltrates, and rounded opacities on the chest radiograph, reduced lung function, marked eosinophilia in the blood and lower respiratory tract, and high titers of specific IgE and IgG antifilarial antibodies. The standard therapy for TPE is a 3-wk course of diethylcarbamazine (DEC) following which there is almost always a marked improvement in all parameters. However, clinical observations suggest that the disease can persist despite DEC therapy and lead to chronic dyspnea with restrictive lung impairment. To evaluate the concept that DEC therapy is not completely 'curative' for TPE, but rather leaves most individuals with a mild, chronic form of TPE defined by persistent inflammation of the lower respiratory tract, we evaluated 23 individuals an average of 12 +/- 2 months following a standard 3-wk course of diethylcarbamazine for acute TPE. In the majority there were mild, persistent symptoms referrable to the lung, chest X-ray abnormalities, blood eosinophilia, and elevated serum IgE and filarial specific IgG. On the average, lung function was consistent with the presence of chronic, mild interstitial lung disease. When the inflammatory cells from the lower respiratory tract were examined, there was a persistent eosinophilic alveolitis (TPE/post-DEC 1769 +/- 376 eosinophils/microliters epithelial lining fluid; normal subjects 256 +/- 38, p less than 0.02). Evaluation of the lower respiratory tract inflammatory cells recovered from the TPE/post-DEC-treated individuals demonstrated spontaneous release of exaggerated amounts of O2-. and H2O2 compared to normal subjects (p less than 0.05, both comparisons).(ABSTRACT TRUNCATED AT 250 WORDS)

Coal miners develop focal emphysema characterized by dilatation of second- and third-order respiratory bronchioles with coal mine dust-laden macrophages infiltrating the wall. A reticulin network with small amounts of collagen and atrophy of smooth muscle occurs. To evaluate the mechanisms of lung injury associated with this lesion, 17 long-term non- or ex-smoking West Virginia underground coal miners underwent bronchoalveolar lavage (BAL) and were compared to healthy nonsmoker and smoker controls. The coal miners had evidence of an alveolar macrophage-neutrophil alveolitis with a significant increase in neutrophils/microliter of epithelial lining fluid and an increased gallium lung scan index (206 +/- 26 units). Alveolar macrophages lavaged from coal miners spontaneously released exaggerated amounts of superoxide anion and hydrogen peroxide in vitro compared to nonsmoking controls. Coal workers had significantly elevated levels of neutrophil elastase in BAL fluid complexed with alpha 1-antitrypsin (P less than 0.01) and normal levels of alpha 1-antitrypsin. An accumulation of activated, dust-laden inflammatory cells with increased release of oxidants and elastase may contribute to the development of focal emphysema identified at postmortem in miners with coal workers' pneumoconiosis

Alveolar macrophages recovered by bronchoalveolar lavage from individuals with occupational inorganic dust exposure are laden with particles. We evaluated 42 non-smoking males with long- term exposure to asbestos (27), coal (7), or silica (8) and normals (8) to determine a particle burden per 10(6) alveolar macrophages. Scanning/transmission electron microscopy and energy-dispersive x-ray analysis were utilized to evaluate the particles following bleach digestion of the cells, or of alveolar macrophage sections. There was a four-fold (p < 0.01) increase in the number of particles in the dust-exposed. There was also a striking increase in silica particle number in the silica-exposed (p < 0.02) but not in the other dust-exposed groups. One-third of the coal miner's cells contained silica particles predominantly < 0.5 mu-m. In the asbestos-exposed, there was one chrysotile fiber per 35 cells, and one amosite fiber per 215 cells consistent with the known mixed exposure of workers exposed to insulation products in the United States. No crocidolite was observed in any of the cells and tremolite was identified in two controls and two workers. Computer- generated maps of elements comprising the particles demonstrated the in situ localization of the particles and identified many very small alumino-silicates, particularly in coal miners. Particle analysis is a useful technique to evaluate type and amount of exposure, to evaluate alveolar clearance, and may be useful to investigate macrophage activation

Alveolar macrophages recovered by bronchoalveolar lavage from 43 nonsmoking or greater than 5-yr ex-smoking subjects with occupational exposure to inorganic particles (asbestos, n 1/2 19; silica, n 1/2 10; coal, n 1/2 14) were evaluated by light microscopy and transmission and scanning electron microscopy to determine the morphologic changes resulting in these cells from chronic inorganic particulate inhalation. Alveolar macrophages from dust-exposed subjects, including those who had been free of exposure to particles for more than 1 yr, contained particles of higher proportion than did those of normal unexposed subjects. Most of these particles were located within phagolysosomes. The frequency of multinucleated alveolar macrophages was significantly higher in the dust-exposed groups. Ultrastructural studies showed alterations of the morphologic aspects of the surfaces of alveolar macrophages from the dust-exposed subjects, including increased numbers of rufflings, filopodia, pinocytotic vesicles, subplasmalemmal linear densities, and increased frequency of macrophage-macrophage and macrophage-lymphocyte interactions. Furthermore, the numbers of lysosomes were significantly increased in alveolar macrophages from the dust-exposed subjects. Together, these morphologic changes are consistent with the sequelae of phagocytosis, and they emphasize both the role of alveolar macrophages in eliminating inorganic particles from the alveolar spaces and the consequences this role has in alveolar macrophage activation

Human alveolar macrophages, when activated, release a progression-type growth factor for fibroblasts that signals 'competent' fibroblasts to replicate. The present study demonstrates that this growth activity is an insulin-like growth factor I (IGF-I)-type molecule. Partial purification of medium conditioned by activated alveolar macrophages using ion exchange and gel filtration chromatography revealed an IGF-I molecule as detected by an anti-IGF-I polyclonal antibody and that the specific activity of the progression-type growth activity tracked with the amount of IGF-I present. In a serum-free complementation test, the increase in fibroblast proliferation by alveolar macrophage IGF-I was reduced in a dose-response manner with an anti-IGF-I monoclonal antibody. The alveolar macrophage IGF-I displaced 125I-IGF-I from its receptor in a binding assay utilizing human lung fibroblasts and it stimulated type I IGF receptors purified from human lung fibroblasts to phosphorylate a tyrosine-containing artificial substrate. In contrast to the 7.6-kD serum IGF-I, gel chromatography revealed that the alveolar macrophage IGF-I had an apparent molecular mass of 26 kD, similar to other tissue IGF-Is. Alveolar macrophages expressed IGF-I mRNA transcripts as detected by solution hybridization using a 32P-labeled riboprobe complementary to exons I-II-III of the IGF-I gene. In the context of the known functions of the family of IGF-I molecules in cell growth, IGF-I released by activated alveolar macrophages may play a role in acute and chronic inflammatory disorders

Fibrosis is the accumulation of fibroblasts and the connective tissue products secreted by these cells, usually subsequent to tissue injury. While fibrosis can be useful in preserving the general structural integrity of a tissue, it often alters cell-cell and cell-connective tissue interactions, which leads to loss of tissue function. On the basis of the concept that mononuclear phagocytes can direct the development of fibrosis through the release of specific mediators that stimulate fibroblast proliferation, we propose a therapeutic strategy to prevent fibrosis by preventing the release of these specific mediators. The present study demonstrated that colchicine, a widely used and well-tolerated drug, can block alveolar macrophage release of 2 mediators associated with the development of fibrosis in interstitial lung diseases, fibronectin, and the alveolar-macrophage-derived growth factor (AMDGF). Colchicine blocked the spontaneous release of fibronectin by alveolar macrophages obtained from patients with fibrotic lung disease by 23 +/- 4% after 24 h and by greater than 90% after 72 h. AMDGF release was blocked by 68 +/- 10% after 4 h (p less than 0.01, all comparisons). The effect of colchicine was not due to nonspecific toxicity since [14C]proline tracer studies demonstrated that macrophages treated with colchicine were capable of de novo protein synthesis and the secretion of several protein products, despite the fact that fibronectin and AMDGF release were suppressed. The effect of colchicine on the spontaneous release of both fibronectin and AMDGF could be observed at concentrations less than 10 ng/ml, levels that can be achieved in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)