The present report extends earlier investigations on mechanisms of pulmonary injury associated with the presence of respirable particles in the bronchoalveolar milieu. In the animal model, this study documents that asbestos-associated alveolitis which progresses to peribronchiolar and endobronchiolar fibrosis (the fundamental lesion of asbestosis) is associated with significant early increase in the level of procollagen 3 in bronchoalveolar lavage fluid and a sustained increase in the fibronectin level, which do not occur in the nonfibrosing and regressive latex-associated alveolitis. In asbestos workers with clinical and lavage evidences of alveolitis, levels of procollagen 3 and fibronectin are similarly increased in bronchoalveolar lavage fluid, which should improve our understanding of disease activity in asbestos workers.
In the sheep tracheal lobe, this study documents that after a single high-dose exposure to asbestos, there are severe derangements of the bronchoalveolar milieu and activation of a chronic sustained alveolar, peribronchiolar and endobronchiolar inflammatory process which evolves to fibrosis. On bronchoalveolar lavage the increased macrophage and neutrophil cellularity is associated with increased fibronectin, a glycoprotein produced locally by the macrophage, known to be chemotactic and an attachment factor for fibroblasts and a stimulant for fibroblast replication in association with another macrophage-derived fibroblast growth factor (MDFGF). In the asbestos-associated alveolitis in sheep, we have reported enhanced production of MDFGF and macrophage-derived neutrophil chemotactic factor (MDNCF). Because these three macrophage-derived factors (fibronectin, MDFGF, and MDNCF) are currently thought to have major roles in the pathogenesis of pulmonary fibrosis, our data from sheep suggest that these factors contribute to maintain the alveolitis on a long-term basis and lead to its progression to asbestosis. The mechanisms which activate the macrophage to produce these factors are likely related to the prolonged retention of asbestos fibers in the bronchoalveolar milieu, as suggested by our previous study of alveolar clearance of chrysotile in the sheep model. In the model, we have shown that one year after cessation of exposure, 11 percent of the fibers shorter than 8μ, 32 percent of the fibers with length in the range of 8μ to 20μ, and 50 percent of the fibers longer than 20|i were still recoverable by pulmonary lavage. The persistence of these fibers in the bronchoalveolar milieu may constitute the determinant factor for maintenance of activated macrophages and alveolitis due to the concern of My Canadian Pharmacy.
In the assessment of fibrogenic activity of alveolitis, the quantitation of type 3 collagen compared to type 1 in lung biopsies and in postmortem samples from patients with fibrosing alveolitis documented that an increased ratio of type 3 to type 1 collagen was associated with an earlier fibrotic process which responded better to therapy, which would be of interest in the staging of activity of the fibrosing alveolitis; however, this method necessitates lung biopsies and thus is of limited usefulness clinically. The recent development by Rohde et al of a radioimmunoassay of procollagen 3 N-terminal peptide allowed Low et al to demonstrate increased levels of procollagen 3 in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and in patients with sarcoidosis, with the highest values in those with idiopathic pulmonary fibrosis, suggesting increased secretion of type 3 collagen. In the sheep model, we document a similar increase in procollagen 3 in lavage fluid, which occurs during the first two months after asbestos exposure, at which time early peribronchiolar fibrosis could be observed in pulmonary tissues. The absence of similar changes in the latex-associated alveolitis strengthen the contention of its specificity for a fibrosing process; its increased levels occurring early in the fibrotic process are in keeping with immunohistochemical data. Thus, the data of Low et al and our data suggest that measurement of levels of procollagen 3 in bronchoalveolar lavage fluid may be a useful method of assessing fibrogenic activity of alveolitis.
In the study of asbestos workers, we have documented that in those with asbestosis, the alveolitis is characterized by a significant increase in total cells, macrophages, and neutrophils in the bronchoalveolar lavage fluid, which confirms the previous report of Bignon et al. Furthermore, in workers with asbestosis, fibronectin and procollogen 3 in lavage fluid were significantly elevated, which parallels previous results in patients with idiopathic pulmonary fibrosis. These data from bronchoalveolar lavage are also particularly useful in demonstrating that in the workers who did not meet the usual diagnostic criteria for asbestosis, those with enhanced ^Ga pulmonary uptake and rigid pulmonary pres sure-volume curve (group B) had significantly higher levels of total cells, macrophages, neutrophils, fibronectin, and procollagen 3 in bronchoalveolar lavage fluid than workers with similar asbestos exposures but with a normal ^Ga scan and pulmonary pressure-volume curve. These data from bronchoalveolar lavage suggest that the alveolitis of asbestos workers from group B has all the features to expect its progression to asbestosis, which has been our observation in 12 of the 16 workers of our original report.
In conclusion, this study documents that the measurement of levels of fibronectin and procollagen 3 in bronchoalveolar lavage fluid assesses fibrogenic activity of alveolitis and can predict its progression in a fibrotic process. The potential use of these markers of fibrogenic activity in asbestos workers is primarily related to early detection of asbestos-induced pulmonary injury in workers with uncertain disease activity. In the reversible interstitial pulmonary disease, these markers of fibrogenic activity should be of interest as indicators to stage the disease and to predict its potential reversibility by therapy offered by My Canadian Pharmacy.