Quartz exposure, retention, and early silicosis in sheep.

The purposes of this study were (1) to investigate the chronology of events in cellular and biochemical changes thought to be important in the development of silicosis, (2) to relate these to changes in lung function and radiograph, and (3) to evaluate the relation of quartz exposure and retention to individual response leading to early silicosis. Thirty-six sheep were exposed by repeated intratracheal infusion at 10-day intervals to 100 mg Minusil-5 in 100 ml saline (Si group), and 10 sheep were exposed at the same intervals to 100 ml saline (control). All sheep were investigated at 3-month intervals by chest radiograph, lung function, and lung lavage. At month 9, chest radiograph score of parenchymal opacities was significantly increased at 2.8 +/- 0.6 versus 0.4 +/- 0.4 in the Si group (p less than .05), establishing early radiologic silicosis. Lung function was significantly altered with reduction in lung compliance, vital capacity, and diffusion capacity (p less than .05). Lung lavage cellularity revealed significant increase in total cells (X 2.5), macrophages (X3), and neutrophils (X3). Albumin in BAL remained at the control level. Fibronectin production was significantly increased, as was the fibroblast growth activity, without significant change in procollagen 3 at this early stage of disease. Total phospholipids were significantly elevated in the Si-exposed sheep, and the profile demonstrated an increase in all the phospholipid components. Spontaneous release of hydrogen peroxide by alveolar cells was not increased, but in the presence of phorbol myristate acetate (PMA) higher levels of peroxide were found in the quartz-exposed sheep (p less than .05). The cellular and biochemical alterations of lung lavage preceded other changes. At month 12, there were good correlations (r greater than .49, p less than .001) between parameters evaluating related phenomena but poor correlations between measurements evaluating different aspects of the disorder. To investigate the heterogeneity in the individual response of sheep to the same exposure (susceptibility), individual quartz retention levels at month 12 were measured and found to correlate well with individual parameters of disease activity. We concluded that in early silicosis of sheep, cellular and biochemical changes in lung lavage preceded derangements of pulmonary function and radiographic abnormalities. Thereafter, parameters of lung lavage, lung function, and radiograph were significantly interrelated, but for a given exposure the degree of quartz retention appeared to determine the intensity of the silicotic process.

Effects of cyclophosphamide treatment in experimental asbestosis.

The potential role of immunosuppressive therapy in asbestosis was evaluated in the sheep model of experimental asbestosis. A diffuse peribronchiolar alveolar and interstitial fibrosing alveolitis was developed in 10 animals following 2 years of exposure consisting of slow intratracheal infusion of 100 mg Canadian chrysotile in 100 ml saline every 2 weeks. A control group of 10 sheep concomitantly receiving only 100 ml saline intratracheally was also enrolled in the study. One group of 5 control sheep and one group of 5 asbestosis sheep received 1 mg/kg cyclophosphamide in 10 ml saline iv every 2 weeks, the other 10 sheep receiving only saline. One year after beginning of therapy, survival rates were comparable in the 2 control groups and the asbestosis group without therapy at 80%, whereas it was significantly reduced at 20% in the asbestosis group with therapy. Deaths in the latter were associated with significant increase in peripheral blood and lung lavage neutrophils, increased intensity of fibrosing alveolitis, worsening of lung functions, and worsening in the radiographic diffuse lung opacities. This was documented on histopathology to be associated with more intense fibrotic disease and bacterial pneumonia in the group of sheep with asbestosis receiving the immunosuppressor drug. We conclude that cyclophosphamide therapy in experimental asbestosis accelerated the fibrotic process and reduced significantly the survival rate of the animals.

Asbestos exposure and retention as determinants of airway disease and asbestos alveolitis.

To evaluate the relationships of asbestos exposure, retention, airway response, and the asbestos alveolitis, we exposed 2 groups of sheep every 2 wk for 3 yr to either 100 ml phosphate-buffered saline (PBS) or 100 mg UICC chrysotile fibers in 100 ml PBS. The sheep were evaluated periodically by pulmonary function tests (PFT), chest radiograph (CR), bronchoalveolar lavage (BAL), and transbronchial lung biopsy (TLB). At Month 24 of the study, all asbestos-exposed sheep had significant increases in lung resistance and upstream resistance. However, only 9 of the 16 asbestos-exposed sheep had significant changes in TLB, CR, Cst, and VC, which clearly separated them from the other 6 sheep in these parameters. The 2 groups, however, had similar air-flow limitation. At lung biopsy, all asbestos-exposed sheep had significant peribronchiolar fibrosis, with significant alveolitis only in the group of 9 sheep with radiographic and functional changes of early asbestosis. The 9 sheep also had significant changes in BAL cellularity and biochemical profile, which differentiated them from the other 6 asbestos-exposed sheep. Analysis of BAL fiber content at that point revealed that despite identical exposure, the group with interstitial lung disease had significantly more fiber retention (p less than 0.01). The data demonstrate that whereas asbestos airway disease appears to be primarily an exposure-dose-related response, the lung response appears to be more closely related to alveolar retention of the dust.

Gallium-67 uptake in the lung of asbestos exposed sheep: early association with enhanced macrophage-derived fibronectin accumulation.

To evaluate the time course and mechanisms of enhanced 67Ga lung uptake in asbestosis, we exposed two groups of sheep every 2 wk to either 100 ml saline (controls) or 100 mg UICC chrysotile fibers in 100 ml saline. The sheep were evaluated periodically by pulmonary function tests (PFT), thoracic radiograph (TR), 67Ga lung scan bronchoalveolar lavage (BAL), and transbronchial lung biopsy (TLB). By month 24 of the study, 9/15 exposed sheep had developed the initial alveolitis and had significant changes in PFT, TR, and TLB. The other six exposed sheep differed from controls only by a 75% increase in BAL fibronectin until month 30, where significant changes in albumin occurred and 67Ga scan score increased. The nine sheep with alveolitis had significant sustained increases in 67Ga scan and BAL levels from month 6, associated with a 150% increase in BAL fibronectin and other parameters of disease activity changed from month 18 to 30. We concluded that in the sheep model of asbestosis, significant changes in 67Ga scan, 67Ga BAL counts, and excessive elevation of BAL fibronectin preceded other parameters of disease activity. The data suggest that excessively activated macrophages are primarily responsible for the early 67Ga lung uptake.