Previous studies of surface modification of quartz particles have suggested that the biological activity of silica is at least in part related to its surface properties. In the present study, we exposed the tracheal lobe of 8 sheep to either 100 ml saline (saline group), 100 mg of quartz (Minusil-5) in 100 ml saline (SI group) or 100 mg of Al lactate treated quartz in 100 ml saline (SI-Al group). The 24 sheep were studied by bronchoalveolar lavage at days 0, 12, 24, 40, 60 and by autopsy at day 60. In the saline group, BAL analyses were as previously reported [1]. In the SI group, we found significant and sustained increases in total BAL cells (x 2, P less than 0.05), macrophages and lymphocytes (x 2, P less than 0.05), neutrophils (x 5-10, P less than 0.01), IgG (x 1.2-1.8, P less than 0.05), fibronectin (x 2-3, P less than 0.05), lactate dehydrogenase (x 3, P less than 0.01) and alkaline phosphatase (x 2, P less than 0.05). Histologically, a macrophagic and lymphocytic alveolitis was observed at day 60. In the SI-Al group, these changes were significantly attenuated and in the above parameters, SI-Al group did not differ from saline group after day 24. These data of BAL and histology of the sheep tracheal lobe model document clearly that aluminum lactate treatment alters the biological activity of quartz.
Transforming growth factor-beta (TGFbeta) is synthesized as a precursor protein, pro-TGFbeta, that must be cleaved by a furin-like proteinase before it becomes biologically active. We hypothesized that alkalinization of the trans-Golgi network (TGN)/endosome system may suppress pro-TGFbeta processing and decrease TGFbeta secretion. This hypothesis was tested in human A549 alveolar epithelial and T98G glioblastoma cell lines and in C57BL/6 mice. Inhibition of furin-like activity with decanoyl-RVKR chloromethylketone suppressed pro-TGFbeta processing, thereby significantly reducing the levels of secreted TGFbeta. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGFbeta processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGFbeta. Reduced levels of secreted TGFbeta were also associated with a decrease in Smad2 signaling. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFbeta. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGFbeta processing.
In a recent study of the sheep tracheal lobe model, we have demonstrated that surface chemistry modification of quartz by aluminum lactate significantly alters the biological activity of quartz for at least 2 months after exposure. In the present study, we have extended our observations of the biological reaction of the lung tissue to aluminum treated quartz and to untreated quartz, added lung lavage analyses of surfactant and glycosaminoglycans as additional indicators of activity of the quartz-induced lung injury and analyzed lung lavage and tissue retention of the minerals. The tracheal lobe of 8 sheep was exposed to either 11 mg of aluminum lactate in 100 ml saline (Al group), 100 mg of quartz (Minusil-5) in 100 ml saline (Si group) or 100 mg of quartz treated with 11 mg of Al lactate in 100 ml saline (Si-Al group). The 24 sheep were studied by lung lavage at month 9, 0.13, 1, 2, 3, 5, 7, 9, and 10 and by autopsy at month 10. In the Al group, we found no significant change over time, the pathologic score was 0.38 +/- 0.15 and Si undetectable. In the Si group, we found significant sustained increases in total lavage cells, macrophages, lymphocytes, neutrophils, glycosaminoglycans, lactate dehydrogenase, phosphatidylcholine and phosphatidylglycerol. Histologically we found a macrophagic lymphocytic alveolitis with early nodular silicotic lesions; the pathological score was 3.0 +/- 0.8 at month 10 with an average quartz tissue level of 1.4 +/- 0.4 micrograms/mg. In the Si-Al group, all these changes were significantly reduced early and remained so up to 10 months after exposure; the pathological score was 1.1 +/- 0.4 and lung levels of quartz were undetectable. The data thus demonstrated that Al treatment of quartz significantly reduces the biological activity of quartz and increases its clearance with essentially no detectable particle retention in the lung 10 months after exposure.
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