Abstract
There is considerable variation in methods to induce experimental silicosis with the effects of dose and route of exposure being well documented. However, to what extent the volume of silica suspension alters the dispersion and severity of silicosis has not been adequately investigated. In this study, the optimal volume of a crystalline silica suspension required to obtain uniform distribution and greatest incidence and severity of silicosis was determined in inbred and outbred mice. Silica dispersal, detected by co-inspiration with India ink and polarized light microscopy, was highly dependent upon volume. Furthermore, although peribronchitis, perivasculitis, and increases in bronchoalveolar lavage fluid cell numbers were detected a lower doses and volumes, significant alveolitis required exposure to 5 mg of silica in 50 μl. This dose and volume of transoral instillation led to a greater penetrance of silicosis in the genetically heterogeneous Diversity Outbred strain as well as greater alveolar inflammation typical of the silicosis in human disease. These findings underscore the critical importance of instillation volume on the induction, severity, and type of inflammatory pathology in experimental silicosis.
Highlights
Silica exposure is a well-known occupational hazard for individuals working in the dusty trades and can result in the fibrotic lung disease silicosis[1,2,3]
The observations made in this study are significant because there is no standardized method for crystalline silica exposure in experimental animals
In this study we further establish the critical importance of volume in TO aspiration and its impact on the severity of alveolitis, perivasculitis and peribronchitis, and numbers of inflammatory infiltrating bronchoalveolar lavage fluid (BALF) cells
Summary
Silica exposure is a well-known occupational hazard for individuals working in the dusty trades and can result in the fibrotic lung disease silicosis[1,2,3]. Inhalation of silica containing dust leads to chronic inflammation of the lung, with development of silicosis being dependent upon the cumulative dose of silica exposure[4,5,6,7,8] This is supported by animal model studies, which have shown a direct correlation between dose and severity of lung disease[9,10]. Notably 1–2 ml/kg (50–100 μls/20 gram mouse)[28] and 3 μl/gram of body weight[32], have been recommended for IT instillation of particulate material, these were not based on studies using the TO route or crystalline silica for the induction of silicosis
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