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Outline
To investigate the therapeutic efficacy and underlying mechanism of ZSP1603, a novel independently developed small-molecule tyrosine kinase inhibitor, against lung tissue injury in silicotic mice, so as to provide an experimental basis for clinical research on the treatment of silicosis.
Based on the molecular toxicological network induced by silica dust, molecular docking was performed to predict the potential targets and mechanisms of ZSP1603 in alleviating silica dust-mediated respiratory toxicities. A silica-induced mouse silicosis model was established. Pathological staining, immunohistochemistry and multi-omics analyses were comprehensively applied to evaluate the protective effects and molecular mechanisms of ZSP1603 on silica-associated silicosis-like lesions in mice.
A total of 50 intersecting genes were identified between the pharmacological targets of ZSP1603 and the toxicity-related genes triggered by silica dust, which were mainly enriched in signaling pathways associated with inflammation, oxidative stress and fibrosis. Long-term administration of ZSP1603 at the experimental dose (60 mg/kg) significantly ameliorated silica-induced pulmonary inflammation, lung tissue damage and collagen deposition (at 12 weeks, the Szapiel and Ashcroft scores in the ZSP1603 group were significantly lower than those in the model group, P<0.01), and downregulated the expression of proteins related to silica toxicity (the expression levels of Collagen I, Collagen III, α-SMA, FN, TNF-α, IL-6, and IL-1β were significantly downregulated compared to the model group, P<0.001). Moreover, ZSP1603 effectively corrected the gut microbiota dysbiosis in silicotic mice. In addition, no obvious systemic in vivo toxicity was observed following treatment with the experimental dose of ZSP1603.
The novel tyrosine kinase inhibitor ZSP1603 alleviates silicosis-related inflammation and fibrosis in a mouse silicosis model. These findings provide a reference for the research and development of therapeutic agents for the secondary and tertiary prevention and clinical intervention of silicosis.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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