Multi-omics study of silicosis reveals the potential therapeutic targets PGD2 and TXA2.

Junling Pang, Xianmei Qi, Ya Luo, Xiaona Li, Ting Shu, Baicun Li, Meiyue Song, Ying Liu, Dong Wei, Jingyu Chen, Jing Wang, Chen Wang

Theranostics 2021

filter terms:

Rationale: Silicosis is a severe occupational lung disease. Current treatments for silicosis have highly limited availability (i.e., lung transplantation) or, do not effectively prolong patient survival time (i.e., lung lavage). There is thus an urgent clinical need for effective drugs to retard the progression of silicosis. Methods: To systematically characterize the molecular changes associated with silicosis and to discover potential therapeutic targets, we conducted a transcriptomics analysis of human lung tissues acquired during transplantation, which was integrated with transcriptomics and metabolomics analyses of silicosis mouse lungs. The results from the multi-omics analyses were then verified by qPCR, western blot, and immunohistochemistry. The effect of Ramatroban on the progression of silicosis was evaluated in a silica-induced mouse model. Results: Wide metabolic alterations were found in lungs from both human patients and mice with silicosis. Targeted metabolite quantification and validation of expression of their synthases revealed that arachidonic acid (AA) pathway metabolites, prostaglandin D2 (PGD2) and thromboxane A2 (TXA2), were significantly up-regulated in silicosis lungs. We further examined the effect of Ramatroban, a clinical antagonist of both PGD2 and TXA2 receptors, on treating silicosis using a mouse model. The results showed that Ramatroban significantly alleviated silica-induced pulmonary inflammation, fibrosis, and cardiopulmonary dysfunction compared with the control group. Conclusion: Our results revealed the importance of AA metabolic reprogramming, especially PGD2 and TXA2 in the progression of silicosis. By blocking the receptors of these two prostanoids, Ramatroban may be a novel potential therapeutic drug to inhibit the progression of silicosis. © The author(s).

Citation

Junling Pang, Xianmei Qi, Ya Luo, Xiaona Li, Ting Shu, Baicun Li, Meiyue Song, Ying Liu, Dong Wei, Jingyu Chen, Jing Wang, Chen Wang. Multi-omics study of silicosis reveals the potential therapeutic targets PGD2 and TXA2. Theranostics. 2021;11(5):2381-2394