• 2022-06
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  • br Materials and methods br Results br Discussion


    Materials and methods
    Discussion Pulmonary fibrosis could be caused by >200 factors, including autoimmune diseases, environmental and occupational exposure [30]. Particularly, silica serves as a serious risk factor in respiratory occupational diseases. To be specific, inhalation of silica particles causes tissue remodeling and impairment of lung function, which leads to silicosis, and patient succumbs to death due to respiratory failure [1]. In developing countries, silica-induced pulmonary fibrosis is still a severe public health concern with high prevalence [31]. The mechanism of silicosis is not fully revealed, deepened investigation is needed for efficient treatment. Hence, our research group established a silicosis mice and USP7/USP47 inhibitor models for in vivo and in vitro experiments [25]. In the recent years, the relationship between fibrosis and TGF-β induced EMT has been doubted. Lineage tracing experiment in mouse kidney fibrosis model indicate that EMT does not contribute markedly to myofibroblast population [32], [33]. Further studies suggest that tubular epithelial cells de-differentiate and engage a profibrotic gene expression programme without completely transform to myofibroblasts, which is referred as partially EMT [34]. Consistently, this partial EMT hypothesis is also supported by studies of lung fibrosis in vivo, scientists found a subset of epithelial cells in IPF patients expresses both epithelial and mesenchymal markers [7]. However, another opinion has been proposed in several studies. By performing lineage tracing experiments in bleomycin-induced mice pulmonary fibrosis, Rock et al. [35] presented that ACEIIs weren't the source of myofibroblasts, meanwhile, bleomycin accelerated the conversion of AECII into AECI cells. Further study suggested a potential role of AECIIs that activated epithelial cells may produce mesenchymal proteins to promote activation of fibroblasts, leading to progressive fibrosis [36], [37]. In the cell microenvironment, the initial injury could leads to aberrant activation of AECs, activated AECs creating a profibrotic environment by secreting cytokines to accumulate collagen-producing fibroblasts and myofibroblasts [38]. Our results also support the hypothesis by using two different pulmonary epithelia cell lines and primary ACEIIs, the TGF-β1 activated AECIIs did expressed a relatively high levels of mesenchymal genes. However, further co-culture of AECIIs and fibroblasts and genetic lineage tracing experiments maybe helpful to further confirm this epithelial-mesenchymal crosstalk. In any case, in-depth study about underlying mechanisms of EMT would contribute to find beneficial therapy of pulmonary fibrosis. Our results were supportive to the hypothesis, expanded the potential role of EMT in pulmonary fibrosis. Functional lncRNAs regulate various pathophysiological pathways by acting as regulators, including cell apoptosis, metastasis, and EMT [39], [40]. For example, lncRNA Arid-IR promoted NF-κB-dependent inflammation of renal fibrosis [41]. However, in a mouse model of pulmonary fibrosis, over-expressed lncRNAs uc.77 and 2700086A05Rik aggravated fibrosis by inducing EMT [16]. In another research, elevated level of lncRNA MEG3 suppressed TGF-β1-induced activation of hepatic stellate cells and reduced experimental liver fibrosis [42]. These studies indicate lncRNAs could involve in various aspects of organ fibrosis by different modes. Nevertheless, the researches of fibrosis-related lncRNAs are still relatively superficial compared with studies of cancer, especially in occupational fibrosis. Here we established that lncRNA-ATB is induced in EMT process of silicosis. LncRNA-ATB is a long-noncoding RNA with a length of 2446bp and played a functional role in EMT [18]. Although this lncRNA was found to be associated with EMT in liver cancer for the first place, following studies suggested lncRNA-ATB could also regulate keloids [43] and liver fibrosis [44]. Notably, one previous study of CWP patients proved that lncRNA-ATB expression is commonly increased and significantly correlated with levels of TGF-β1 in the serum of CWP patients [21], but the molecular mechanism hasn't been explored. These studies remind us the potential regulating role of lncRNA-ATB in pulmonary fibrosis. Here we found that lncRNA-ATB could be elevated in TGF-β1 treated lung epithelial cells, and knockdown of lncRNA-ATB significantly blocked TGF-β1-induced EMT process. The present results identify lncRNA-ATB as an EMT regulator, indicating its possible role in EMT progression in the silicosis.