Abstract
BackgroundPulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis.ResultsHere, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance and subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected using CCK-8, western blot, cell count and flow cytometry (FCM) assays. Although the three cell types showed similar increases in proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferation mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO2-induced inflammatory response activated the MAPK/PI3K signaling pathway in lung fibroblasts and then induced the expression of the ZC3H4 protein, which specifically mediated anoikis resistance, followed by pulmonary fibrosis.ConclusionsThe current study revealed a specific pattern of fibroblast proliferation, and strategies targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights into the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis.
Highlights
Pulmonary fibrosis is a lung disease caused by abnormal wound healing in susceptible people with repeated alveolar injury
Human pulmonary fibroblasts from adults (HPF-a) cells were selected to screen the appropriate conditioned medium (CM), and CM from macrophages exposed to Silicon dioxide (SiO2) for 6 h induced a significant increase in HPF-a cell viability; this CM was selected for all subsequent experiments (Fig. 1A)
Immunofluorescence staining showed that the expression levels of the fibroblast markers vimentin, α-SMA and collagen 1 in lung tissue were increased in the SiO2 group compared with the normal saline (NS) group, confirming the occurrence of pulmonary fibrosis (Fig. 1I and Additional file 1: Figure S1F, G)
Summary
Pulmonary fibrosis is a lung disease caused by abnormal wound healing in susceptible people with repeated alveolar injury This condition mainly manifests as chronic inflammation and collagen deposition in the extracellular matrix (ECM), which eventually leads to diminished lung function and is the final step in the development of many lung diseases [1, 2]. Anoikis occurs by preventing the reattachment of exfoliated cells to a new matrix, preventing improper aggregation and growth This process is closely related to growth and development, tissue homeostasis, and cancer metastasis [6]. The zinc finger protein ZC3H4 was shown to promote anoikis resistance in fibroblasts and subsequently induce pulmonary fibrosis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis
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