Long‐term exposure to respirable silica particles causes pulmonary inflammation and fibrosis primarily promoted by cytokines released from alveolar macrophages, yet the underlying mechanism is still unclear. From the perspective of nuclear factor kappa B (NF‐κB), we studied the mechanism of IL‐1β biosynthesis and release. Utilizing BAY 11‐7082, an NF‐κB specific inhibitor, we showed the alteration of macrophage viability and examined the expression of both IL‐1β and NF‐κB in vitro. We found that silica nanoparticles (SiNPs) were internalized by macrophages and caused damage to cell integrity. The immunofluorescence assay showed that SiNPs exposure enhanced the expression of IL‐1β and NF‐κB, which could be effectively suppressed by BAY 11‐7082. Besides, we built silica exposure mouse model by intratracheally instilling 5 mg of SiNPs and checked the effect of silica exposure on pulmonary pathological changes. Consistently, we found an upregulation of IL‐1β and NF‐κB after SiNPs exposure, along with the aggravated inflammatory cell infiltration, thickened alveolar wall, and enhanced expression of collagens. In conclusion, SiNPs exposure causes pulmonary inflammation and fibrosis that is regulated by NK‐κB through upregulating IL‐1β in alveolar macrophages.

Silica nanoparticles (SiNPs) are one of the most widely used inorganic nanomaterials, and exposure to SiNP has been demonstrated to induce pulmonary inflammation, primarily promoted by the NLRP3-mediated macrophage pyroptosis. However, mechanisms underlying the activation of NLRP3 signaling are complex, and whether cathepsin B (CTSB), an enzyme released by the ruptured lysosome, could trigger NLRP3 assembly is controversial. Methods: To further characterize the role of CTSB in silica-induced pyroptosis, we conducted this study by establishing SiNP exposure models in vitro. The morphological features of SiNPs were exhibited by the SEM and TEM, and the effects of SiNPs' internalization on macrophages were examined by the TEM and immunofluorescent staining. Moreover, Western blot was performed to detect the expression of proteins related to pyroptosis and CTSB after blocking the expression of NLRP3 and CTSB. Results: We found that SiNPs internalization caused the rupture of macrophage membrane and promoted the aging of cells with increased intracellular vacuoles. Also, the expression of NLRP3, ASC, Caspase-1, GSDMD, Pro-IL-1β, IL-1β, and CTSB increased under the stimulation of SiNP, which could be suppressed by additional treatment with MCC950, an NLRP3-specific inhibitor. Besides, we found SiNP joint treatment with leupeptin, a CTSB inhibitor, could inhibit the expression of CTSB, but it had no effect on the expression of NLRP3, ASC, and Caspase-1, and the process of macrophage pyroptosis was also not affected. Conclusion: SiNP exposure induces rupture of macrophages and the release of lysosomal CTSB, but CTSB fails to specifically act on the NLRP3 inflammasome to induce pyroptosis which is causally linked to lung inflammation and fibrosis.

Exposure to silica nanoparticles (SiNPs) is related to the dysregulation of pulmonary surfactant that maintains lung stability and function. Nevertheless, there are limited studies concerning the interaction and influence between SiNPs and pulmonary surfactant, and the damage and mechanism are still unclear. Herein, we used A549 cells to develop an in vitro model, with which we investigated the effect of SiNPs exposure on the expression of pulmonary surfactant and the potential regulatory mechanism. The results showed that SiNPs were of cytotoxicity in regarding of reduced cell viability and promoted the production of excessive reactive oxygen species (ROS). Additionally, the JNK/c‐Jun signaling pathway was activated, and the expression of surfactant protein A (SP‐A) and surfactant protein B (SP‐B) was decreased. After the cells being treated with N‐acetyl‐L‐cysteine (NAC), we found that the ROS content was effectively downregulated, and the expression of proteins related to JNK and c‐Jun signaling pathways was suppressed. In contrast, the expression of SP‐A and SP‐B was enhanced. Furthermore, we treated the cells with JNK inhibitor and c‐Jun‐siRNA and found that the expression of protein related to JNK and c‐Jun signaling pathways, as well as SP‐A and SP‐B, changed in line with that of NAC treatment. These findings suggest that SiNPs exposure can upregulate ROS and activate the JNK/c‐Jun signaling pathway in A549 cells, thereby inhibiting the expression of SP‐A and SP‐B proteins.

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Silicosis is an occupational lung disease that results from long-term inhalation of free silica dust, the expression is sustained inflammation response, fibroblast hyperplasia, and excessive collagen deposit, bringing about pulmonary interstitial fibrosis. Wnt signaling pathway exists in various kinds of eukaryotic cells, is a highly conservative signaling pathway in biological evolution, and participates in cell proliferation, differentiation, migration, and polarity of physiological activity, such as in embryonic development, organ morphology, and tumor. In addition, it plays an important role in the progress of fibrosis disease. At present, studies related to silicosis are increasing, but the pathogenesis of silicosis still is not clear. In recent years, more and more studies have suggested that the Wnt signaling pathway could participate in the pathogenesis of silicosis fibrosis. In the study, we explored the mechanism of the Wnt signaling pathway in the pathogenesis of silicosis fibrosis and evaluated the effect of XAV-939 treatment epithelial-mesenchymal transformation (EMT) induced by silica. In addition, the results showed that EMT and activation of the Wnt signaling pathway would occur after stimulation of silica or TGF-β1. However, after treatment with the Wnt signaling pathway inhibitor XAV-939, EMT was reversed and the expression of the β-catenin decreased. These results suggested that the Wnt signaling pathway is associated with EMT induced by silica and it could be a potential target for the treatment of silicosis.