Biomass fuels related-PM2.5 promotes lung fibroblast-myofibroblast transition through PI3K/AKT/TRPC1 pathway.

Emerging evidence has suggested that exposure to PM2.5 is a significant contributing factor to the development of chronic obstructive pulmonary disease (COPD). However, the underlying biological effects and mechanisms of PM2.5 in COPD pathology remain elusive. In this study, we aimed to investigate the implication and regulatory effect of biomass fuels related-PM2.5 (BRPM2.5) concerning the pathological process of fibroblast-to-myofibroblast transition (FMT) in the context of COPD. In vivo experimentation revealed that exposure to biofuel smoke was associated with airway inflammation in rats. After 4 weeks of exposure, there was inflammation in the small airways, but no significant structural changes in the airway walls. However, after 24 weeks, airway remodeling occurred due to increased collagen deposition, myofibroblast proliferation, and tracheal wall thickness. In vitro, cellular immunofluorescence results showed that with stimulation of BRPM2.5 for 72 h, the cell morphology of fibroblasts changed significantly, most of the cells changed from spindle-shaped to star-shaped irregular, α-SMA stress fibers appeared in the cytoplasm and the synthesis of type I collagen increased. The collagen gel contraction experiment showed that the contractility of fibroblasts was enhanced. The expression level of TRPC1 in fibroblasts was increased. Specific siRNA-TRPC1 blocked BRPM2.5-induced FMT and reduced cell contractility. Additionally, specific siRNA-TRPC1 resulted in a decrease in the augment of intracellular Ca2+ concentration ([Ca2+]i) induced by BRPM2.5. Notably, it was found that the PI3K inhibitor, LY294002, inhibited enhancement of AKT phosphorylation level, FMT occurrence, and elevation of TRPC1 protein expression induced by BRPM2.5. The findings indicated that BRPM2.5 is capable of inducing the FMT, with the possibility of mediation by PI3K/AKT/TRPC1. These results hold potential implications for the understanding of the molecular mechanisms involved in BRPM2.5-induced COPD and may aid in the development of novel therapeutic strategies for pathological conditions characterized by fibrosis.

B7-H3 promotes nasopharyngeal carcinoma progression by regulating CD8+ T cell exhaustion.

BACKGROUND: B7-H3 protein is an important regulator of the adaptive immune response in human tumorigenesis. 4-1BB is a co-stimulatory receptor expressed on activated CD8+ T cells, and regulates T cell immunity. Here, we investigated the role of B7-H3 in the growth and invasion of nasopharyngeal carcinoma (NPC) and the effect of its interaction with 4-1BB on tumor immunity. METHODS: Short hairpin (sh) RNA was designed to knock down B7-H3 expression in NPC cells. NPC cells with stable knockdown of B7-H3 were established and injected into nude mice. The effects of B7-H3 on cell proliferation, apoptosis, and epithelial-to-mesenchymal transition (EMT) were detected by the CCK8 assay, flow cytometry, TUNEL assay, and western blot analysis. The migration and invasion abilities were determined using the Transwell assay and scratch assay. Co-immunoprecipitation (Co-IP) assays were performed to study the interaction between B7-H3 and 4-1BB. Anti-4-1BB antibody was used in a co-culture system and xenograft mice to study the effect of 4-1BB on NPC development. RESULTS: NPC cells transfected with sh-B7-H3 showed a higher rate of apoptosis, slower growth rate, impaired migration, and less EMT in vitro. Xenograft mice with stable knockout of B7-H3 had lower tumor burdens, and the stripped tumors had lower rates of cell proliferation, higher rates of apoptosis, and less EMT in vivo. Additionally, decreased B7-H3 expression was positively correlated with interferon-γ, tumor necrosis factor-α, and 4-1BB+CD8+ tumor-infiltrating lymphocytes. Co-IP studies showed that B7-H3 interacts with 4-1BB. Also, the inhibitory effects of sh-B7-H3 on NPC tumor growth, invasion, and tumor immunity could be alleviated by the anti-4-1BB antibody both in vivo and in vitro. CONCLUSION: Our findings suggest that B7-H3 may accelerate tumor growth, tumor cell invasion, and EMT, and interact with 4-1BB to produce CD8+ T cell exhaustion that inhibits tumor immunity. B7-H3 might serve as a novel target for treating NPC.