PM2.5 induces lung inflammation and fibrosis via airway smooth muscle cell expression of the Wnt5a/JNK pathway
Background: In recent years, exposure to particulate matter 2.5 (PM2.5) has emerged as a significant risk factor for chronic obstructive pulmonary disease (COPD). Airway smooth muscle cell (ASMC) dysfunction plays a critical role in the development of lung inflammation and fibrosis in COPD. This study aimed to investigate whether PM2.5 exposure could trigger inflammation and fibrosis in ASMCs both in vivo and in vitro through the Wnt5a/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway.
Methods: Wnt5a expression in the bronchoalveolar lavage fluid (BALF) of COPD patients exposed to PM2.5 was measured using enzyme-linked immunosorbent assay (ELISA). In animal models, mice were intratracheally injected with PM2.5 and the Wnt5a antagonist (BOX5). ASMCs were transfected with Wnt5a small interfering RNA (siRNA), BOX5, or the JNK inhibitor SP600125 before being exposed to PM2.5. Hematoxylin and eosin (H&E) staining was conducted to assess the inflammatory response and airway fibrosis. Western blot analysis was used to evaluate the expression of Wnt5a, JNK, and NF-κB pathway factors. The secretion levels of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α) were measured by ELISA, while the expression of α-smooth muscle actin (α-SMA), collagen I, and collagen III was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.
Results: The study revealed that elevated Wnt5a levels in the BALF of COPD patients were positively correlated with increased PM2.5 exposure. In both PM2.5-exposed animal models and ASMCs, activation of the Wnt5a/JNK/NF-κB pathway led to increased production of α-SMA, collagen I, and collagen III, as well as heightened secretion of IL-6, IL-8, and TNF-α. Additionally, BOX5 was found to prevent these effects. Wnt5a siRNA suppressed the activation of the Wnt5a/JNK/NF-κB pathway, mitigating the inflammatory and fibrotic responses induced by PM2.5 in ASMCs. Moreover, SP600125 inhibited NF-κB phosphorylation, effectively reducing inflammation and fibrosis in PM2.5-exposed ASMCs.
Conclusions: These results indicate that PM2.5 exposure activates the Wnt5a/JNK/NF-κB signaling pathway in ASMCs, driving inflammation and collagen deposition in COPD. Modulating the Wnt5a/JNK pathway may offer a promising therapeutic strategy to mitigate the effects of PM2.5 in COPD.