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Apelin/APJ Preserves Mitochondrial Homeostasis in Alveolar Type II Cells to Restrain EMT and Silica-Induced Pulmonary Fibrosis

ABSTRACT: Silicosis is a chronic fibrotic lung disorder for which mechanism-based therapeutic options remain limited, partly because the processes driving alveolar epithelial dysfunction are still not fully understood. Here, we identify the Apelin/APJ axis as an intrinsic protective pathway in alveolar type II (AT2) cells that preserves mitochondrial homeostasis and limits EMT-related changes during silicosis. Apelin expression was markedly reduced in AT2 cells from patients with silicosis and silica-exposed mice and inversely correlated with epithelial–mesenchymal transition (EMT)-associated marker changes. Administration of Apelin or its analog MM07 in vivo significantly attenuated silica-induced pulmonary fibrosis and EMT. Conversely, AT2 cell-specific deletion of Aplnr exacerbated fibrotic remodeling, mitochondrial dysfunction, and EMT progression. Transcriptomic profiling identified oxidative phosphorylation as the top dysregulated pathway associated with APJ loss. Mechanistically, Apelin/APJ activation enhanced mitochondrial respiration, stabilized the mitochondrial membrane potential, lowered mitochondrial reactive oxygen species levels, and preserved ultrastructural integrity in AT2 cells. Proteomic and pharmacological analyses further supported that these effects are mediated through engagement of the AMPK–PGC-1α axis together with its downstream mitochondrial biogenesis-related program. Collectively, our findings identify an AT2 cell-intrinsic Apelin/APJ–AMPK–PGC-1α signaling axis that maintains mitochondrial homeostasis and constrains EMT-related changes under silica-induced fibrotic stress. These results expand the epithelial cell-specific biology of Apelin/APJ signaling and suggest that this pathway may represent a potential therapeutic target for silicosis and other fibrotic lung diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE333254 | GEO | 2026/05/29

REPOSITORIES: GEO

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Project description:Silicosis, a fibrotic granulomatous lung disease, may occur through accidental high-dose or occupational inhalation of silica, leading to acute/accelerated and chronic silicosis, respectively. While chronic silicosis has a long asymptomatic latency, lung inflammation and apoptosis are hallmarks of acute silicosis. In animal models, histiocytic granulomas develop within days after high-dose intratracheal silica instillation. However, following chronic inhalation of occupationally relevant doses of silica, discrete granulomas resembling human silicosis arise months after the final exposure without significant lung inflammation/apoptosis. To identify molecular events associated with chronic silicosis, lung RNAs from controls or chronically silica-exposed rats were analyzed by Affymetrix at 28 wk after silica exposures. Results suggested a significant upregulation of 144 genes and downregulation of seven genes. The upregulated genes included complement cascade, chemokines/chemokine receptors, G-protein signaling components, metalloproteases, and genes associated with oxidative stress. To examine the kinetics of gene expression relevant to silicosis, qPCR, ELISA, Luminex-bead assays, Western blotting, and/or zymography were performed on lung tissues from 4 d, 28 wk, and intermediate times after chronic silica exposure and compared with 14 d acute silicosis samples. Results indicated that genes regulating fibrosis (secreted phosphoprotein-1, CCL2, and CCL7), redox enzymes (superoxide dismutase-2 and arginase-1), and the enzymatic activities of matrix metalloproteinases 2 and 9 were upregulated in acute and chronic silicosis; however, proinflammatory cytokines were strongly upregulated only in acute silicosis. Thus, inflammatory cytokines are associated with acute but not chronic silicosis; however, genes regulating fibrosis, oxidative stress, and metalloproteases may contribute to both acute and chronic silicosis. 3 rats were chronically exposed to silica by inhalation. Briefly, exposure chambers were maintained with an airflow rate of ~15 cfm and temperature range of 22‚Äì26¬?C. Animals were exposed to 6.2 mg/m3 aerosolized silica (Min-U-Sil 5; U.S. Silica, Mill Creek, OK) with an average particle size of 1.75 ¬± 0.05 mm (mass median aerodynamic diameter) 6 h/d, 5 d/wk (Monday‚ÄìFriday) for 6 wk. 3 control animals received filtered air under similar inhalation conditions.

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Apelin/APJ Preserves Mitochondrial Homeostasis in Alveolar Type II Cells to Restrain EMT and Silica-Induced Pulmonary Fibrosis

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