Inhibition of HIF-1α Attenuates Silica-Induced Pulmonary Fibrosis

Abstract

Background: Excessive accumulation of extracellular matrix is a key feature of pulmonary fibrosis (PF), and myofibroblasts are the main producers of extracellular matrix. Fibroblasts are the major source of myofibroblasts, but the mechanisms of transdifferentiation are unclear. Methods: In vitro, transforming growth factor-β1 was used to induce NIH-3T3 cell transdifferentiation. DMOG was used to increase hypoxia-inducible factor-1α subunit (HIF-1α) expression. KC7F2 and siRNA decreased HIF-1α expression. In vivo, silica particles were used to induce PF in C57BL/6N mice, and KC7F2 was used to reduce HIF-1α expression in C57BL/6N mice. Western blot was used to detect the expression of collagen type 1 alpha 1(COL1A1), α-smooth muscle actin (α-SMA), SMAD family member (SAMD) 3, Phospho-SMAD3 (PSMAD3), and HIF-1α. PCR was used to detect the expression of COL1A1, α-SMA, and HIF-1α. Immunohistochemistry was used to detect the expression of COL1A1 and HIF-1α. Results: In vitro, compared to the control group, COL1A1, α-SMA, PSMAD3, and HIF-1α expression were elevated in the DMOG group, and COL1A1, α-SMA, PSMAD3, and HIF-1α expression were decreased in the KC7F2 group and siRNA group. Compared to the DMOG group, COL1A1, α-SMA, and PSMAD3 expression were decreased in the DMOG + SIS3 group. In vivo, compared to the saline group, COL1A1, α-SMA, PSMAD3, and HIF-1α expression were increased in the pulmonary tissue of C57BL/6N mice in the silica group. Compared to the silica group, COL1A1, α-SMA, PSMAD3, and HIF-1α expression and the degree of PF were decreased in the silica + KC7F2 group. Conclusion: Inhibition of HIF-1α reduced α-SMA, decreased COL1A1 expression, and attenuated the degree of PF in C57BL/6N mice. Therefore, HIF-1α may be a new target for the treatment of silica-induced PF.

HIF‐1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid‐induced osteonecrosis of the femoral head

“…KC7F2 is a type of HIF‐1α inhibitor that specifically reduces HIF‐1α protein levels in a dose‐dependent manner under low oxygen (Xu et al, 2022). It primarily inhibits the synthesis of HIF‐1α protein rather than degrading it to interfere with its functionality (Xu et al, 2022). Additionally, KC7F2 suppresses the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4EBP1), where activated 4EBP1 can further promote the translation of HIF‐1α (Mushaben et al, 2011).…”

“…KC7F2 is a type of HIF-1α inhibitor that specifically reduces HIF-1α protein levels in a dose-dependent manner under low oxygen (Xu et al, 2022). It primarily inhibits the synthesis of HIF-1α protein rather than degrading it to interfere with its functionality (Xu et al, 2022).…”