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

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-beta 1 was used to induce NIH-3T3 cell transdifferentiation. DMOG was used to increase hypoxia-inducible factor-1 alpha subunit (HIF-1 alpha) expression. KC7F2 and siRNA decreased HIF-1 alpha expression. In vivo, silica particles were used to induce PF in C57BL/6N mice, and KC7F2 was used to reduce HIF-1 alpha expression in C57BL/6N mice. Western blot was used to detect the expression of collagen type 1 alpha 1(COL1A1), alpha-smooth muscle actin (alpha-SMA), SMAD family member (SAMD) 3, Phospho-SMAD3 (PSMAD3), and HIF-1 alpha. PCR was used to detect the expression of COL1A1, alpha-SMA, and HIF-1 alpha. Immunohistochemistry was used to detect the expression of COL1A1 and HIF-1 alpha. Results: In vitro, compared to the control group, COL1A1, alpha-SMA, PSMAD3, and HIF-1 alpha expression were elevated in the DMOG group, and COL1A1, alpha-SMA, PSMAD3, and HIF-1 alpha expression were decreased in the KC7F2 group and siRNA group. Compared to the DMOG group, COL1A1, alpha-SMA, and PSMAD3 expression were decreased in the DMOG + SIS3 group. In vivo, compared to the saline group, COL1A1, alpha-SMA, PSMAD3, and HIF-1 alpha expression were increased in the pulmonary tissue of C57BL/6N mice in the silica group. Compared to the silica group, COL1A1, alpha-SMA, PSMAD3, and HIF-1 alpha expression and the degree of PF were decreased in the silica + KC7F2 group. Conclusion: Inhibition of HIF-1 alpha reduced alpha-SMA, decreased COL1A1 expression, and attenuated the degree of PF in C57BL/6N mice. Therefore, HIF-1 alpha may be a new target for the treatment of silica-induced PF.