Telocytes protect against lung tissue fibrosis through hexokinase 2‐dependent pathway by secreting hepatocyte growth factor

Abstract Pulmonary fibrosis (PF) is one of the common manifestations of end‐stage lung disease. Chronic lung failure after lung transplantation is mainly caused by bronchiolitis obliterans syndrome (BOS) and is mainly characterized by lung tissue fibrosis. Pulmonary epithelial‐mesenchymal transformation (EMT) is crucial for pulmonary fibrosis. Telocytes (TCs), a new type of mesenchymal cells, play a protective role in various acute injuries. For exploring the anti‐pulmonary fibrosis effect of TCs in the BOS model in vitro and the related mechanism, rat tracheal epithelial (RTE) cells were treated with transforming growth factor‐β (TGF‐β) to simulate lung tissue fibrosis in vitro. The RTE cells were then co‐cultured with TCs primarily extracted from rat lung tissue. Western blot, Seahorse XF Analysers and enzyme‐linked immunosorbent assay were used to detect the level of EMT and aerobic respiration of RTE cells. Furthermore, anti‐hepatocyte growth factor (anti‐HGF) antibody was exogenously added to the cultured cells to explore further mechanisms. Moreover, hexokinase 2 (HK2) in RTE cells was knocked down to assess whether it influences the blocking effect of the anti‐HGF antibody. TGF‐β could induce lung tissue fibrosis in RTE cells in vitro. Nevertheless, TCs co‐culture decreased the level of EMT, glucose metabolic indicators (lactate and ATP) and oxygen levels. Furthermore, TCs released hepatocyte growth factor (HGF). Therefore, the exogenous addition of anti‐HGF antibody in the co‐culture system blocked the anti‐lung tissue fibrosis effect. However, HK2 knockdown attenuated the blocking effect of the anti‐HGF antibody. In conclusion, TCs can protect against lung tissue fibrosis by releasing HGF, a process dependent on HK2.