Background: The lung is a highly complex organ comprised of diverse cell types. Recent studies have revealed that lung fibroblasts have various unique phenotypes, some of which are involved in airway homeostasis. Lipofibroblast (LiF), which is a stromal fibroblast containing lipid droplets, has been reported to exist in the vicinity of type II alveolar epithelial cells (AT2) and support AT2. It has also been reported that LiFs can be induced by metabolic modulators in vitro. Recently, extracellular vesicles (EVs) have attracted attention as novel therapeutic agents. In this study, we investigated whether LiF-derived EVs induced by metabolic modulators may ameliorate cigarette smoke (CS)-induced pathologies of COPD.

Methods and Results: Some metabolic modulators could induce LiFs from human primary lung fibroblasts. We found that induced LiFs have significant accumulation of lipid droplets and activation of lipogenic genes. EVs derived from LiFs were isolated by conventional ultracentrifugation. EVs fulfilled the minimal experimental criteria for identification exosomes, as described in the position statement from the ISEV. The effect of LiFs was evaluated on CS extract (CSE)-treated human bronchial epithelial cells (HBECs) and CS-exposed mice. We found that LiF-derived EVs suppressed cellular senescence and inflammation in CSE-treated HBEC model. Furthermore, intratracheal administration of LiF-derived EVs effectively inhibited inflammation of the airway wall, fibrosis, airway obstruction, and increases in bronchoalveolar lavage total cells in a mouse model of COPD.

Conclusion:Our data indicate that LiF-derived EVs induced by metabolic modulators may be a novel therapeutic modality for COPD.