Lipid peroxidation in macrophages essentially contributes to the development of lung fibrosis

Abstract

Particle-induced pulmonary fibrosis is a common health threat issue, which gives rise to considerable morbidity and even death worldwide. Nonetheless, the roles and underlying molecular mechanisms for different types of cells in driving fibroblast transformation remain elusive. Growing evidence suggests that macrophages crucially determine the initiation of fibroblast transformation through the well-known pro-inflammatory responses and inappropriate repair of inflammation. Encouragingly, we here observed remarkable lipid peroxidation (LPO) in macrophages in bronchoalveolar lavage fluid (BALF) from patients with pneumoconiosis (namely occupational dust-induced pulmonary fibrosis) in comparison to lower levels of LPO in BALF macrophages from the control individuals without pulmonary fibrosis. To corroborate these observations, we examined LPO and the downstream events (including ferroptosis and fibroblast activation) in vitro and in vivo. Strikingly, macrophages exhibited differential responses to diverse particles, and the most remarkable LPO was observed in cells upon exposure to graphene oxide nanosheets (GON), a fundamental composition of carbon-based airborne fine particles, relative to other widely spread particles, such as SiO₂ and Fe₂O₃. The subsequent mechanistic investigations revealed that GON enhanced the induction of transforming growth factor-beta 1, a decisive cytokine in promoting lung fibrosis, accounting for reinforced fibroblast activation. Animal experiments further validated GON-induced LPO in macrophages and fibroblast activation. This study opens a new avenue to understand particle-induced lung fibrosis, and also pinpoints the therapeutic significance of macrophagic LPO.