Idiopathic pulmonary fibrosis (IPF) is a progressive
interstitial lung disease characterized by chronic non-specific
inflammation of the interstitial lung and extensive deposition of
collagen fibers leading to destruction of lung function. Studies have demonstrated that exposure to fine
particulate matter (PM2.5) increases the risk of IPF. In order to recover from PM2.5-induced
lung injury, alveolar epithelial cells need to be repaired and regenerated to maintain lung function. Type 2 alveolar epithelial cells (AEC2) are stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that RAB6, a RAS family member lowly expressed in
lung cancer, inhibited
lung cancer stem cell self-renewal, but it is unclear whether or not and how RAB6 may regulate AEC2 cell proliferation and self-renewal in PM2.5-induced
pulmonary fibrosis. Here, we demonstrated that knockout of RAB6 inhibited
pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, knockout of RAB6 decreased Dickkopf 1(DKK1) autocrine and activated proliferation, self-renewal, and wnt/β-
catenin signaling of PM2.5-injured AEC2 cells. RAB6 overexpression increased DKK1 autocrine and inhibited proliferation, self-renewal and wnt/β-
catenin signaling in AEC2 cells in vitro. Furthermore, DKK1 inhibitors promoted proliferation, self-renewal and wnt/β-
catenin signaling of RAB6 overexpressing AEC2 cells, and attenuated PM2.5-induced
pulmonary fibrosis in mice. These data establish RAB6 as a regulator of DKK1 autocrine and wnt/β-
catenin signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that RAB6 disruption may promote AEC2 cell proliferation and self-renewal to enhance lung repair following PM2.5 injury.