Small GTPase RAB6 deficiency promotes alveolar progenitor cell renewal and attenuates PM2.5-induced lung injury and fibrosis

Abstract

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.

Astragaloside IV Protects from PM2.5-Induced Lung Injury by Regulating Autophagy via Inhibition of PI3K/Akt/mTOR Signaling in vivo and in vitro

“…39 AS-IV is widely used to prevent respiratory diseases, but its protective effect on PM2.5-induced lung injury is rarely reported. Although many advances have been made in understanding the molecular mechanisms of PM2.5-induced lung injury, [40][41][42] there is still a lack of preventive and therapeutic strategies. In our study, we found that AS-IV significantly ameliorated pulmonary edema in rats with PM2.5-induced lung injury.…”

Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities

“… 77 , 84 , 85 In PM2.5-induced lung injury, knockout of RAB6 activates the Wnt/β-catenin signalling pathway by inhibiting the secretion of DKK1, thus promoting the self-renewal of type II alveolar epithelial cells (AEC2) during lung repair. 86 Folliculin (FLCN) deletion in pulmonary mesenchymal cells is the leading cause of cystic lesions in Birt-Hogg-Dubé (BhD) syndrome. A significant decrease in the activity of the Wnt/β-catenin signalling pathway was detected in lung tissues with FLCN knockout, indicating that inhibition of the Wnt signalling pathway is related to the abnormal development of alveoli.…”

The Causes and Consequences of miR-503 Dysregulation and Its Impact on Cardiovascular Disease and Cancer

“…Fibrosis can a significant pathological state in many organs, such as heart ( Gao et al, 2012 ; Liu et al, 2017 ; Ge Z. D. et al, 2019 ), lung ( Yang et al, 2020 ), kidney and liver, and may result in the distortions of organ structure and organ dysfunction ( Li et al, 2016 ; Warisara et al, 2020 ). Pro-fibrotic mediator TGF-β ( Guo et al, 2010 ) and its signaling pathways play an important role in the process of epithelial-mesenchymal transition and tissue fibrosis ( Li et al, 2016 ; Warisara et al, 2020 ).…”