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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic nonspecific inflammation of the interstitial lung and extensive deposition of collagen fibers leading to destruction of lung function[1]
We have recently shown that RAB6 inhibits the migration of lung cancer cells and inhibits the selfrenewal and proliferation of lung cancer stem cells[28,29]
These results indicated that RAB6 was involved in the development of PM2.5-induced lung injury and pulmonary fibrosis in mice
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic nonspecific inflammation of the interstitial lung and extensive deposition of collagen fibers leading to destruction of lung function[1]. Unlike other forms of lung disease, the pathogenesis of IPF is poorly understood. There is currently no IPF is increasing worldwide, with a median survival of only 3–4 years. The recently approved drugs for IPF, such as Nintedanib and Pirfenidone, can reduce the occurrence of lung dysfunction, but no drugs so far have been shown to improve survival or the quality of life[3,4]. The incidence of pulmonary fibrosis has increased with the increasing severity of air pollution. Epidemiological studies have shown that the increase in the incidence of pulmonary fibrosis is associated with increasing fine particulate matter (PM2.5, aerodynamic diameter ≤ 2.5 μm) levels in the atmosphere[5]. Due to its Official journal of the Cell Death Differentiation Association
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
