Abstract
Cellular senescence has been considered an important driver of many chronic lung diseases. However, the specific mechanism of cellular senescence in silicosis is still unknown. In the present study, silicotic rats and osteoclast stimulatory transmembrane protein (Ocstamp) overexpression of MLE-12 cells were used to explore the mechanism of OC-STAMP in cellular senescence in alveolar epithelial cell type II (AEC2). We found an increasing level of OC-STAMP in AEC2 of silicotic rats. Overexpression of Ocstamp in MLE-12 cells promoted epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and cellular senescence. Myosin heavy chain 9 (MYH9) was a potential interacting protein of OC-STAMP. Knockdown of Ocstamp or Myh9 inhibited cellular senescence in MLE-12 cells transfected with pcmv6-Ocstamp. Treatment with 4-phenylbutyrate (4-PBA) to inhibit ER stress also attenuated cellular senescence in vitro or in vivo. In conclusion, OC-STAMP promotes cellular senescence in AEC2 in silicosis.
Highlights
Silicosis is a chronic occupational lung disease caused by long-term inhalation of free crystalline silica dust and is characterized by silicotic lesions and progressive massive fibrosis [1]
Silicotic rats were investigated in the present study, and our published reports have well documented that inhalation of silica promotes macrophage activation, myofibroblast differentiation, and collagen deposition [1, 6]
AEC2 in silicotic rats showed a “hyperplastic” phenotype, most of these cells showed expression of p21 but not of PCNA (Figures 1(b) and 1(c)). These results suggested that an increased level and activation of AEC2 showed a cellular senescence phenotype in rats exposed to silica
Summary
Silicosis is a chronic occupational lung disease caused by long-term inhalation of free crystalline silica dust and is characterized by silicotic lesions and progressive massive fibrosis [1]. Cellular senescence is considered an important driving mechanism for chronic lung diseases, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) [3]. Cellular senescence occurs due to replicative and stress-related senescence with activation of p53 and p16INK4a, respectively, leading to activation of p21CIP1 and cell cycle arrest [3, 4]. As silicosis is an age-related and chronic occupational lung disease, silicotic patients showed significantly shorter and telomerase gene variants compared with healthy controls in response to exposure to silica [5]. Cellular senescence may be a key contributor to silicosis, but the exact mechanism is still unknown
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