OC‐STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis

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.

Thalidomide Alleviates Pulmonary Fibrosis Induced by Silica in Mice by Inhibiting ER Stress and the TLR4-NF-κB Pathway

“…Research has shown that endoplasmic reticulum stress (ER stress) facilitates fibrotic remodeling through the activation of pro-apoptotic pathways, the induction of epithelial-mesenchymal transition, and the promotion of inflammatory responses [ 16 ]. Our previous studies discovered that both inflammation and ER stress play vital roles in the progression of silicosis [ 17 , 18 , 19 , 20 ]. It is worth noting that early studies on ER stress have focused on epithelial cells [ 16 , 18 , 19 ] with researchers since turning their attention to macrophages [ 17 , 20 ].…”

“…Our previous studies discovered that both inflammation and ER stress play vital roles in the progression of silicosis [ 17 , 18 , 19 , 20 ]. It is worth noting that early studies on ER stress have focused on epithelial cells [ 16 , 18 , 19 ] with researchers since turning their attention to macrophages [ 17 , 20 ]. Previous data indicated that silica inhalation might activate the Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling pathway in lung macrophages [ 20 ].…”

Oxamate Attenuates Glycolysis and ER Stress in Silicotic Mice

“…In our preliminary study, we found that SiO 2 induced ER stress in A549 cells [ 7 ] and MLE-12 cells [ 8 ]. As a follow-up, this study was aimed at further investigating whether ER stress was also manifested in silica-induced macrophages.…”

“…Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been linked to lung fibrosis through the regulation of alveolar epithelial cell (AEC) apoptosis, epithelial–mesenchymal transition (EMT), fibroblast proliferation, myofibroblast differentiation, and M2 macrophage polarization [ 5 , 6 ]. Our previous studies also found that ER stress was abnormally activated in silica-induced A549 cells [ 7 ] and MLE-12 cells [ 8 ]. Other studies have shown that ER stress and the UPR were critical to the function and phenotypic transformation of macrophages [ 9 ].…”

“…We observed previously that SiO 2 induced ER stress-associated apoptosis in A549 cells [ 7 ]. In addition, supplementation with 4-PBA inhibited the activation of senescence signaling in silica-induced MLE-12 cells [ 8 ]. In this study, we discovered that the proteins related to ER stress, p-PERK, p-IRE-1α, and p-eIF-2α, were up-regulated in the silica-exposed macrophages, suggesting that silica activated ER stress in the macrophages.…”