Abstract
Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease with high morbidity and high mortality. Menstrual blood-derived stem cells (MenSCs) have proven to be an attractive tool for the treatment of acute lung injury and fibrosis-related diseases through immunosuppression and antifibrosis. However, whether MenSC-derived exosomes have the similar function on pulmonary fibrosis remains unclear. In the present study, exosomes secreted from MenSCs (MenSCs-Exo) were verified by transmission electron microscope (TEM), nanoparticle tracking analyzer (NTA), and western blotting. And MenSC-Exo addition significantly improved BLM-induced lung fibrosis and alveolar epithelial cell damage in mice, mainly reflected in BLM-mediated enhancement of the fibrosis score, blue collagen deposition, dry/wet gravity ratio, hydroxyproline and malondialdehyde levels, and downregulation of glutathione peroxidase, which were all robustly reversed by MenSC-Exo management. Additionally, BLM- and TGF-β1-evoked cellular reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and cell apoptosis were rescued by MenSCs-Exo in vivo and in vitro. Further study indicated that the MenSCs-Exo could transport miRNA Let-7 into recipient alveolar epithelial cells. Let-7 inhibitor administration significantly blocked the exosome-mediated improvement role on lung fibrosis in mice. Mechanistically, Let-7 was able to regulate the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX1) through binding to its 3′-UTR region. Forced expression of LOX1 promoted the expression of apoptosis-related protein and mtDNA damage markers via regulating NLRP3 which was also confirmed in BLM model mice under the combination therapy of the exosome and Let-7 inhibitor. Collectively, this study demonstrates that exosomal Let-7 from MenSCs remits pulmonary fibrosis through regulating ROS, mtDNA damage, and NLRP3 inflammasome activation. This provides a new approach of exocytosis on the treatment of fibrotic lung disease.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal interstitial lung disease that usually manifests as interstitial pneumonia in radiology or histology with a poor prognosis [1, 2].According to the statistics, the mortality rate of IPF is estimated to be 2.54 to 11.08 per 100,000 people which is increasing with age [3]
The results showed that the predominant gross lesions of the lung were pale, mottled, and swollen, which was relieved by the administration of Menstrual blood-derived stem cells (MenSCs)-secreted exosomes (Figure 1(a))
The Let-7 inhibitor treatment neutralized the intervention effect of exosomes on LOX1/NLRP3/caspase 3 and mitochondrial DNA (mtDNA) damage (Figure 6(d) and Figure S4B). These results demonstrate that LOX1 can promote the apoptosis of alveolar epithelial cells via affecting mtDNA processes and NLRP3 activities and reversing the protective process of exocyoids on pulmonary fibrosis
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal interstitial lung disease that usually manifests as interstitial pneumonia in radiology or histology with a poor prognosis [1, 2].According to the statistics, the mortality rate of IPF is estimated to be 2.54 to 11.08 per 100,000 people which is increasing with age [3]. Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal interstitial lung disease that usually manifests as interstitial pneumonia in radiology or histology with a poor prognosis [1, 2]. IPF primarily affects individuals between the ages of 60 and 75 and exhibits a highly variable disease process [4]. Oxidative Medicine and Cellular Longevity cytotoxic agents such as prednisone are usually used to cure IPF disease [5]. Lung transplantation combined with drugs such as nintedanib and pirfenidone is used to alleviate the progression of IPF. These therapeutic strategies are not effective for the treatment of fibrotic process, and more exploration to address this issue is needed
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