a-mouse-model-pulmonary-fibrosis-induced-nasal-bleomycin

A Mouse Model of Pulmonary Fibrosis Induced by Nasal Bleomycin Nebulization

Pulmonary fibrosis is characteristic of several human lung diseases that arise from various causes. Given that treatment options are fairly limited, mouse ...

Chinese Academy of Medical Sciences

Chinese Academy of Medical Science and Peking Union Medical College

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, which is characterized by the progressive deterioration in lung function. In the pathogenesis of IPF, insulin-like growth factor-1 (IGF-1) has been found to be heavily involved. Metformin, a commonly used oral antidiabetic agent, is known to inhibit IGF-1 by the reversal of hyperinsulinemia. In this study, we evaluated the effects of metformin in pulmonary fibrosis in C57/BL6J mice, and further understand the role of IGF-1 signaling pathway involving in this process. Pulmonary fibrosis was induced experimentally in these mice by the intratracheal injection of bleomycin (BLM). Metformin was given orally the day before or 14 days after bleomycin injection, while pirfenidone was used as the positive control. Our study showed that intratracheal injection of bleomycin induced pulmonary fibrosis in mice, with observed elevation in collagen, fibronectin and α-SMA level, characterized by the enhanced IGF-1 and PI3K expression. Metformin was able to inhibit these effects significantly, and its antifibrotic effect had no marked difference with pirfenidone. Our results show that metformin attenuates bleomycin-induced pulmonary fibrosis via IGF-1 pathway.

Metformin ameliorates bleomycin-induced pulmonary fibrosis in mice by suppressing IGF-1.

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.

Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis.

Silicosis is one of the potentially fatal occupational diseases characterized by respiratory dysfunction, chronic interstitial inflammation, and fibrosis, for which treatment options are limited. Previous studies showed that a novel N-arylpyridone compound named AKEX0011 exhibited anti-inflammatory and anti-fibrotic effects in bleomycin-induced pulmonary fibrosis; however, it is unknown whether it could also be effective against silicosis. Therefore, we sought to investigate the preventive and therapeutic roles of AKEX0011 in a silicosis rodent model and in a silica-stimulated macrophage cell line. , our results showed that AKEX0011 ameliorated silica-induced imaging lung damages, respiratory dysfunction, reduced the secretion of inflammatory and fibrotic factors (TNF-α, IL-1β, IL-6, TGF-β, IL-4, and IL-10), and the deposition of fibrosis-related proteins (collagen I, fibronectin, and α-SMA), regardless of early or advanced therapy. Specifically, we found that AKEX0011 attenuated silicosis by inhibiting apoptosis, blocking the ASK1-p38 MAPK signaling pathway, and regulating polarization of macrophages. , AKEX0011 inhibited macrophages from secreting inflammatory cytokines and inhibited apoptosis of macrophages in pre-treated and post-treated models, concurrent with blocking the ASK1-p38 pathway and inhibiting M1 polarization. Collectively, AKEX0011, as a novel N-arylpyridone compound, exerted protective effects for silica-induced pulmonary inflammation and fibrosis both  and , and hence, it could be a strong drug candidate for the treatment of silicosis.

A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration.

Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes.

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-gamma receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found up-regulated FcγRIIB in human and mouse lungs following exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific over-expression of FcγRIIB, and in mice treated with adenovirus by intra-tracheal instillation to up-regulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral over-expression, representing a potential therapeutic strategy for PF-ILDs.

Adenovirus-mediated Over-Expression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis.

We sought to evaluate the prognostic value of blood routine parameters and biochemical parameters, especially inflammation-related biomarkers, and establish an inflammation-related prognostic model in Chinese patients with idiopathic pulmonary fibrosis (IPF).

Blood monocyte counts as a prognostic biomarker and predictor in Chinese patients with idiopathic pulmonary fibrosis.

The GAP model was widely used as a simple risk "screening" method for patients with idiopathic pulmonary fibrosis (IPF).

Article	Year
Metformin ameliorates bleomycin-induced pulmonary fibrosis in mice by suppressing IGF-1. American journal of translational research\| PubMed ID: 32269725	2020
Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis. Cell research\| PubMed ID: 32546764	2020
A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization. Frontiers in pharmacology\| PubMed ID: 35401236	2022
Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models ... Stem cell research & therapy\| PubMed ID: 35413874	2022
Adenovirus-mediated Over-Expression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis. American journal of respiratory cell and molecular biology\| PubMed ID: 36227848	2022
Blood monocyte counts as a prognostic biomarker and predictor in Chinese patients with idiopathic pulmonary fibrosis. Frontiers in medicine\| PubMed ID: 36425108	2022
External validation of the GAP model in Chinese patients with idiopathic pulmonary fibrosis. The clinical respiratory journal\| PubMed ID: 36437511	2022

Dingyun Song

Biography

JoVE Journal Publications

Other Publications