External validation of the GAP model in Chinese patients with idiopathic pulmonary fibrosis.

INTRODUCTION: The GAP model was widely used as a simple risk "screening" method for patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We sought to validate the GAP model in Chinese patients with IPF to evaluate whether it can accurately predict the risk for mortality. METHODS: A total of 212 patients with IPF diagnosed at China-Japan Friendship Hospital from 2015 to 2019 were enrolled. The latest follow-up ended in September 2022. Cumulative mortality of each GAP stage was calculated and compared based on Fine-Gray models for survival, and lung transplantation was treated as a competing risk. The performance of the model was evaluated in terms of both discrimination and calibration. RESULTS: The cumulative mortality in patients with GAP stage III was significantly higher than that in those with GAP stage I or II (Gray's test p < 0.0001). The Harrell c-index for the GAP calculator was 0.736 (95% CI: 0.667-0.864). The discrimination for the GAP staging system were similar with that for the GAP calculator. The GAP model overestimated the mortality rate at 1- and 2-year in patients classified as GAP stage I (6.90% vs. 1.77% for 1-year, 14.20% vs. 6.78% for 2-year). CONCLUSIONS: Our findings indicated that the GAP model overestimated the mortality rate in mild group.

Adenovirus-mediated Overexpression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis.

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-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after 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 overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate 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 overexpression, representing a potential therapeutic strategy for PF-ILDs.

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.

BACKGROUND: 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. METHODS: To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations. RESULTS: IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-ß. CONCLUSION: IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.

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

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.