RESUMEN
BACKGROUND: Silicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play a crucial role in mediating the initiation of silicosis. However, the phenotypic and functional heterogeneities of pulmonary macrophages in silicosis have not been well-studied. METHODS: The silicosis mouse model was established by intratracheal administration of silica suspension. Bronchoalveolar lavage fluids (BALFs) of mice were collected for the multiplex cytokine analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed to reveal the heterogeneity and spatial localization of macrophages in the lung tissues. The formation of the fibrotic nodules was characterized by histology, hydroxyproline assay, and immunohistochemical staining, respectively. The expression of the pro-inflammatory or pro-fibrotic genes was investigated by quantitative polymerase chain reaction (qPCR). RESULTS: We found that the level of pro-inflammatory cytokines and chemokines is significantly increased in the BALFs of silicosis mice. Apparent collagen deposition can also be observed in the silicotic lung tissues. By scRNA-seq, we have identified a subpopulation of Mmp12hi macrophages significantly expanding in the lung tissues of mice with silicosis. Spatial transcriptomics analysis further confirmed that the Mmp12hi macrophages are mainly enriched in silicosis nodules. Pseudotime trajectory showed that these Mmp12hi macrophages, highly expressing both pro-inflammatory and pro-fibrotic genes, are derived from Ly6c+ monocytes. Additionally, 4-octyl itaconate (4-OI) treatment, which can alleviate pulmonary fibrosis in silicosis mice, also reduces the enrichment of the Mmp12hi macrophages. Moreover, we found a subset of macrophages in BALFs derived from patients with silicosis exhibited similar characteristics of Mmp12hi macrophages in silicosis mice models. CONCLUSIONS: Our study suggested that a group of Mmp12hi macrophages highly express both pro-inflammatory and pro-fibrotic factors in silicosis mice, and thus may contribute to the progression of fibrosis. The findings have proposed new insights for understanding the heterogeneity of lung macrophages in silicosis, suggesting that the subset of Mmp12hi macrophages may be a potential therapy target to further halt the progression of silicosis.
RESUMEN
BACKGROUND: Awake prone positioning (APP) has been considered as a feasible treatment for patients with acute hypoxemic respiratory failure in non-intubated coronavirus disease 2019 (COVID-19). However, the efficacy and safety of APP remain uncertain. This meta-analysis aims to assess the effect of APP on intubation rate and mortality in COVID-19 patients with acute respiratory failure. METHODS: Relevant studies published from January 1, 2020, to June 17, 2022, were systematically searched. The primary outcomes were the intubation rate and mortality; the secondary outcome was the incidence of adverse events. RESULTS: Of 5746 identified publications, 22 were eligible for inclusion in the meta-analysis (N = 5146 patients). In comparison to the non-APP group, APP could decrease the intubation rates (OR 0.64; 95% CI 0.48-0.83; P = .001), particularly in the subgroup of the daily median duration of APP > 8â h and in the subgroup of receiving high flow nasal cannula (HFNC) or non-invasive ventilation (NIV). Patients treated with APP were associated with lower mortality rates (OR 0.61; 95% CI 0.45-0.81; P = .0008), but no mortality benefit was found in the APP group in the subgroup of randomized controlled trials (RCTs). No significant difference was found in the incidence of adverse events between the groups (OR 1.13; 95% CI 0.75-1.71; P = .56). CONCLUSION: Our results demonstrated that APP could be an effective strategy to avoid intubation without detrimental effects in non-intubated patients with COVID-19, especially for patients requiring HFNC or NIV, and the daily APP duration with the target of minimally eight hours was suggested. In the subgroup of RCTs, the pooled results did not demonstrate any benefit of APP on mortality. Given the limited number of RCTs, further high-quality RCTs are needed to confirm the results. INPLASY REGISTRATION NUMBER: INPLASY2021110037.