Qiao Ye

Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease marked by excessive extracellular matrix deposition and deteriorating lung function. Although macrophage migration inhibitory factor (MIF) has been implicated in pulmonary fibrosis, the downstream mechanisms-particularly whether MIF drives fibrosis through its receptor CD74-remain insufficiently understood. This study investigated whether MIF/CD74 signaling promotes fibroblast activation through specific downstream pathways that regulate proliferation and matrix production. Single-cell RNA sequencing and ELISA were used to characterize MIF-CD74 interactions and circulating MIF levels in IPF patients. Bleomycin-induced fibrosis models were established using C57BL/6J mice, Mif⁻/⁻ mice, and the MIF inhibitor 4-IPP. Macrophage-fibroblast co-culture systems were treated with bleomycin, 4-IPP, or CD74 shRNA. Lung injury, fibrosis, and signaling activation were assessed by histology, qRT-PCR, Western blotting, and functional assays. scRNA-seq identified MIF-CD74 as a dominant macrophage-fibroblast signaling axis in fibrotic lungs, and serum MIF levels were elevated in IPF patients. In mice, bleomycin markedly increased MIF and CD74 expression and activated MAPK signaling. Genetic deletion or pharmacologic inhibition of MIF attenuated collagen deposition, improved lung architecture, and reduced profibrotic and inflammatory signaling. In vitro, MIF promoted fibroblast proliferation, migration, and matrix synthesis, whereas CD74 knockdown or MIF inhibition significantly attenuated fibroblast profibrotic responses. MIF promotes pulmonary fibrosis by activating CD74-dependent MAPK signaling in fibroblasts, enhancing their proliferation and extracellular matrix production. Targeting the MIF/CD74 axis reduces tissue remodeling and represents a promising therapeutic strategy for IPF.

Secreted phosphoprotein 1-positive (SPP1+) macrophages play a critical role in the progression of silicosis, but their regulatory mechanisms remain unclear. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics to characterize crucial macrophage subpopulations and their associated regulatory pathways during silicosis. Our results demonstrate that silica exposure significantly promotes the accumulation of SPP1+ macrophages within silicotic nodules. These macrophages contribute to inflammation by releasing pro-inflammatory cytokines such as TNF-α, MCP-1, and IL-6. Concurrently, they exhibit elevated ACTA2 RNA transcription levels, which enhance TGF-β production and drive fibrotic progression. These functional transitions are regulated by the ERK1/2 and JNK signaling pathways. Inhibition of SPP1 markedly attenuated silica-induced lung inflammation and fibrosis. Moreover, plasma SPP1 levels in silicosis patients were strongly correlated with disease onset and severity. Collectively, our findings indicate that SPP1+ macrophages are involved throughout the entire course of silicosis development, under the regulation of ERK/JNK signaling. Targeting SPP1+ macrophages may thus represent a promising therapeutic strategy for silicosis.

Asbestosis and idiopathic pulmonary fibrosis (IPF) share overlapping clinical and pathological features; however, differences in comorbidities and prognost

The COVID-19 pandemic has raised concerns about respiratory sequelae, particularly in the patients with preexisting interstitial lung disease (ILD). This study aimed to evaluate the longitudinal impacts of SARS-CoV-2 reinfection on patients with preexisting ILD, focusing on differential outcomes between single and multiple infection episodes. A prospective cohort study was conducted (December 2022–March 2023), enrolling 347 adults with preexisting ILD and confirmed COVID-19 infection. Follow-up assessments were performed at baseline, 6-, 12-, and 24-month intervals. Data included demographics, pulmonary function tests (PFTs), high-resolution computed tomography (HRCT) scores, and clinical outcomes. Composite deterioration endpoint incorporating acute exacerbation (AE), decline in forced vital capacity (FVC), decline in diffusing capacity (DLCO), and radiographic progression of lung fibrosis on HRCT. Among 347 patients (82.13% single infection, 17.87% multiple infections), the multiple infection group exhibited significantly higher disease deterioration rates (61.29% vs. 41.75%, P = 0.005). Multivariable Cox analysis identified multiple infections (HR = 1.50, 95% CI 1.03–2.19), higher baseline fibrosis scores (HR = 1.64), respiratory failure (HR = 1.84), and COVID-19 pneumonia (HR = 1.58) as independent risk factors. Patients with multiple infections showed accelerated FVC% decline (P = 0.016). All-cause mortality did not differ significantly between groups (11.29% vs. 9.12%, P = 0.598). Subgroup analyses suggested broadly consistent risks across ILD subtypes. Repeated SARS-CoV-2 infections may be associated with disease deterioration in patients with preexisting lung fibrosis. Not applicable.

Background and Purpose: Silicosis is a major cause of occupational disease‐related morbidity and mortality worldwide, yet effective pharmacological treatments remain limited. Nerandomilast, a novel inhibitor of phosphodiesterase‐4B (PDE4B), has demonstrated anti‐fibrotic potential in idiopathic pulmonary fibrosis (IPF); however, its efficacy and mechanisms in silicosis have not been investigated. Experimental Approach: The therapeutic effects (and their underlying mechanisms) of PDE4B inhibition was evaluated in in models of silicosis, both in vivo (male C57BL/6N mice) and in vitro (THP‐1 macrophages and MRC‐5 cells). Single‐cell RNA sequencing, using lung tissue, was first performed to identify PDE4B as a key regulatory target in the pathogenesis of silicosis. Based on this finding, the therapeutic effects and underlying mechanisms of PDE4B inhibition were assessed using nerandomilast. Pulmonary function tests, inflammatory marker analyses and fibrosis evaluations were conducted to determine treatment efficacy. In addition, bulk RNA sequencing and transcriptomic analyses were performed to explore the molecular pathways modulated by nerandomilast. Key Results: PDE4B inhibition effectively prevented and attenuated silica‐induced lung inflammation in the mouse model by suppressing both canonical and non‐canonical NLRP3 inflammasome pathways in lung macrophages. Furthermore, PDE4B inhibition down‐regulated TGF‐β/Smad signalling in lung fibroblasts of silicosis, leading to a significant reduction in fibrosis‐related gene expression. Conclusions and Implications: These findings suggest that nerandomilast, a PDE4B inhibitor, may be a promising treatment for silicosis, which currently lacks effective therapies.

Background Silicosis and asbestosis, distinct forms of pneumoconiosis, manifest progressive interstitial fibrosis due to exposure to silica dust or asbestos fibers. This study aimed to identify potential biomarkers for diagnosing silicosis and asbestosis, while also evaluating disease severity and prognosis. We undertook an prospective observational study involving patients with silicosis or asbestosis. The correlation between baseline CC-chemokine ligand 18 (CCL18), CXC motif chemokine 13 (CXCL13), osteopontin (OPN), periostin, and fibulin-3 and clinical variables was analyzed. Diagnostic sensitivity was evaluated using receiver operating characteristic curves, and correlations between baseline biomarker levels and disease severity were analyzed. Multivariable Cox regression assessed the baseline concentrations’ strength in predicting all-cause mortality for silicosis and asbestosis. Of 231 silicosis and 163 asbestosis included in the study, 29 silicosis (12.6%) and 28 (17.2%) asbestosis died within the five years follow-up period. Elevated baseline concentrations of CCL18, CXCL13, and OPN were observed in 231 silicosis patients and 163 asbestosis patients compared to 118 HCs. Diagnostic accuracy for silicosis or asbestosis, in order, was CCL18, OPN, and CXCL13. Combining CCL18, OPN, and CXCL13 enhanced diagnostic accuracy. In silicosis patients, these concentrations were significantly associated with lung function values. However, these biomarkers were not the risk factor for all-cause mortality. CCL18, CXCL13, and OPN stand out as promising biomarkers for diagnosing silicosis and asbestosis. Meanwhile, CCL18, CXCL13, and OPN may be used for the evaluation of silicosis conditions.

Silicosis and coal worker’s pneumoconiosis primarily result from exposure to silica and coal dust. Despite similar exposure levels, individuals exhibit varying responses. This study aimed to address these gaps to explore the genetic factors influencing the development, severity, and associated complications. A systematic literature search was performed across four databases—PubMed, Embase, Web of Science, and Cochrane Library—until July, 2023. Qualitative and quantitative analyses were applied to identify candidate genes. This study involved 83 articles and encompassed 545 individual studies, reviewing a total of 378 gene loci. After rigorous evaluation, we selected 8 candidate genes (TNFα-308, TNFα-238, GSTT1, IL-1α + 4845, IL-1β-511, IL-1β + 3953, IL-1RA + 2018, and IL-6–174) for meta-analysis. The analysis revealed that allele A of TNFα-308, allele A of TNFα-238, and allele C of IL-1RA + 2018 were identified as risk factors for the development of diseases. This study established associations between specific genetic polymorphisms (TNFα-308, TNFα-238, and IL-1RA + 2018) and susceptibility to silicosis and coal worker’s pneumoconiosis.

Background: There is uncertainty with respect to the baseline tumor markers and clinical outcomes for patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). The study aimed to assess the association between baseline tumor markers and progressive pulmonary fibrosis (PPF) and prognosis. Methods: This is a prospective cohort study. Serum levels of nine tumor markers, including carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125), neuron-specific enolase (NSE), squamous cell carcinoma (SCC) antigen, cytokeratin fraction 21-1 (CYFRA21-1), serum ferritin (SF), alpha-fetoprotein (AFP) and carbohydrate antigen 724 (CA724) were collected at baseline in patients with CTD-ILD and healthy controls (HCs). Logistic regression and receiver operating characteristic (ROC) curves were used to assess the strength of baseline tumor markers in identifying PPF in CTD-ILD. Correlation analysis was performed to explore associations between tumor markers and disease severity. The relationship of prognosis and these markers was also evaluated. Results: There were 224 patients with CTD-ILD and 63 HCs included in the analysis. The serum CEA and CA125 levels were significantly higher in the PPF group than in the non-PPF and HC groups. The area under the ROC curve (AUC) of CEA was 0.64 [95% confidence interval (CI): 0.56–0.72], the highest among the tested tumor markers. For CA125, the AUC was 0.59 (95% CI: 0.51–0.68). Patients were then stratified into low-titre and high-titre groups based on the median levels of CEA or CA125. Compared with the low CEA group, patients in the high CEA group showed a higher risk for PPF [odds ratio (OR): 3.42, 95% CI: 1.74–6.72, PConclusions: Circulating CEA may be associated with pulmonary fibrosis progression and prognosis of CTD-ILD.

Background: Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs.Methods: We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases.Results: The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, P _IVW-FE = 1.01 × 10^-21), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, P_IVW-MRE = 9.88 × 10^-2). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All P < 6.25 × 10^-3). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (P < 6.25 × 10^-3).Conclusion: The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.

Background: Although extensive research has established associations between chronic obstructive pulmonary disease (COPD) and environmental pollutants, the connection between furan and COPD remains unclear. This study aimed to explore the association between furan and COPD while investigating potential mechanisms. Methods: The study involved 7,482 adults from the National Health and Nutrition Examination Survey 2013–2018. Exposure to furan was assessed using blood furan levels. Participants were categorized into five groups based on quartiles of log10-transformed blood furan levels. Logistic regression and restricted cubic spline regression models were used to assess the association between furan exposure and COPD risk. Mediating analysis was performed to assess the contribution of inflammation to the effects of furan exposure on COPD prevalence. Cox regression was used to assess the association between furan exposure and the prognosis of COPD. Results: Participants with COPD exhibited higher blood furan levels compared to those without COPD (P < 0.001). Log10-transformed blood furan levels were independently associated with an increased COPD risk after adjusting for all covariates (Q5 vs. Q1: OR = 4.47, 95% CI = 1.58–12.66, P = 0.006, P for trend = 0.001). Inflammatory cells such as monocytes, neutrophils, and basophils were identified as mediators in the relationship between furan exposure and COPD prevalence, with mediated proportions of 8.73%, 20.90%, and 10.94%, respectively (all P < 0.05). Moreover, multivariate Cox regression analysis revealed a positive correlation between log10-transformed blood furan levels and respiratory mortality in COPD patients (HR = 41.00, 95% CI = 3.70–460.00, P = 0.003). Conclusions: Exposure to furan demonstrates a positive correlation with both the prevalence and respiratory mortality of COPD, with inflammation identified as a crucial mediator in this relationship.