Clinical and Experimental Medicine最新文献

Macrophages play a pivotal role in modulating immune responses in connective tissue disease-associated interstitial lung disease (CTD-ILD). The role of programmed death ligand-2 (PD-L2), an immune checkpoint molecule expressed on macrophages, in macrophage polarization in CTD-ILD remains poorly understood. Serum PD-L2 levels were measured in CTD-ILD patients, CTD-nonILD patients, and healthy controls. Alveolar macrophages (AMs) were transfected with PD-L2-targeting shRNA or control constructs, and their effects on macrophage phenotype and fibroblast fate were evaluated. M1/M2 polarization was assessed by RT-PCR, Western blotting, and flow cytometry. Human embryonic lung fibroblasts (HELFs) were co-cultured or treated with macrophage-conditioned media, and assays for cell viability, apoptosis, fibrosis, and ferroptosis were performed. A bleomycin (BLM)-induced CTD-ILD mouse model was used to evaluate the effects of PD-L2 knockout on lung fibrosis and ferroptosis markers. Serum PD-L2 levels were significantly lower in CTD-ILD patients compared with CTD-nonILD patients and healthy controls, and negatively correlated with the extent of lung fibrosis. In vitro, PD-L2 knockdown in AMs promoted M1 polarization, suppressed M2 related markers, and induced fibroblast apoptosis, fibrosis, and ferroptosis. Conditioned media from PD-L2-deficient macrophages produced similar effects. In vivo, PD-L2 knockout mice exhibited decreased numbers of CD206⁺ macrophages and regulated ferroptosis markers (ACSL4 upregulation, GPX4 and FTH1 downregulation) in lung tissues following BLM treatment. This study identifies PD-L2 as an important regulator of macrophage polarization and fibroblast responses in CTD-ILD. Our findings suggest that serum PD-L2 levels may reflect disease severity, and that restoring PD-L2 function could represent a potential therapeutic direction warranting further investigation in preclinical models.

Multiple myeloma (MM) is a heterogeneous hematologic cancer marked by clonal plasma cell expansion in the bone marrow. Although treatments have improved, relapse remains common due to clonal evolution, tumor microenvironment changes, ultimately leading to drug resistance. This study utilized single-cell RNA sequencing data analysis to explore immune microenvironment dynamics during MM progression and relapse, aiming to uncover key pathways and cellular interactions correlated with disease relapse. ScRNA-seq data from 20 MM patients (10 primary, 2 remission, 8 relapsed) from the GEO dataset GSE223060 were analyzed. After quality control and batch correction, cells were clustered and annotated. Differential gene expression and functional enrichment analyses were conducted to explore cellular functions. Pseudotime analysis was used to trace plasma cell differentiation, and cell-cell communication was analyzed. Immunohistochemistry and flow cytometry were used for validation.60,234 high-quality single cells were classified into 12 distinct populations. Relapsed MM showed increased T cell infiltration and decreased plasma cells. Relapsed samples had more regulatory T cells (Tregs) and impaired CD8 + T cells. MIF was identified as a key regulator in plasma cell evolution, linked to B cell receptor and interferon-alpha signaling. Enhanced MIF pathway activity was noted between plasma cells and CD8 + T cells in relapsed MM. Increased MIF expression was confirmed in relapsed tissues. Our findings reveal profound immune microenvironment remodeling in relapsed MM, characterized by MIF-mediated signaling, NF-κB suppression, and CD8⁺ T cell dysfunction. These results provide new insights into the mechanisms of MM relapse and highlight potential therapeutic targets for preventing disease relapse.

Human serum albumin (HSA) possesses oncotic, antioxidant, and immunomodulatory properties. Although recent studies suggest that albumin may promote resolution of acute-on-chronic liver failure (ACLF) and reduce the incidence of infection, its impact on overall prognosis with daily administration remains unestablished. Patients meeting the Asian Pacific Association for the Study of the Liver (APASL) criteria for ACLF were extracted from the Medical Information Mart for Intensive Care (MIMIC-IV 2.2) database. The primary outcome was 30-day mortality. To balance baseline characteristics between the albumin and non-albumin groups, we applied stabilized inverse probability of treatment weighting (SIPTW). The association between daily albumin infusion and 30-day mortality was subsequently assessed using Cox regression analyses. A total of 505 patients were enrolled in the study, of whom 325 received albumin therapy within the first 24 h of ICU admission. After applying SIPTW, the cohort comprised 169 patients in the non-albumin group and 319 in the albumin group. Overall, albumin administration was not significantly associated with 30-day mortality in patients with ACLF. However, subgroup analyses revealed that albumin infusion conferred the most substantial survival benefit in specific patient populations. These included individuals with spontaneous bacterial peritonitis, a Model for End-Stage Liver Disease score of ≥ 30.1, a mean arterial pressure below 73 mmHg, a daily albumin dosage of ≤ 1.0 g/kg, or those receiving a combination of 5% and 25% albumin concentrations. Conversely, a dosage exceeding 1.0 g/kg/day was associated with inferior 30-day survival. Albumin administration is associated with reduced mortality in specific subpopulations of patients with ACLF. Key clinical parameters-including serum albumin concentration, SBP, MELD score, and MAP-were identified as significant modifiers of treatment efficacy and should be incorporated into clinical decision-making when initiating albumin therapy.