Gut microbiota-derived short-chain fatty acids (SCFAs) impact asthma outcomes, highlighting the importance of understanding the disease mechanisms through the gut–lung axis. In this study, we identified that among SCFAs, butyrate uniquely alleviates asthma through specifically inhibiting a newly identified pathogenic T follicular helper (Tfh) cell subset, Tfh13 cells. Tfh13 cell depletion (Il13 ^Cre/+ Bcl6 ^fl/fl ) or adoptive transfer of Tfh13 cells in an OVA-induced asthma model conclusively demonstrated their indispensable role in driving anaphylactic IgE production and asthma pathogenesis. Mechanistically, the inhibitory function of butyrate on Tfh13 cells is mediated by the interaction between butyrate and G-protein coupled receptor 43 (GPR43), leading to the suppression of p38 MAPK/NF-κB signaling in Tfh13 cells. To address the clinically observed deficiency of butyrate in patients with asthma and recapitulated in murine models, we developed a novel therapeutic strategy using a butyrate-yielding diet enriched with butylated high amylose maize starch (HAMSB). Remarkably, supplementation with HAMSB diet in murine and humanized asthma models significantly reduced Tfh13 cell frequencies and anaphylactic IgE levels, leading to significantly improved disease outcomes. Our findings not only unveil a novel mechanism underlying butyrate-mediated asthma alleviation, termed the butyrate–Tfh13–IgE axis, but also propose a clinically translatable dietary intervention strategy targeting microbial metabolites for stopping asthma.

An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking. The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA. We conducted a systematic search across standard databases using specific key words until May 13, 2021. We performed a meta-analysis to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, and patient-reported asthma control) and safety of pre- and post-omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease. In total, 49 studies (n = 267) were included in the qualitative synthesis and 14 case series (n = 186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate compared with pretreatment (mean difference, -2.09 [95% CI, -3.07 to -1.11]; P < .01). There was a reduction in OCS use (risk difference, 0.65 [95% CI, 0.46-0.84]; P < .01), an increase in termination of OCS use (risk difference, 0.53 [95% CI, 0.24-0.82]; P < .01), and a reduction in OCS dose (milligrams per day) (mean difference, -14.62 [95% CI, -19.86 to -9.39]; P < .01) in ABPA patients receiving omalizumab. Omalizumab improved FEV₁ % predicted by 11.9% (95% CI, 8.2-15.6; P < .01) and asthma control, and was well-tolerated. Omalizumab treatment reduced exacerbations and OCS use, improved lung function and asthma control in patients with ABPA, and was well-tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.

Background: Chronic obstructive pulmonary disease (COPD) has become a major cause of morbidity and mortality worldwide. Increasing evidence indicates that aberrantly expressed microRNAs (miRNAs) are involved in the pathogenesis of COPD. However, an integrative exploration of miRNA–mRNA regulatory network in COPD plasma remains lacking. Methods: The microarray datasets GSE24709, GSE61741, and GSE31568 were downloaded from the GEO database and analyzed using GEO2R tool to identify differentially expressed miRNAs (DEMs) between COPD and normal plasma. The consistently changing miRNAs in the three datasets were screened out as candidate DEMs. Potential upstream transcription factors and downstream target genes of candidate DEMs were predicted by FunRich and miRNet, respectively. Next, GO annotation and KEGG pathway enrichment analysis for target genes were performed using DAVID. Then, PPI and DEM-hub gene network were constructed using the STRING database and Cytoscape software. Finally, GSE56768 was used to evaluate the hub gene expressions. Results: A total of nine (six upregulated and three downregulated) DEMs were screened out in the above three datasets. SP1 was predicted to potentially regulate most of the downregulated DEMs, while YY1 and E2F1 could regulate both upregulated and downregulated DEMs. 1139 target genes were then predicted, including 596 upregulated DEM target genes and 543 downregulated DEM target genes. Target genes of DEMs were mainly enriched in PI3K/Akt signaling pathway, mTOR signaling pathway, and autophagy. Through the DEM-hub gene network construction, most of the hub genes were found to be potentially modulated by miR-497-5p, miR-130b-5p, and miR-126-5p. Among the top 12 hub genes, MYC and FOXO1 expressions were consistent with that in the GSE56768 dataset. Conclusion: In the study, potential miRNA–mRNA regulatory network was firstly constructed in COPD plasma, which may provide a new insight into the pathogenesis and treatment of COPD.

Background. Particulate matter (PM) exposure is related to mitochondria dysfunction and airway inflammation. Antioxidant drug edaravone (EDA) is reported to improve the occurrence and development of oxidative stress‐related diseases. At present, there is no data on whether EDA can alleviate lung inflammation caused by PM. Methods. The anti‐inflammatory effects of EDA were investigated in urban PM‐induced human bronchial epithelial cells (HBECs) and C57/BL6J mouse models. In vitro, its effects on the production of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory cytokines were assessed by DCFH‐DA staining, JC‐1 assay, and real‐time PCR, respectively. In vivo, the oxidant stress in lung tissues was assessed by dihydroethidium (DHE) staining and malondialdehyde (MDA) activity, and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were assessed by ELISA, respectively. Furthermore, the potential signaling pathways were studied by siRNA transfection and western blot. Results. PM increased the expression of inflammatory cytokines and protein, including IL‐6, IL‐1α, IL‐1β, and COX‐2, while these alternations were significantly alleviated following EDA treatment in a dose‐dependent manner. EDA treatment also alleviated the inflammatory responses in lung tissues of PM‐exposed mice. We further showed mitochondrial dysfunction in PM‐exposed HBECs and mice, which were reversed by EDA treatment. Moreover, the phosphorylation of NF‐κB p65 in PM‐exposed HBECs and mice was weakened by EDA. Transfection with NF‐κB p65 siRNA further inhibited PM‐induced inflammation in HBECs. Conclusion. We demonstrated that EDA treatment had a protective role in PM‐induced lung inflammation through maintaining mitochondrial balance and regulating the ROS‐NF‐κB p65 signaling pathway. This provided a new therapeutic method for PM‐induced lung inflammation in the future.

Background: In 2015, large cell neuroendocrine carcinoma (LCNEC) was removed from the large cell carcinoma group and classified with small cell lung carcinoma (SCLC) constituting two members of the high-grade neuroendocrine tumors (NETs) of the lung. However, the difference between high-grade LCNEC and SCLC in terms of clinicopathological characteristics and prognosis has not been fully understood owing to the rarity of LCNEC. Patients and methods: Patients with high-grade LCNEC and SCLC at initial diagnosis between 2001 and 2014 were identified using the Surveillance, Epidemiology, and End Results (SEER) program database. Clinicopathological characteristics between high-grade LCNEC and SCLC were compared using the Pearson's chi-squared test or Fisher's exact test. Differences in overall survival (OS) and cancer-specific survival (CSS) were compared using the log-rank test, Cox models and propensity score matching (PSM) analysis. Results: A total of 1223 patients with high-grade LCNEC and 18182 patients with high-grade SCLC were enrolled. To the best of our knowledge, this study involved the largest number of high-grade LCNEC patients to date, with respect to a comparison between high-grade LCNEC and high-grade SCLC patients. There were significant differences in age, sex, race, laterality, SEER stage, nodal status, surgery, radiation and chemotherapy, but not marital status, between high-grade LCNEC and SCLC patients. High-grade LCNEC patients had a better OS and CSS than high-grade SCLC patients. Subgroup analysis also confirmed the better prognosis of the high-grade LCNEC patients in the regional stage, distant stage and surgery subgroups. However, no significant difference in prognosis was observed between the two non-surgery subgroups, which was confirmed using PSM analysis. Furthermore, high-grade LCNEC patients showed different metastatic patterns to high-grade SCLC patients. Conclusion: These results suggested that high-grade LCNEC and high-grade SCLC were different histological types, and that a detailed classification for high-grade NETs of the lung was needed.

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8⁺ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8⁺ T cell responses and increasing the number of CD8⁺ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines. Graphical Abstract