Background: Macrophages and monocytes orchestrate inflammatory processes in the lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an inflammatory condition, is not well known. Here, we determined the characteristics of these cells in lungs of COPD patients and identified novel therapeutic targets. Methods: We analyzed the RNA sequencing (scRNA-seq) data of explanted human lung tissue from COPD (n = 18) and control (n = 28) lungs and found 16 transcriptionally distinct groups of macrophages and monocytes. We performed pathway and gene enrichment analyses to determine the characteristics of macrophages and monocytes from COPD (versus control) lungs and to identify the therapeutic targets, which were then validated using data from a randomized controlled trial of COPD patients (DISARM). Results: In the alveolar macrophages, 176 genes were differentially expressed (83 up- and 93 downregulated; P_adj < 0.05, |log₂FC| > 0.5) and were enriched in downstream biological processes predicted to cause poor lipid uptake and impaired cell activation, movement, and angiogenesis in COPD versus control lungs. Classical monocytes from COPD lungs harbored a differential gene set predicted to cause the activation, mobilization, and recruitment of cells and a hyperinflammatory response to influenza. In silico, the corticosteroid fluticasone propionate was one of the top compounds predicted to modulate the abnormal transcriptional profiles of these cells. In vivo, a fluticasone–salmeterol combination significantly modulated the gene expression profiles of bronchoalveolar lavage cells of COPD patients (p < 0.05). Conclusions: COPD lungs harbor transcriptionally distinct lung macrophages and monocytes, reflective of a dysfunctional and hyperinflammatory state. Inhaled corticosteroids and other compounds can modulate the transcriptomic profile of these cells in patients with COPD.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, with its incidence continuously increasing in recent years. DN causes renal tissue damage and functional decline, expedites the aging process of the kidneys, and may ultimately progress leading to end-stage renal disease, severely impacting the patient's quality of life and prognosis. Mesenchymal stem cells (MSCs) are highly valued for their multipotent differentiation, paracrine functions, immunomodulatory effects, and capacity for tissue repair. Particularly, exosomes (Exo) derived from MSCs (MSCs-Exo) are rich in bioactive molecules and facilitate intercellular communication, participating in various physiological and pathological processes. MSCs and MSCs-Exo, in particular, have been demonstrated to have therapeutic effects in DN treatment research by encouraging tissue repair, fibrosis inhibition, and inflammation reduction. Research has shown that MSCs and MSCs-Exo have therapeutic effects in DN treatment by promoting tissue repair, inhibiting fibrosis, and reducing inflammation. Recent studies underscore the potential of MSCs and MSCs-Exo, highlighting their broad applicability in DN treatment. This review aims to provide a comprehensive summary of the scientific developments in treating DN using MSCs and MSCs-Exo from diverse sources, while also exploring their future therapeutic possibilities in detail.

Background: A subset of COPD patients have high levels of eosinophils in the distal airways (“airway eosinophilia”).Objectives: To compare the gene expression of type 2 inflammation in airway epithelial brushings of COPD patients with and without airway eosinophilia and to investigate the changes after inhaled corticosteroids (ICS).Methods: Post hocanalyses of the DISARM randomised controlled trial investigated the expression of airway inflammation (type 1, 2 and 17), interleukin (IL)-13 and mast cell gene signatures at baseline and after 12-week ICS treatment. Gene signatures were generated from RNA sequencing of airway epithelial brushings. Airway eosinophilia was defined as eosinophils >1% of the total leukocyte count in bronchoalveolar lavage. Gene set enrichment analyses identified upregulated canonical pathways in airway eosinophilia.Results: Among 58 COPD patients, 38% had airway eosinophilia at baseline. Patients with airway eosinophilia had more severe airflow obstruction and more radiographic emphysema than the non-eosinophilia group. Patients with airway eosinophilia showed a higher epithelial expression of type 2 airway inflammation and IL-13 and mast cell activation at baseline, but the expression of type 1 and type 17 airway inflammation was similar to patients without airway eosinophilia. The airway eosinophilia group showed an upregulation of canonical pathways related to type 2 immune response and asthma. Treatment with ICS for 12 weeks reduced the epithelial expression of type 2 inflammation and mast cell gene signatures in patients with airway eosinophilia, while this change was not significant in patients without airway eosinophilia.Conclusions: Airway eosinophilia marks a subset of COPD patients with increased airway epithelial expression of type 2 inflammation and a response to ICS treatment.

Background: Patients with chronic obstructive pulmonary disease (COPD) are commonly treated with inhaled corticosteroid/long-acting ß2-agonist combination therapy. While previous studies have investigated the host–microbiome interactions in COPD, the effects of specific steroid formulations on this complex cross-talk remain obscure. Methods: We collected and evaluated data from the Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM), a randomized controlled trial. Bronchoscopy was performed on COPD patients before and after treatment with salmeterol/fluticasone, formoterol/budesonide or formoterol-only. Bronchial brush samples were processed for microbial 16S rRNA gene sequencing and host mRNA sequencing. Longitudinal changes in the microbiome at a community, phylum and genus level were correlated with changes in host gene expression using a Spearman’s rank correlation test. Findings: In COPD patients treated with salmeterol/fluticasone, the expression levels of 676 host genes were significantly correlated to changes in the alpha diversity of the small airways. At a genus level, the expression levels of 122 host genes were significantly related to changes in the relative abundance of Haemophilus. Gene enrichment analyses revealed the enrichment of pathways and biological processes related to innate and adaptive immunity and inflammation. None of these changes were evident in patients treated with formoterol/budesonide or formoterol alone. Interpretation: Changes in the microbiome following salmeterol/fluticasone treatment are related to alterations in the host transcriptome in the small airways of patients with COPD. These data may provide insights into why some COPD patients treated with inhaled corticosteroids may be at an increased risk for airway infection, including pneumonia. Funding: The Canadian Institute of Health Research, the British Columbia Lung Association, and an investigator-initiated grant from AstraZeneca.

Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD. The LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n = 4024), exhaled carbon monoxide (eCO) (n = 2854), cigarettes per day (CPD) (n = 2706) and smoking cessation at year 5 follow-up (n = 717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components. For cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 × 10− 8) with top SNP rs10023464, P = 1.27 × 10− 11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 × 10− 8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 × 10− 8). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD. The study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies. The Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999.

One key feature of Chronic Obstructive Pulmonary Disease (COPD) is that its prevalence increases exponentially with age. DNA methylation clocks have become powerful biomarkers to detect accelerated aging in a variety of diseases and can help prognose outcomes in severe COPD. This study investigated which DNA methylation clock could best reflect airway epigenetic age when used in more accessible blood samples. Our analyses showed that out of six DNA methylation clocks investigated, DNAmGrimAge demonstrated the strongest correlation and the smallest difference between the airway epithelium and blood. Our findings suggests that blood DNAmGrimAge accurately reflects airway epigenetic age of individuals and that its elevation is highly associated with COPD.