Interleukin-2/anti-interleukin-2 complex attenuates inflammation in a mouse COPD model by expanding CD4+ CD25+ Foxp3+ regulatory T cells.

BACKGROUND AND PURPOSE: Chronic, nonspecific inflammation of the alveoli and airways is an important pathological feature of chronic obstructive pulmonary disease (COPD), while sustained inflammatory reactions can cause alveolar damage. Regulatory T cells (Tregs) inhibit inflammation, whereas the interleukin-2/anti-interleukin-2 complex (IL-2C) increases the number of Tregs; however, whether the IL-2C has a therapeutic role in COPD remains unknown. Therefore, this study investigated whether IL-2C alleviates lung inflammation in COPD by increasing the number of Tregs. EXPERIMENTAL APPROACH: A mouse COPD model was created by exposing mice to lipopolysaccharides (LPS) and cigarette smoke (CS), and the effects of IL-2C treatment on COPD were evaluated. The number of Tregs in the spleen and lung, pulmonary pathological changes, and inflammatory damage were examined through flow cytometry, histopathology, and immunofluorescence, respectively. KEY RESULTS: IL-2C increased the number of Treg cells in the spleen and lungs after exposure to CS and LPS, reduced the number of T helper 17 (Th17) cells in lung tissue, and improved the Th17/Treg balance. IL-2C decreased the number of inflammatory cells and reduced the levels of pro-inflammatory cytokines IL-6, TNF-α, IL-1ß, CCL5, KC, and MCP-1 in bronchoalveolar lavage fluid and serum. IL-2C significantly reduced the pathological scores for lung inflammation, as well as decreased airway mucus secretion and infiltration of neutrophils and macrophages in the lungs. The depletion of Tregs using anti-CD25 antibodies eliminated the beneficial effects of IL-2C. CONCLUSIONS AND IMPLICATIONS: IL-2C is a potential therapeutic agent for alleviating excessive inflammation in the lungs of patients with COPD.

Sociodemographic correlates with prevalence of comorbidities in patients with chronic obstructive pulmonary disease: a study from a Chinese National Survey.

Background: An increase in the prevalence of comorbidities has been reported in patients with chronic obstructive pulmonary disease (COPD). However, contemporary estimates of the overall prevalence of the sociodemographic correlates of COPD comorbidities are scarce and inconsistent in China. This study aimed to investigate the prevalence of sociodemographic correlates of comorbidities in patients with COPD across China. Methods: This was a cross-sectional study. We used data from the Enjoying Breathing Program between May 2020 and April 2022. Participants with COPD from 17 provinces (or equivalent) were included. Comorbidity clusters were stratified based on the number of comorbidities per person. Univariable and multivariable analyses were used to determine the sociodemographic associations of patients with COPD with specific clusters of comorbidities after adjusting for age, sex, and other prespecified covariates. Tetrachoric correlation analyses were performed to determine the associations between specific comorbidities. Findings: A total of 3913 participants with COPD were included, of whom 1744 (44.7%) had at least one comorbidity; 25.4% had one comorbid disease, 12.9% had two, and 6.4% had three or more concurrent diseases. The most common comorbidities were hypertension (17.8%), asthma (9.9%), bronchiectasis (8.2%), diabetes (8.2%), and coronary artery disease (7.7%). In the logistic regression models adjusted for a broad set of factors, patients with COPD residing in the east region of China and having health insurance experienced a decreased likelihood of comorbidities (from OR = 0.70 [95% confidence interval [CI], 0.53-0.93] to OR = 0.50 [95% CI, 0.25-0.99]). However, patients over 80 years had increased risk (OR 1.43 [95% CI 1.01-2.03]), as did those in all Modified Medical Research Council (mMRC) grade categories (grade 1: OR = 1.30 [95% CI, 1.02-1.65]; grade 2: OR = 1.39 [95% CI, 1.07-1.8]; grade 3: OR = 1.67 [95% CI, 1.23-2.26]; and grade 4: OR = 1.81 [95% CI, 1.00-3.28]) and in Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 classification (OR = 1.30 [95% CI, 1.03-1.65]) relative to their respective references. The associations observed in these subgroups were consistent regardless of the number of comorbidities per person. Tetrachoric correlations demonstrated negative associations in pairwise comparisons of the top five comorbidities, ranging from -0.03 to -0.31 (p < 0.001 in all groups). Interpretation: In China, comorbidities are highly prevalent among patients with COPD, with older age, higher mMRC grade, and lung function decline being the major risk factors. Studies with larger sample sizes are required to elucidate the complex mechanisms underlying COPD comorbidities. Funding: This study was funded by CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-049 and 2022-I2M-C&T-B-107).

GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.

IRAK-M has effects in regulation of lung epithelial inflammation.

BACKGROUND: Epithelial barrier is important for asthma development by shaping immune responses. Airway expressing-IL-1 receptor-associated kinase (IRAK)-M of Toll-like receptor pathway was involved in immunoregulation of airway inflammation through influencing activities of macrophages and dendritic cells or T cell differentiation. Whether IRAK-M has effect on cellular immunity in airway epithelial cells upon stimulation remains unclear. METHODS: We modeled cellular inflammation induced by IL-1ß, TNF-α, IL-33, and house dust mite (HDM) in BEAS-2B and A549 cells. Cytokine production and pathway activation were used to reflect the effects of IRAK-M siRNA knockdown on epithelial immunity. Genotyping an asthma-susceptible IRAK-M SNP rs1624395 and measurement of serum CXCL10 levels were performed in asthma patients. RESULTS: IRAK-M expression was significantly induced in BEAS-2B and A549 cells after inflammatory stimulation. IRAK-M knockdown increased the lung epithelial production of cytokines and chemokines, including IL-6, IL-8, CXCL10, and CXCL11, at both mRNA and protein levels. Upon stimulation, IRAK-M silencing led to overactivation of JNK and p38 MAPK in lung epithelial cells. While antagonizing JNK or p38 MAPK inhibited increased secretion of CXCL10 in IRAK-M silenced-lung epithelium. Asthma patients carrying G/G genotypes had significantly higher levels of serum CXCL10 than those carrying homozygote A/A. CONCLUSION: Our findings suggested that IRAK-M has effect on lung epithelial inflammation with an influence on epithelial secretion of CXCL10 partly mediated through JNK and p38 MAPK pathways. IRAK-M modulation might indicate a new insight into asthma pathogenesis from disease origin.

Polymorphisms in the FCER2 gene have associations with asthma and chronic obstructive pulmonary disease.

Background: Asthma and chronic obstructive pulmonary disease (COPD) are heterogenetic diseases and exhibit many similarities. Dutch hypothesis proposed that these two diseases may have common genetic origins. This study aims to investigate whether asthma and COPD share a common genetic background in Chinese patients. Methods: In this case-control study, single nucleotide polymorphisms (SNPs) were genotyped using SNaPshot. Haplotype disease analysis and haplotype phenotype analysis were applied to assess the relationship between three polymorphisms of the FCER2 gene and the risk of COPD/asthma. Additionally, associations between polymorphisms of the FCER2 gene and phenotypes were analyzed. Results: We detected ten SNPs of seven genes (FCER1A, FCGR2A, FCGR2B, CHI3L1, ADRB2, STAT6, and FCER2) expressed by airway epithelial cells. We detected genotypes and allele distributions in 251 COPD patients, 597 asthma patients, and 632 healthy controls. A significant difference was found in the FCER2 gene (rs28364072) between COPD patients and controls (P=0.009). Significant differences were observed in the genotype and allele distributions of rs1801274 (FCGR2A), rs12368672 (STAT6), and rs2228137 (FCER2) between asthma patients and controls (P=0.004, 0.007 and 0.010, respectively). Notably, polymorphisms of FCER2 gene were associated with the risk of both COPD (P=0.009 for rs28364072) and asthma (P=0.01 for rs2228137). Haplotype analysis revealed that haplotype T-G-T (alleles of rs28364072, rs2228137, and rs3760687, respectively) was significantly associated with a higher risk of asthma [odds ratios (OR) =2.25, 95% confidence interval (CI): 1.26-4.01, P=0.006]. Further analysis showed that the C-A-C haplotype and C-G-T haplotype were associated with increased blood eosinophils in either COPD or asthma patients (P=0.034, and P<0.001, respectively). Moreover, haplotypes C-A-C, C-G-C, and T-G-C showed significant associations with serum IgE levels in asthma patients (P=0.002, 0.041, and 0.004, respectively). Conclusions: Our data suggest that the FCER2 gene might associate with predisposition to asthma and COPD, while FCER2 haplotypes were associated with pulmonary function measurements and blood eosinophils counts in both diseases. Our findings support the common genetic basis for asthma and COPD, suggesting a potential therapeutic target for the two diseases.

IRAK-M Regulates Proliferative and Invasive Phenotypes of Lung Fibroblasts.

Lung fibroblasts play an important role in subepithelial fibrosis, one feature for airway remodeling. IL-1 receptor-associated kinase (IRAK)-M was shown to involve fibrosis formation in airways and lung through regulation of inflammatory responses. IRAK-M is expressed by lung fibroblasts, whether IRAK-M has direct impact on lung fibroblasts remains unclear. In this investigation, we evaluated in vitro effect of IRAK-M on phenotypes of lung fibroblasts by silencing or overexpressing IRAK-M. Murine lung fibroblasts (MLg) were stimulated with house dust mite (HDM), IL-33, and transforming growth factor (TGF) ß1. Techniques of small interfering RNA or expression plasmid were employed to silence or overexpress IRAK-M in MLg fibroblast cells. Proliferation, migration, invasiveness, and fibrosis-related events were evaluated. Significant upregulation of IRAK-M expression in MLg cells was caused by these stimuli. Silencing IRAK-M significantly increased proliferation, migration, and invasiveness of lung fibroblasts regardless of stimulating conditions. By contrast, IRAK-M overexpression significantly inhibited proliferation and motility of MLg lung fibroblasts. IRAK-M overexpression also significantly decreased the expression of fibronectin, collagen I, and α-SMA in MLg cells. Under stimulation with TGFß1 or IL-33, IRAK-M silencing reduced MMP9 production, while IRAK-M overexpression increased MMP9 production. Modulation of IRAK-M expression affected cytokines production, either decreased or increased expression of TNFα and CXCL10 by the cells regardless of stimulation. Our in vitro data reveal that IRAK-M directly impacts on lung fibroblasts through modulation of cellular motility, release of inflammatory, and fibrotic cytokines of lung fibroblasts. These might suggest a new target by regulation of IRAK-M in slowing airway remodeling.

Total bilirubin is associated with all-cause mortality in patients with acute respiratory distress syndrome: a retrospective study.

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening disease for which biomarkers to predict mortality are needed. Total bilirubin (TBIL), an end-product of hemoglobin catabolism in mammals reflecting liver dysfunction, has been demonstrated as an independent risk indicator for critically ill patients. This study aimed to examine whether TBIL on intensive care unit (ICU) admission is associated with ARDS mortality. Methods: We analyzed the data of patients diagnosed with ARDS according to the Berlin definition from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The primary endpoint was 30-day ICU mortality after admission to the ICU, and the second endpoint was in-hospital mortality. Multivariable logistic analysis adjusted for potential confounders was used to determine the association between TBIL and short-term mortality. Results: Of 1,539 ARDS patients enrolled, 261 patients died within 30 days of admission to the ICU. In the multivariable logistic analysis, each 1 g/dL increase in TBIL levels led to a 4% increase in the odds of 30-day ICU mortality [adjusted odds ratio (OR) =0.04; 95% confidence interval (CI): 0.01 to 0.08] and a 4% increase in the odds of in-hospital mortality (adjusted OR =0.04; 95% CI: 0.01 to 0.07). Furthermore, TBIL levels ≥2 mg/dL were significantly associated with 30-day ICU mortality (adjusted OR =1.51, 95% CI: 1.02 to 1.07) and in-hospital mortality (OR =1.41; 95% CI: 1.01 to 1.87). Similarly, associations between serum TBIL levels and 30-day ICU mortality were found in all subgroups stratified by comorbidities, the severity of ARDS, and other variables. Conclusions: A higher serum TBIL on ICU admission was independently associated with mortality in ARDS patients. Intensive care and observation should be provided to ARDS patients with increased TBIL.

Randomised trials of proton pump inhibitors for gastro-oesophageal reflux disease in patients with asthma: an updated systematic review and meta-analysis.

OBJECTIVE: Asthma often coexists with gastro-oesophageal reflux disease (GERD). The effect of proton pump inhibitors (PPIs) treatment on asthma concomitant with GERD was inconsistent. This study aimed to assess whether PPIs treatment improved morning peak expiratory flow (mPEF) in asthma patients with GERD. DATA SOURCES: PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov; hand searching for reference lists; contacted with authors if necessary. STUDY SELECTION: All eligible trials were randomised clinical trials comparing PPIs with placebo in asthma patients accompanying with GERD. RESULTS: Fourteen randomised clinical trials (2182 participants) were included. Overall, PPIs versus placebo did not affect mPEF in patients with asthma having GERD (weighted mean difference 8.68 L/min, 95% CI -2.02 to 19.37, p=0.11). Trial sequential analysis (TSA) further confirmed this finding (TSA adjusted 95% CI -1.03 to 22.25). Subgroups analyses based on the percentage of patients with symptomatic GERD≥95%, treatment duration >12 weeks also found no statistically significant benefit on mPEF. Similarly, analyses of secondary outcomes (evening PEF, forced expiratory volume in 1 s, asthma symptoms score, asthma quality of life score and episodes of asthma exacerbation) did not show significant difference between PPIs and placebo. CONCLUSION: In this meta-analysis, PPIs therapy did not show a statistically significant improvement on mPEF in asthma patients having GERD, neither in subgroup with symptomatic GERD nor in subgroup with treatment duration >12 weeks. This analysis does not support a recommendation for PPIs therapy as empirical treatment in asthma patients with GERD. PROSPERO REGISTRATION NUMBER: CRD42020177330.

Effects of growth hormone on cognitive, motor, and behavioral development in Prader-Willi syndrome children: a meta-analysis of randomized controlled trials.

PURPOSE: The benefits of growth hormone (GH) therapy in Prader-Willi syndrome (PWS) children are well established, but there is still considerable controversy regarding whether GH treatment can improve cognitive, motor, and behavioral development in PWS children. The objectives of this meta-analysis were to quantitatively evaluate the effects of GH on cognitive, motor function, and behavioral development in PWS children. METHODS: Randomized controlled trials (RCTs) examining the effects of GH on cognitive, motor, and behavioral development in PWS children were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases. Intervention effects were represented by Hedges'g and pooled to calculate effect sizes using a random-effects model. RESULTS: Ten relevant studies comprising data from 302 participants were finally included. We observed no significant difference in cognitive performance between the GH treatment group and the control group (p = 0.197). GH treatment was shown to remarkably improve motor development in PWS children compared with the control treatment (p < 0.001), with moderate positive treatment effects (Hedges'g [95% CI] = 0.71 [0.38, 1.03]). There were no significant differences between the GH group and the control group based on objective assessments of behavioral development (p = 0.53). CONCLUSIONS: The meta-analysis suggested that GH treatment had a significantly positive effect on motor development, with moderate treatment effects in PWS children; however, there was no evidence of effects on cognitive or behavioral development.

Network analyses elucidate the role of SMYD3 in esophageal squamous cell carcinoma.

SMYD3 is a member of the SET and myeloid-Nervy-DEAF-1 (MYND) domain-containing protein family of methyltransferases, which are known to play critical roles in carcinogenesis. Expression of SMYD3 is elevated in various cancers, including esophageal squamous cell carcinoma (ESCC), and is correlated with the survival time of patients with ESCC. Here, we dissect gene expression data, from a previously described KYSE150 ESCC cell line in which SMYD3 had been knocked down, by integration with the protein-protein interaction (PPI) network, to find the new potential biological roles of SMYD3 and subsequent target genes. By construction of a specific PPI network, differentially expressed genes (DEGs), following SMYD3 knockdown, were identified as interacting with thousands of neighboring proteins. Enrichment analyses from the DAVID Functional Annotation Chart found significant Gene Ontology (GO) terms associated with transcription activities, which were closely related to SMYD3 function. For example, YAP1 and GATA3 might be a target gene for SMYD3 to regulate transcription. Enrichment annotation of the total DEG PPI network by GO 'Biological Process' generated a connected functional map and found 532 significant terms, including known and potential biological roles of SMYD3 protein, such as expression regulation, signal transduction, cell cycle, cell metastasis, and invasion. Subcellular localization analyses found that DEGs and their interacting proteins were distributed in multiple layers, which might reflect the intricate biological processes at the spatial level. Our analysis of the PPI network has provided important clues for future detection of the biological roles and mechanisms, as well as the target genes of SMYD3.