Dietary Fiber-Derived Microbial Butyrate Suppresses ILC2-Dependent Airway Inflammation in COPD.

Group 2 innate lymphoid cells (ILC2) strongly modulate COPD pathogenesis. However, the significance of microbiota in ILC2s remains unelucidated. Herein, we investigated the immunomodulatory role of short-chain fatty acids (SCFAs) in regulating ILC2-associated airway inflammation and explores its associated mechanism in COPD. In particular, we assessed the SCFA-mediated regulation of survival, proliferation, and cytokine production in lung sorted ILC2s. To elucidate butyrate action in ILC2-driven inflammatory response in COPD models, we administered butyrate to BALB/c mice via drinking water. We revealed that SCFAs, especially butyrate, derived from dietary fiber fermentation by gut microbiota inhibited pulmonary ILC2 functions and suppressed both IL-13 and IL-5 synthesis by murine ILC2s. Using in vivo and in vitro experimentation, we validated that butyrate significantly ameliorated ILC2-induced inflammation. We further demonstrated that butyrate suppressed ILC2 proliferation and GATA3 expression. Additionally, butyrate potentially utilized histone deacetylase (HDAC) inhibition to enhance NFIL3 promoter acetylation, thereby augmenting its expression, which eventually inhibited cytokine production in ILC2s. Taken together, the aforementioned evidences demonstrated a previously unrecognized role of microbial-derived SCFAs on pulmonary ILC2s in COPD. Moreover, our evidences suggest that metabolomics and gut microbiota modulation may prevent lung inflammation of COPD.

Effect of nitric oxide synthase gene polymorphism on inflammatory response in patients with chronic obstructive pulmonary disease.

This study aimed to investigate the association between nitric oxide synthase gene polymorphisms and the inflammatory responses in patients with 'fast-' and 'slow-' developing chronic obstructive pulmonary disease (COPD). In the main process, 190 patients with slow-developing COPD, 94 patients with fast-developing COPD and 105 healthy volunteers were selected for inclusion. Endothelial nitric oxide synthase (eNOS) was detected using western-blot eNOS sites, and inducible nitric oxide synthase (iNOS) was detected through SNPshot. T helper 17 cells (Th17) and regulator T (Treg) cells were detected via flow cytometry, and interferon-gamma, tumour necrosis factor-alpha, interleukin (IL)-17, IL-10, IL-6, IL-4 and IL-2 were detected using a cytometric bead array. The final results and conclusions drawn from the tests suggest that Th17/Treg-mediated immune inflammation plays an important role in the pathogenesis of COPD, but whether it affects the development of COPD needs further investigation. Overall, COPD patients with a young age of onset, young age of smoking initiation and small body mass index, as well as COPD patients with CC at rs3729508 in the iNOS gene and non-GG at rs7830 in the eNOS gene, may be more likely to contract fast-developing COPD.

Butyrate inhibits iILC2-mediated lung inflammation via lung-gut axis in chronic obstructive pulmonary disease (COPD).

BACKGROUND: The study investigated the effects and underlying mechanisms of intestinal flora metabolite butyrate on inflammatory ILC2 cells (iILC2s)-mediated lung inflammation in chronic obstructive pulmonary disease (COPD). METHODS: Mouse models of COPD and acute exacerbation of COPD (AECOPD) were established. Flow cytometry was used to detect natural ILC2 cells (nILC2s) and iILC2s in lung and colon tissues. The 16s rRNA and GC-MS were used to detect microbial flora and short chain fatty acids (SCFAs) in feces. ELISA was used to detect IL-13 and IL-4. Western blot and qRT-PCR were used to detect the relative protein and mRNA levels, respectively. In vitro experiments were performed with sorted ILC2s from colon tissues of control mice. Mice with AECOPD were treated with butyrate. RESULTS: The nILC2s and iILC2s in lung and colon tissues of AECOPD mice were significantly higher than control groups. The abundance of the flora Clostridiaceae was significantly reduced, and the content of SCFAs, including acetate and butyrate, was significantly reduced. The in vitro experiments showed that butyrate inhibited iILC2 cell phenotype and cytokine secretion. Butyrate treatment reduced the proportion of iILC2 cells in the colon and lung tissues of mice with AECOPD. CONCLUSIONS: The nILC2s and iILC2s in the colon tissues are involved in the course of COPD. Decreased Clostridiaceae and butyrate in AECOPD mice caused the accumulation of iILC2 cells in the intestines and lungs. Supplementation of butyrate can reduce iILC2 in the intestine and lung tissues. Our data may provide new ideas for prevention and treatment of COPD.

Nonlinear relationship between visceral adiposity index and lung function: a population-based study.

BACKGROUND: As one of the critical indicators of obesity, the interaction between visceral fat content and lung disease is the focus of current research. However, the exact relationship between Visceral adipose index (VAI) and lung function is not fully understood. The purpose of this study was to evaluate the relationship between VAI and lung function, METHODS: Our study included all participants from the baseline survey population in Xinjiang in the Natural Population Cohort Study in Northwest China. A field survey was conducted in rural areas of Moyu County, Xinjiang, China, between 35 and 74 years old from June to December 2018. We collected standard questionnaires and completed physical examinations, visceral fat tests, and lung function measurements. RESULTS: The study included 2367 participants with a mean VAI of 10.35 ± 4.35, with males having a significantly higher VAI than females: 13.17 ± 3.91 vs. 7.58 ± 2.65. The piecewise linear spline models indicated a significant threshold effect between lung function and VAI in the general population and the males population, showing an inverted U-shaped curve. But there was no significant association between VAI and lung function in females. FEV1% predicted and FVC% predicted increased with the increase of VAI (ß 0.76; 95% CI 0.30, 1.21) and (ß 0.50; 95% CI 0.06, 0.94) in males with VAI ≤ 14, while FEV1% predicted and FVC% predicted decreased with the increase of VAI (ß - 1.17; 95% CI - 1.90, - 0.45) and (ß - 1.36; 95% CI - 2.08, - 0.64) in males with VAI ≥ 15. CONCLUSIONS: The relationship between lung function and VAI in male participants showed an inverted U-shaped curve, with the turning point of VAI between 14 and 15. The association between visceral fat and lung function was more robust in males than in females.

Regulatory Effect of PD1/PD-Ligand 1 (PD-L1) on Treg Cells in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a serious irreversible lung disease. The mechanism of immune checkpoint in idiopathic pulmonary fibrosis is still unknown. MATERIAL AND METHODS First, the expression levels of PD-1/PD-L1 on the surface of CD4+ T cells and the proportion of Treg cells in IPF or controls were detected by flow cytometry. Then, expression of TGF-ß in blood samples was detected with ELISA. Moreover, a co-culture system was composed of fibroblasts stimulated by TGF-ß and CD4+ T cells from healthy people. The proportions of Treg cells and PD-1 in the co-culture system were detected. In addition, we detected the proportion of Treg cells and the level of collagen-1 after adding PD-1 or PD-L1 protein antibody blocker to the co-culture system. RESULTS Flow cytometry revealed the upregulated expression of PD-1/PD-L1 in CD4+ T cells of IPF patients. PD-1 appears to inhibit the differentiation of CD4+ T cells into Treg cells. Co-culture of myofibroblasts and CD4+ T cells induced the generation of collagen-1 and reduced the proliferation of CD4+ T cells. When PD-1 was blocked, the inhibition of Treg cell differentiation was reversed, accompanied by decreased collagen-1 production. CONCLUSIONS This work identified the molecular mechanism of PD-1 in patients with IPF. It may provide a new perspective on the therapeutic effect of PD-1.

ILC2s Induce Adaptive Th2-Type Immunity in Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

To investigate the effect of ILC2s on Th2-type adaptive immunity during the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), the study enrolled healthy people, stable COPD patients, and AECOPD patients. Flow cytometry was used to detect Th1, Th2, and ILC2 in the peripheral blood and CD80 and MHC II levels on ILC2. The mRNA levels of GATA3, RORα, and CRTH2 of ILC2s were detected by RT-PCR. In addition, ILC2s from the peripheral blood of AECOPD patients were cocultured with CD4+ T cells from the peripheral blood of healthy controls. Cytokine levels in serum of the three groups and the in vitro coculture supernatants were measured by ELISA. Compared with the stable COPD group or the healthy control group, Th2 in the peripheral blood of AECOPD group increased dramatically, inducing an increase of Th2/Th1 ratio in AECOPD patients. Meanwhile, the level of IL-4 in the serum of this group was also increased. However, we also detected ILC2s in the peripheral blood of the AECOPD group and found that it was also increased, alone with the increased GATA3, RORα, and CRTH2 mRNA levels. We also found that the CD80 and MHC II on ILC2 were significantly upregulated and the proportion of MHC II+ ILC2 cells was significantly positively correlated with the proportion of Th2 cells in AECOPD patients. To further demonstrate the effect of ILC2 on Th2 cells, we cocultured ILC2 with CD4+ T cells in vitro, which also showed a significant increase of Th2 ratio as well as Th2-associated cytokines IL-4, IL-5, and IL-13. However, we found that this effect of ILC2s on Th2 cells could be inhibited by the addition of anti-MHC II. The Th2/Th1 balance shifts to Th2 in AECOPD. ILC2s may function as APC by the upregulation of MHC II and regulate adaptive immunity shift to Th2-type response in AECOPD.

Expression of airway mucus-associated proteins in rats with chronic obstructive pulmonary disease with a cold-dryness symptom pattern.

OBJECTIVE: To reveal the effects on expression of airway mucus-associated proteins in rats with chronic obstructive pulmonary disease (COPD) and a cold-dryness symptom pattern induced by elastase and smoking. METHODS: The COPD model was established with an elastase dose into the trachea combined with exposure to smoking; the COPD model cold-dryness symptom pattern was further developed by exposure to a cold, dry environment. After 90 days, pathologic lung sections, inflammatory cytokine levels (measured by enzyme linked immunosorbent assay), mRNA and protein expression of mucus-associated proteins and aquaporins (measured by real-time polymerase chain reaction and western blots) were examined. RESULTS: Cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) in the COPD and the cold-dryness symptom pattern COPD groups were all significantly higher than in controls (each P < 0.01). IL-6 and IL-8 levels were higher in the cold-dryness symptom pattern COPD group than in the COPD group (each P < 0.05). The AQP5 mRNA expression in the cold-dryness symptom pattern COPD and COPD groups was lower than in the control group (P < 0.01), and that in the cold-dryness symptom pattern COPD group was lower than the COPD group (P < 0.05). The expression of MUC5AC and MUC5B mRNAs in the cold-dryness symptom pattern COPD group and COPD group was higher than in the control group (each P < 0.01), and that in the cold-dryness symptom pattern COPD group was higher than the COPD group (P < 0.01, and P < 0.05, respectively). The ratio of MUC5AC mRNA/MUC5B mRNA was COPD group < the cold-dryness symptom pattern COPD group < the control group. AQP4 and AQP5 protein expression in the cold-dryness symptom pattern COPD group was lower than that in the COPD group which was lower again than in the control group. MUC5AC and MUC5B expression in the cold-dryness symptom pattern COPD group was higher than in the COPD group and higher again than in the control group. CONCLUSION: Cold-dryness affects the expression of mucus-associated protein mRNA and its corresponding proteins, reducing the secretion of aquaporins and increasing the secretion of mucins. Imbalance in aquaporins and mucins can affect the function of mucus, increasing airway obstruction.

Effect of cold-dryness on pulmonary and immunologic function in chronic obstructive pulmonary disease model rats.

OBJECTIVE: To study the effects of cold-dryness on pulmonary and immunologic function of peripheral T-lymphocytes in chronic obstructive pulmonary disease (COPD) model rats, and to provide references for the prevention and treatment of cold-dryness COPD in the Xinjiang region. METHODS: The COPD model was established with an elastase drip into the trachea combined with smoking. The cold-dryness COPD model was developed by stressing with a cold-dry environment. Success of the model was determined by observation of pathologic lung sections. Rats were sacrificed by exsanguination from the femoral artery and changes of peripheral blood CD4+, CD8+, and CD4+/CD8+ were detected by flow cytometry. Data were analyzed with SAS 11.5 statistical software. RESULTS: On the ninetieth day after ending the experiment, Peak expiratory flow in the cold-dryness COPD group was lower than that in the COPD and normal control groups (P < 0.01). The time of inspiration in the cold-dryness COPD group was higher than that in the COPD and normal groups (P < 0.05). Time of expiration (Te) in the cold-dryness COPD group was higher than that in the COPD and normal groups (P < 0.01). 50% tidal volume expiratory flow (EF50) in the cold-dryness COPD group was lower than that in the COPD and normal groups (P < 0.01), and EF50 in the COPD group was lower than that in the normal group (P < 0.05). CD4+ content of peripheral blood in the cold-dryness COPD group was lower than that in the COPD and the normal groups (P < 0.05). CD8+ content in the cold-dryness COPD and COPD groups was higher than that in the normal control group (P < 0.01), and CD8+ content in the cold-dryness COPD group was higher than that in the COPD group (P < 0.01). CD4+/CD8+ in the cold-dryness COPD group and the COPD group was lower than that in the normal control group (P < 0.01), and CD4+/CD8+ in the cold-dryness COPD group was lower than that in the COPD group (P < 0.05). CONCLUSION: In the cold-dryness COPD model, CD8+ increased and CD4+/CD8+ decreased. Moreover, cold-dryness may aggravate this state. The effects of cold-dryness on pulmonary function mainly manifested as prolongation of Te and decrease of EF50, which could be one of causes of cold-dryness environment in the northwest of China leading to COPD with region characteristics.

[Effect of Modified Zhisou Powder on the lung function of chronic obstructive pulmonary disease model rats of northwest China cold dryness syndrome].

OBJECTIVE: To observe Modified Zhisou Powder (MZP) on the lung function of chronic obstructive pulmonary disease (COPD) model rats of northwest China cold dryness syndrome (NCCDS). METHODS: Totally 90 male Wistar rats were randomly divided into three groups, i.e., the normal control group (n =20), the COPD model group (n =35), and the COPD of NCCDS group (n =35). The COPD model was established by tracheal dripping porcine pancreatic elastase (PEE) in combination with fumigation for 90 days. The COPD of NCCDS model was set up by tracheal dripping PEE +fumigation + cold and dry environmental stress for 90 days. Then rats in the COPD of NCCDS were randomly divided into the MZP intervention group (n =11 )and the normal saline intervention group (n =10).All intervention lasted for 15 successive days. The lung function was detected using Small Animal Lung Function Device at day 90 and day 105. And the lung pathology was also observed. RESULTS: Little amount of sputum sound could be heard in the airway of the COPD model group and the COPD of NCCDS group. Pathological section showed alveolar ectasia, narrowed and broken alveolar septa, forming larger capsular space with infiltration of inflammatory cells. Rats in the COPD of NCCDS group showed chills, increased amount of drinking water, and loose stool. MZP could improve their symptoms. As for lung function test, compared with the normal control group, Te increased in the COPD model group (P <0.01), and EF50 decreased (P<0.05). PEF and EF50 decreased (P <0.01), Ti and Te increased (P <0.01, P <0.05) in the COPD of NCCDS group. Compared with the normal saline intervention group, PEF and EF50 increased (P < 0.01), Ti and Te decreased (P <0.01) in the MZP intervention group. CONCLUSION: MZP could improve the symptoms of COPD rats of NCCDS, and delay the velocity of decreased lung function.

[The anti-apoptotic effect of cytoplasmic alpha-fetoprotein in hepatoma cells induced by all-trans retinoic acid involves activation of the PI3K/AKT signaling pathway].

OBJECTIVE: To explore the effect of alpha-fetoprotein (AFP) on transduction of the PI3K/ AKT signal in hepatocellular carcinoma cells and the role played by AFP in resistance to cytotoxicity of all-trans retinoic acid (ATRA). METHODS: The effects of ATRA of human liver cancer cells was assessed using the BEL-7402 cell line with the MTT assay (to evaluate proliferation), microscopy (to evaluate morphology), flow cytometry (to evaluate apoptosis), laser confocal microscopy and coimmunoprecipitation (co-IP; to evaluate co-localization and interaction of AFP with PTEN), Western blotting (to evaluate expression of phosphorylated-protein kinase B (pAKT) and Src, and RNA interference (RNAi)-mediated knockdown of AFP. Finally, application of the PI3K-specific inhibitor Ly294002 was used to monitor the influence of AFP in transduction of the PI3K signal pathway. RESULTS: The human hepatoma cell line BEL-7402 were resistant to ATRA cytotoxicity. PTEN and AFP co-localized in the cytoplasm, and co-IP indicated that AFP interacts with PTEN in BEL-7402 cells.RNAi knockdown of AFP expression led to reduced growth of BEL-7402 cells.BEL-7402 cells transfected with AFP-short interfering (si)RNA vectors showed enhanced sensitivity to ATRA and reduced expression of pAKT(Ser473) and Src; Ly294002 reduced the role of AFP in stimulating expression of pAKT(Ser473) and Src. CONCLUSION: AFP can activate transduction of the PI3K/AKT signal, and expression of AFP in hepatoma cells is a pivotal event for resisting ATRA-induced apoptosis.

Effect of Novel Inflammatory Biomarkers on Adverse Outcomes in Patients with Interstitial Lung Disease and Pneumonia: A Multicenter Retrospective Cohort Study.

BACKGROUND: Interstitial lung disease frequently coincides with pneumonia in clinical settings, and both conditions are closely associated with immunoinflammation. The Systemic Immune Inflammatory Index (SII) is a recently identified marker, and its connection to the prognosis of individuals suffering from interstitial lung disease and concurrent pneumonia remains unclear. The objective of this study was to scrutinize the correlation between varying SII levels and unfavorable outcomes in patients grappling with interstitial lung disease complicated by pneumonia. METHODS: This study encompassed a retrospective multicenter cohort of 324 patients diagnosed with interstitial lung disease and pneumonia, all receiving glucocorticoid treatment during their hospitalization. We initially conducted ROC analysis to determine the optimal SII threshold. Subsequently, we examined disparities in clinical symptoms, physical signs, clinical test data, and other clinical attributes among patients with differing SII levels. Later, we employed the Kaplan-Meier survival curve method to assess the association between distinct SII levels and the 30-day and 90-day mortality rates in patients dealing with interstitial lung disease complicated by pneumonia. Finally, a Cox regression model was employed to identify factors influencing adverse prognosis in these patients. RESULTS AND DISCUSSION: The findings demonstrated that the optimal SII threshold for predicting 30-day mortality was 1416.97, with an AUC of 0.633 (95% CI: 0.559-0.708) and a P value of <0.001. For 90-day mortality, the optimal SII threshold was 994.59, yielding an AUC of 0.628 (95% CI: 0.56-0.697) and a P value of <0.001. Noteworthy statistical distinctions emerged in dyspnea, cyanosis, and oxygenation index among patients with varying SII levels. Additionally, invasive mechanical ventilation, non-invasive ventilation, and extended infection duration independently constituted 30-day and 90-day mortality risk factors. Elevated heart rate and higher SII levels emerged as independent risk factors for 90-day mortality. CONCLUSION: To some extent, SII levels exhibit correlations with the clinical manifestations in patients grappling with interstitial lung disease complicated by pneumonia. Notably, a high SII level is an independent predictor for an unfavorable prognosis in these patients. Nevertheless, these findings warrant further validation through prospective cohort studies.

Differential miRNA Profiling Reveals miR-4433a-5p as a Key Regulator of Chronic Obstructive Pulmonary Disease Progression via PIK3R2- mediated Phenotypic Modulation.

OBJECTIVE: In this study, a high-throughput sequencing technology was used to screen the differentially expressed miRNA in the patients with "fast" and "slow" progression of chronic obstructive pulmonary disease (COPD). Moreover, the possible mechanism affecting the progression of COPD was preliminarily analyzed based on the target genes of candidate miRNAs. METHODS: The "fast" progressive COPD group included 6 cases, "slow" and Normal progressive COPD groups included 5 cases each, and COPD group included 3 cases. The peripheral blood samples were taken from the participants, followed by total RNA extraction and high throughput miRNA sequencing. The differentially expressed miRNAs among the progressive COPD groups were identified using bioinformatics analysis. Then, the candidate miRNAs were externally verified. In addition, the target gene of this miRNA was identified, and its effects on cell activity, cell cycle, apoptosis, and other biological phenotypes of COPD were analyzed. RESULTS: Compared to the Normal group, a total of 35, 16, and 7 differentially expressed miRNAs were identified in the "fast" progressive COPD, "slow" progressive COPD group, and COPD group, respectively. The results were further confirmed using dual-luciferase reporter assay and transfection tests with phosphoinositide- 3-kinase, regulatory subunit 2 (PIK3R2) as a target gene of miR-4433a-5p; the result showed a negative regulatory correlation between the miRNA and its target gene. The phenotype detection showed that the activation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway might participate in the progression of COPD by promoting the proliferation of inflammatory A549 cells and inhibiting cellular apoptosis. CONCLUSIONS: MiR-4433a-5p can be used as a marker and potential therapeutic target for the progression of COPD. As a target gene of miR-4433a-5p, PIK3R2 can affect the progression of COPD by regulating phenotypes, such as cellular proliferation and apoptosis.

Yiqigubiao pill treatment regulates Sirtuin 5 expression and mitochondrial function in chronic obstructive pulmonary disease.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of pathophysiological bases of airway inflammation and its anti-inflammatory response. Aberrant mitochondrial signaling and mitochondrial dysfunction underlie the pathomechanisms leading to COPD. This study aims to investigate the effects of the Yiqigubiao (YQGB) pill, a traditional Chinese medicine (TCM), on Sirtuin 5 (SIRT5) and mitochondrial function in patients with COPD. Methods: Thirty-four patients with COPD were randomized into oral YQGB or placebo groups concurrent with a 24-week routine treatment. The pulmonary function was assessed by examining the levels of forced expiratory volume in one second (FEV1)/forced vital capacity (FVC), FEV1, and FVC. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect SIRT5 expression in mitochondria isolated from peripheral blood. Flow cytometry was used to detect changes in mitochondrial membrane potential and reactive oxygen species (ROS) in peripheral blood lymphocytes. Human bronchial epithelial (HBE) cells stimulated by cigarette smoke extract (CSE) were treated with YQGB. After SIRT5 was knocked down in cells, the changes in mitochondrial membrane potential, levels of adenosine triphosphate (ATP), and ROS were detected. Results: YQGB treatment significantly improved lung function in patients with COPD. The expression of SIRT5 and the mitochondrial membrane potential significantly increased and ROS decreased in patients with COPD after YQGB treatment. The CSE decreased cell proliferation and SIRT5 expression, which was alleviated after YQGB treatment. Furthermore, SIRT5 was knocked down in CSE-stimulated HBE cells, and its expression was elevated upon YQGB treatment. The knockdown of SIRT5 significantly altered the CSE-stimulation-induced dysregulation of mitochondrial membrane potential, ATP levels, and ROS. This was also restored after YQGB treatment. Conclusions: YQGB treatment can elevate SIRT5 expression, restore mitochondrial function in COPD, and exert protective effects.

Impact of Previous Pulmonary Tuberculosis on Chronic Obstructive Pulmonary Disease: Baseline Results from a Prospective Cohort Study.

OBJECTIVE: Pulmonary tuberculosis (PTB) is a significant risk factor for COPD, and Xinjiang, China, has a high incidence of pulmonary tuberculosis. The effects of tuberculosis history on airflow restriction, clinical symptoms, and acute episodes in COPD patients have not been reported in the local population. Besides, the exact relationship between lung function changes in people with a history of tuberculosis and COPD risk is not clear. METHODS: This study is based on the Xinjiang baseline survey data included in the Natural Population Cohort Study in Northwest China from June to December, 2018. Subjects' questionnaires, physical examination, and lung function tests were performed through a face-to-face field survey to analyze the impact of previous pulmonary tuberculosis on local COPD. Furthermore, we clarified the specific relationship between pulmonary function decline and the probability of developing COPD in people with a history of tuberculosis. RESULTS: A total of 3249 subjects were eventually enrolled in this study, including 87 with a history of tuberculosis and 3162 non-TB. The prevalence of COPD in the prior TB group was significantly higher than that in the control group (p-value = 0.005). First, previous pulmonary tuberculosis is an essential contributor to airflow limitation in the general population and patients with COPD. In all subjects included, pulmonary function, FEV1% predicted (p-value < 0.001), and FEV1/FVC (%) (p-value < 0.001) were significantly lower in the prior TB group than in the control group. Compared to non-TB group, FEV1% prediction (p-value = 0.019) and FEV1/FVC (%) (p-value = 0.016) were found to be significantly reduced, and airflow restriction (p-value = 0.004) was more severe in prior TB group among COPD patients. Second, COPD patients in the prior TB group had more severe clinical symptoms. Compared with no history of tuberculosis, mMRC (p-value = 0.001) and CAT (p-value = 0.002) scores were higher in the group with a history of tuberculosis among COPD patients. Third, compared with the non-TB group, the number of acute exacerbations per year (p-values=0.008), the duration of each acute exacerbation (p-values=0.004), and hospitalization/ patient/year (p-values<0.001) were higher in the group with a history of tuberculosis among COPD patients. Finally, a dose-response relationship between FEV1/FVC (%) and the probability of developing COPD in people with previous pulmonary TB was observed; when FEV1/FVC (%) was < 80.8, the risk of COPD increased by 13.5% per unit decrease in lung function [0.865(0.805, 0.930)]. CONCLUSION: COPD patients with previous pulmonary tuberculosis have more severe airflow limitations and clinical symptoms and are at higher risk for acute exacerbations. Furthermore, lung function changes in people with a history of tuberculosis were associated with a dose-response relationship with the probability of developing COPD.

Body Composition and COPD: A New Perspective.

The proportion of obese or overweight patients in COPD patients is increasing. Although BMI, WC and other easy to measure indicators have been proven to be related to the risk of COPD, they cannot accurately reflect the distribution and changes of body composition, ignoring the body composition (such as fat distribution, muscle content, water content, etc.), the relationship between it and disease risk may be missed. By analyzing the correlation between different body composition indexes and COPD patients, we can provide new research ideas for the prognosis judgment or intervention of COPD disease.

Identification of Genes Related to Endoplasmic Reticulum Stress (ERS) in Chronic Obstructive Pulmonary Disease (COPD) and Clinical Validation.

Objective: Endoplasmic reticulum stress (ERS) is key in chronic obstructive pulmonary disease (COPD) incidence and progression. This study aims to identify potential ERS-related genes in COPD through bioinformatics analysis and clinical experiments. Methods: We first obtained a COPD-related mRNA expression dataset (GSE38974) from the Gene Expression Omnibus (GEO) database. The R software was then used to identify potential differentially expressed genes (DEGs) of COPD-related ERS (COPDERS). Subsequently, the identified DEGs were subjected to protein-protein interaction (PPI), correlation, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Following that, qRT-PCR was used to examine the RNA expression of six ERS-related DEGs in blood samples obtained from the COPD and control groups. The genes were also subjected to microRNA analysis. Finally, a correlation analysis was performed between the DEGs and key clinical indicators. Results: Six ERS-related DEGs (five upregulated and one downregulated) were identified based on samples drawn from 23 COPD patients and nine healthy individuals enrolled in the study. Enrichment analysis revealed multiple ERS-related pathways. The qRT-PCR and mRNA microarray bioinformatics analysis results showed consistent STC2, APAF1, BAX, and PTPN1 expressions in the COPD and control groups. Additionally, hsa-miR-485-5p was identified through microRNA prediction and DEG analysis. A correlation analysis between key genes and clinical indicators in COPD patients demonstrated that STC2 was positively and negatively correlated with eosinophil count (EOS) and lymphocyte count (LYM), respectively. On the other hand, PTPN1 showed a strong correlation with pulmonary function indicators. Conclusion: Four COPDERS-related key genes (STC2, APAF1, BAX, and PTPN1) were identified through bioinformatics analysis and clinical validation, and the expressions of some genes exhibited a significant correlation with the selected clinical indicators. Furthermore, hsa-miR-485-5p was identified as a potential key target in COPDERS, but its precise mechanism remains unclear.

Exploration of the Mechanism of Shengxian Decoction Against Chronic Obstructive Pulmonary Disease Based on Network Pharmacology and Experimental Verification.

Shengxian decoction (SXT) is clinically used in chronic obstructive pulmonary disease (COPD) treatment. This study aimed to explore the mechanism and target genes of SXT acting on COPD. Differentially expressed genes (DEGs) between COPD and controls were identified and then performed enrichment analysis. The effective active compounds and corresponding target genes were obtained from the traditional Chinese medicine systems pharmacology database. We also compiled COPD related genes from the GeneCards database. Through the protein-protein interaction (PPI) network and least absolute shrinkage and selection operator (LASSO) regression was performed to identify key genes. Molecular docking was used for docking of key genes and compounds. The expression of key genes was detected by quantitative real-time PCR in COPD patients and bronchial epithelial cells stimulated with cigarette stroke extract (CSE). We identified 1,458 intersected DEGs from GSE47460 and GSE57148 datasets. Compared with intersected DEGs, we obtained 33 SXT target COPD-related genes. PI3K-Akt signaling pathway, MAPK signaling pathway, and focal adhesion were enriched by these 33 genes, as well as intersected DEGs. According to LASSO regression, there were 12 genes considered as signature genes. Then we constructed active compounds and corresponding six target genes. Finally, HIF1A and IL1B were selected as key genes by combining PPI network. HIF1A and IL1B were all upregulated expression in COPD and CSE stimulated cells and recovered in SXT treated CSE stimulated cells. This study provides a scientific basis for the identification of active compounds and target genes of SXT in the treatment of COPD.

Study on the mechanism promoting oxidation of long-chain alkanes by self-produced surfactant-like substance at the solid-liquid interface.

The Fenton method to remediate oil-contaminated soils has long suffered from low utilization of ·OH, resulting in waste of costs during practical application. This study investigated the efficient utilization of ·OH in oxidation using three different soils contaminated with oil (S1, S2, and S3). The mechanisms of promoting oxidation of long-chain alkanes by self-produced surfactant-like substance at the solid-liquid interface were studied. These results (take S1 as an example) showed that the average ·OH utilization rate of oxidized long-chain alkanes (Ka) at the solid-liquid interface reached 88.34 (mg/kg∙(a.u.)), which was higher than the non-solid-liquid interface stage (I: 54.02 (mg/kg∙(a.u.)), II: 67.36 (mg/kg∙(a.u.))). Meanwhile, the average oxidation of long-chain alkanes could increase unit ·OH intensity added (Kb) in the solid-liquid interface (990.00 mg/kg), which was much higher than Kb of the non-solid-liquid interface stage (I: 228.34 mg/kg, II: -1.48 mg/kg). Furthermore, there was a significant correlation between the proportion of humic acid-like in soil organic matter and the oxidation of long-chain alkanes at the solid-liquid interface. Thus, the surfactant-like substance generated during oxidation promoted the oxidation of long-chain alkanes at the solid-liquid interface. Moreover, when the surfactant-like substance had a matching degree (φ) with the long-chain alkanes (S1 0.18, S2 0.15, and S3 0.25), the efficiency of the ·OH utilization reached the peak, and the direct oxidation of long-chain alkanes at the solid-liquid interface was finally achieved (S1: 1373.00 mg/kg, S2: 1473.18 mg/kg, and S3: 1034.37 mg/kg). The appropriate surfactant-like substance agents in the construction can reduce the dosing of H2O2 and the construction costs by improving the efficient utilization of ·OH. Study on the mechanism promoting oxidation of long-chain alkanes by self-produced surfactant-like substance at the solid-liquid interface.

Immunosuppression by Inflammation-Stimulated Amplification of Myeloid-Derived Suppressor Cells and Changes in Expression of Immune Checkpoint HHLA2 in Chronic Obstructive Pulmonary Disease.

Background: The interaction between immune checkpoint and myeloid-derived suppressor cells (MDSCs) play a significant role in inflammatory diseases. But their correlation with chronic obstructive pulmonary disease (COPD) remains unclear. Methods: The differentially expressed immune checkpoints and immunocytes in the airway tissues of COPD patients were identified by bioinformatics analysis, followed by correlation analysis and identification of immune-related differential genes for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. The results of bioinformatics analysis were verified by ELISA and Real-Time PCR and transcriptome sequencing of the peripheral blood of both COPD patients and healthy subjects. Results: The results of the bioinformatics analysis showed that the level of MDSCs in airway tissue and peripheral blood of COPD patients was higher than that of healthy controls. The expression of CSF1 in airway tissue and peripheral blood of COPD patients increased, and CYBB was increased in airway tissue and decreased in peripheral blood of COPD patients. The expression of HHLA2 in the airway tissue decreased in COPD patients, and showed a negative correlation with MDSCs, with a correlation coefficient of -0.37. The peripheral blood flow cytometry results indicated that MDSCs and Treg cells of COPD patients were higher than those in the healthy control group. The results of peripheral blood ELISA and RT-PCR showed that the HHLA2 and CSF1 levels in COPD patients were higher than those in the healthy control group. Conclusion: In COPD, the bone marrow is stimulated to produce MDSCs, and a large number of MDSCs migrate to airway tissue through peripheral blood and cooperate with HHLA2 to exert an immunosuppressive effect. Whether MDSCs play an immunosuppressive effect during migration needs to be further confirmed.

The Activation of M1 Macrophages is Associated with the JNK-m6A-p38 Axis in Chronic Obstructive Pulmonary Disease.

Background: Excessive activation of M1 macrophages affects the chronic inflammatory response of the airways and leads to the development of chronic obstructive pulmonary disease (COPD). Therefore, it needs to be closely monitored and investigated. MAPK signaling pathway is involved in the activation of M1 macrophages, and N6-methyladenosine (m6A) is involved in the pathogenesis of COPD. However, it is unknown whether activation of the MAPK signaling pathway is mediated by m6A in M1 macrophages in COPD. Methods: The GEO data were analyzed using bioinformatics techniques to assess the differences between COPD and healthy individuals in the levels of M1 macrophages, their secreted cytokines, and m6A regulators. The MAPK signaling pathway was significantly enriched in the list of differentially regulated genes between COPD and healthy individuals. We further analyzed the correlation between M1 macrophages, m6A, and the MAPK signaling pathway. Next, blood samples from COPD and healthy individuals were collected and analyzed by using flow cytometry, ELISA, and RT-PCR. Western blotting was performed using CSE-induced THP-1 cells. COPD and healthy mice were used for Me-RIP sequencing and flow cytometry experiments. Validation of the results of the above bioinformatics analysis by molecular biology experiments and sequencing techniques. Results: We found that GEO data and blood specimens from COPD patients showed increased M1 macrophages, higher levels of IL-6 and TNF-α, and higher mRNA expression of key mediators of the MAPK signaling pathway (p38, ERK, and JNK). Western blotting showed increased expression of p38, ERK, and JNK in the CSE group. In contrast, the expression of m6A regulators was low. Also, M1 macrophages in COPD mice were hyperactivated and had reduced m6A modifications of p38, ERK, and JNK compared with control. Conclusion: m6A may be involved in M1 macrophage hyperactivation by regulating the MAPK signaling pathway, thereby influencing the development of COPD.