Cigarette Smoke-induced Chronic Obstructive Pulmonary Disease Research Articles

Guggulsterone protects against cigarette smoke-induced COPD linked lung inflammation.

Recently, we have shown that guggulsterone is the principal constituent responsible for protective effects of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease (COPD)-linked inflammation/emphysema. Given that cigarette smoke (CS) exposure is a primary risk factor for COPD and beneficial effects of guggulsterone have not been investigated in CS-induced COPD-linked lung inflammation. The present work was designed to validate the potential of guggulsterone in amelioration of COPD-linked lung inflammation by using a CS-based mouse model of the condition. Male BALB/c mice were exposed to 9 cigarettes/day with 1 h interval for 4 days daily. Guggulsterone was administered daily at a dose of 10 mg/kg orally for 4 consecutive days, 1 h before initiation of CS exposure. Mice were subjected to measurement of lung function followed by procurement of bronchoalveolar lavage fluid (BALF)/lung tissue. BALF was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung tissue was subjected to RT-PCR for gene expression analysis. Data showed that CS exposure resulted in a significant increase in total BALF cells, predominantly neutrophils, and macrophages. Interestingly, guggulsterone administration significantly blunted CS-induced inflammation as reflected by reduced neutrophil and macrophage count. Further, the compound inhibited CS-induced gene expression of pro-inflammatory mediators TNF-α/ IL-1β/ G-CSF/and KC in lungs along with the production of pro-inflammatory mediators TNF-α/ IL-1β/ IL-6/ G-CSF/ KC/and MCP-1 in BALF. Further, guggulsterone improved the lung function parameters upon CS exposure. Analysis of mRNA expression of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 suggests that guggulsterone may restore the fine balance between matrix-degrading proteases and its inhibitor in lung tissue upon CS exposure, which may contribute in the development of emphysema at later stages. Overall, our data show that guggulsterone protects against CS-induced COPD-linked lung inflammation by modulating relevant molecular players. Based on the potential effects of guggulsterone in the amelioration of CS-induced lung inflammation, we speculate that guggulsterone might alter chronic CS-induced emphysema.

Analysis of network expression and immune infiltration of disulfidptosis-related genes in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a globally prevalent respiratory disease, and programmed cell death plays a pivotal role in the development of COPD. Disulfidptosis is a newly discovered type of cell death that may be associated with the progression of COPD. However, the expression and role of disulfidptosis-related genes (DRGs) in COPD remain unclear. The expression of DRGs was identified by analyzing RNA sequencing (RNA-seq) data in COPD. Further, COPD patients were classified into two subtypes by unsupervised cluster analysis to reveal their differences in gene expression and immune infiltration. Meanwhile, hub genes associated with disulfidptosis were screened by weighted gene co-expression network analysis. Subsequently, the hub genes were validated experimentally in cells and animals. In addition, we screened potential therapeutic drugs through the hub genes. We identified two distinct molecular clusters and observed significant differences in immune cell populations between them. In addition, we screened nine hub genes, and experimental validation showed that CDC71, DOHH, PDAP1, and SLC25A39 were significantly upregulated in cigarette smoke-induced COPD mouse lung tissues and bronchial epithelial cells (BEAS-2B) treated with cigarette smoke extract. Finally, we predicted 10 potential small molecule drugs such as Atovaquone, Taurocholic acid, Latamoxef, and Methotrexate. We highlighted the strong association between COPD and disulfidptosis, with DRGs demonstrating a discriminative capacity for COPD. Additionally, the expression of certain novel genes, including CDC71, DOHH, PDAP1, and SLC25A39, is linked to COPD and may aid in the diagnosis and assessment of this condition.

Rutaecarpine Protects Against Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease (COPD) in Rats.

Chronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease that causes restricted airflow and breathing difficulties.In this work, we attempted to explore the salutary effects of rutaecarpine on COPD-induced rats. Healthy Wistar rats were employed in this study and exposed to cigarette smoke to initiate COPD. The rutaecarpine was given to the rats at 20 and 30mg/kg dosages, respectively, for 12 weeks. Body weight gain, food uptake, and food efficiency were assessed after treatment completion. The grip strength test was performed to assess muscle strength. The C-reactive protein (CRP), leptin, inflammatory cytokines, and oxidative stress markers were assessed using the corresponding assay kits. The inflammatory cells on the bronchoalveolar lavage fluid (BALF) were counted using Wright-Giemsa staining. The respiratory functions of the experimental rats were measured. The histopathological analysis was done on the lung tissues.The rutaecarpine treatment effectively increased body weight gain, food uptake, and food efficiency in the COPD rats. The levels of leptin were increased, and CRP was reduced by the rutaecarpine. The rutaecarpine regulated the respiratory functions and reduced the inflammatory cell counts and pro-inflammatory markers in the COPD rats. The levels of antioxidants were increased by the rutaecarpine treatment in the COPD rats. The findings of the lung histopathological study also demonstrated the therapeutic effects of rutaecarpine.Overall, the findings of the current study witness the salutary role of rutaecarpine against cigarette smoke-induced COPD in rats. Therefore, it was clear that rutaecarpine could be a promising salutary candidate to treat COPD.

HDAC9 inhibition reduces skeletal muscle atrophy and enhances regeneration in mice with cigarette smoke-induced COPD

Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However, the pathogenesis of CS-related deficient skeletal muscle regeneration has yet to be clarified. The impact of CS on myoblast differentiation was examined, and then we determined which HDAC influenced the myogenic process and muscle atrophy in vitro and in vivo. Finally, we further investigated the potential mechanisms via RNA sequencing. Long-term CS exposure activated skeletal muscle primary SCs while inhibiting differentiation, and defective myogenesis was also observed in C2C12 cells treated with CS extract (CSE). The level of HDAC9 changed in vitro and in vivo in CS exposure models as well as COPD patients, as detected by bioinformatics analysis. Our data showed that CSE impaired myogenic capacity and myotube formation in C2C12 cells via HDAC9. Moreover, inhibition of HDAC9 in mice exposed to CS prevented skeletal muscle dysfunction and promoted SC differentiation. The results of RNA-Seq analysis and verification indicated that HDAC9 knockout improved muscle differentiation in CS-exposed mice, probably by acting on the AKT/mTOR pathway and inhibiting the P53/P21 pathway. More importantly, the serum of HDAC9 KO mice exposed to CS alleviated the differentiation impairment of C2C12 cells caused by serum intervention in CS-exposed mice, and this effect was inhibited by LY294002 (an AKT/mTOR pathway inhibitor). These results suggest that HDAC9 plays an essential role in the defective regeneration induced by chronic exposure to CS.

Formononetin attenuates cigarette smoke-induced COPD in mice by suppressing inflammation, endoplasmic reticulum stress, and apoptosis in bronchial epithelial cells via AhR/CYP1A1 and AKT/mTOR signaling pathways.

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive, and lethal lung disease with few treatments. Formononetin (FMN) is a clinical preparation extract with extensive pharmacological actions. However, its effect on COPD remains unknown. This study aimed to explore the effect and underlying mechanisms of FMN on COPD. A mouse model of COPD was established by exposure to cigarette smoke (CS) for 24 weeks. In addition, bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) for 24 h to explore the in vitro effect of FMN. FMN significantly improved lung function and attenuated pathological lung damage. FMN treatment reduced inflammatory cell infiltration and pro-inflammatory cytokines secretion. FMN also suppressed apoptosis by regulating apoptosis-associated proteins. Moreover, FMN relieved CS-induced endoplasmic reticulum (ER) stress in the mouse lungs. In BEAS-2B cells, FMN treatment reduced CSE-induced inflammation, ER stress, and apoptosis. Mechanistically, FMN downregulated the CS-activated AhR/CYP1A1 and AKT/mTOR signaling pathways in vivo and in vitro. FMN can attenuate CS-induced COPD in mice by suppressing inflammation, ER stress, and apoptosis in bronchial epithelial cells via the inhibition of AhR/CYP1A1 and AKT/mTOR signaling pathways, suggesting a new therapeutic potential for COPD treatment.

Vardenafil alleviates cigarette smoke-induced chronic obstructive pulmonary disease by activating autophagy via the AMPK/mTOR signalling pathway: an in vitro and in vivo study.

Chronic obstructive pulmonary disease (COPD) has always attracted global attention with its high prevalence, incidence rate, and mortality. Exposure to cigarette smoke is one of main causes of COPD. Therefore, it is still necessary to study its pathogenesis and find new therapeutic strategies for early COPD prevention and treatment. Vardenafil, a type 5 phosphodiesterase (PDE5) inhibitor, is known to have an efficient therapy in some cardiovascular, pulmonary, and vascular diseases, which is an important mechanism for COPD. However, it still loss relevant research on whether vardenafil is effective in COPD and its mechanism. In this study, the cigarette smoke inhalation was performed to establish cigarette smoke-induced COPD model using C57BL/6 mice and 16HBE cells were treated with cigarette smoke extract (CSE). Mice were treated with vardenafil for 30 d. Then condition of lung injury was evaluated using histological analysis. The content of cytokines and the number of inflammatory cells in lung tissues or bronchoalveolar lavage fluid were measured. Additionally, western blot analysis was employed to evaluate the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)-mediated autophagy in vitro. The results showed that vardenafil abolished CSE's effect by activating autophagy via the AMPK/mTOR signalling pathway in vitro. Vardenafil attenuated cigarette smoke-induced lung injury and inflammation response by activating autophagy via the AMPK/mTOR signalling pathway in vivo. These results provide valuable insights into the molecular mechanisms underlying vardenafil's beneficial effects in cigarette smoke-induced COPD treatment. In conclusion, vardenafil alleviates cigarette smoke-induced experimental COPD by activating autophagy via the AMPK/mTOR signalling pathway.

Paclobutrazol ameliorates cigarette smoke-induced chronic obstructive pulmonary disease (COPD) in experimental rats

BackgroundThe cigarette smoking epidemic is one of the desperate threats experienced all over the world. Cigarettes cause diseases such as chronic obstructive pulmonary disease (COPD), asthma, lung cancer, stroke, heart diseases, etc. Paclobutrazol is a growth regulator hormone that increases antioxidant enzymes, mineral absorption, carbohydrate synthesis, and flowering and fruit production in plants. ObjectiveIn the current study, we assessed the ameliorative effect of paclobutrazol against chronic cigarette smoke-induced COPD in rats. MethodologyA side-stream cigarette exposure rat model was used for the study, which is a well-accepted model to evaluate cigarette smoke-induced lung damage. The paclobutrazol treatment was given for 12 weeks, and since the reduction in body weight is the primary symptom of COPD, the food efficiency and the weight gain were measured. Muscular strength was analyzed with a grip strength test, and respiratory functions were assessed with a whole-body plethysmograph. Plasma leptin was measured to detect the fat mass index. C-reactive protein was quantified to assess the level of inflammation. Further bronchoaleveolar fluid was collected and analyzed for the total white blood cell count, neutrophils, lymphocytes, and monocytes to evaluate the inflammation. In order to confirm the anti-inflammatory property of paclobutrazol against cigarette smoke-induced lung inflammation, histopathological analysis of lung tissue was done. ResultsThe paclobutrazol treatment increased the body weight, improved respiratory functions, and decreased inflammation in the rats exposed to secondhand cigarette smoke. Our results of histopathological analysis confirm that paclobutrazol has effectively inhibited cigarette smoke-induced lung tissue damage in young Wistrar rats. ConclusionHence, it can be used as a supplementary drug to protect smokers from cigarette smoke-induced lung damage.

Effects of microRNA-21 on endothelial-to-mesenchymal transition and its role in the pathogenesis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airflow restriction. This study aims to explore whether there is endothelial-to-mesenchymal transition (EndMT) in COPD mice and to explore the relationship between microRNA-21 (miR-21) and EndMT. We established the COPD and the miR-21 gene knockout COPD animal model (both cigarette smoke-induced). Mice were divided into 3 groups (n=4): a control group, a COPD group, and a miR-21 knockout COPD (miR-21-/--COPD) group. Masson trichrome staining was used to observe the deposition of collagen around the perivascular. The relative protein levels and positions of endothelial cell markers including vascular endothelial-cadherin (VE-cadherin), endothelial nitric oxide synthase (eNOS), and platelet endothelial cell adhesion molecule-1 (CD31) as well as mesenchymal cell markers including α-smooth muscle actin (α-SMA) and neural cadherin (N-cadherin) in lung tissues were observed by immunohistochemical staining. Compared with the control group, the area of collagen fibril deposition was increased in the COPD group (P<0.05), the expression levels of VE-cadherin, eNOS, and CD31 were all decreased (all P<0.05), and the expression levels of α-SMA and N-cadherin were increased (both P<0.05). Compared with the COPD group, the miR-21-/--COPD group had a reduced area of collagen fiber deposition (P<0.05), the expression levels of VE-cadherin, eNOS, and CD31 were all increased (all P<0.05), and the expression levels of α-SMA and N-cadherin were decreased (both P<0.05). There is a EndMT process in cigarette smoke-induced COPD animal models.MiR-21 gene knockdown could reduce collagen deposition area and inhibit the EndMT process in COPD mice.

Knockdown of circ_0006872 alleviates CSE-induced human bronchial epithelial cells injury in chronic obstructive pulmonary disease

Circular RNAs (circRNAs) have been reported to be related to the initiation and progression of chronic obstructive pulmonary disease (COPD) by affecting the function of human bronchial epithelial cells (HBECs). Here, we aimed to investigate the function and mechanism of circ_0006872 in regulating COPD process using cigarette smoke extract (CSE)-induced 16HBEC in vitro. The results showed that circ_0006872 was increased in smokers without or with COPD, especially in smokers with COPD. Also, its expression was dose-dependently up-regulated by CSE exposure in 16HBECs. Functionally, circ_0006872 knockdown dramatically attenuated CSE-evoked proliferation arrest, apoptosis, inflammatory response and oxidative stress in 16HBECs. Mechanistically, circ_0006872/miR-485-3p/cyclin-dependent kinase inhibitor 1B (CDKN1B) formed a competitive endogenous RNA (ceRNA) network. CDKN1B was increased and miR-485-3p was decreased in COPD patients and CSE-induced 16HBECs. MiR-485-3p overexpression or CDKN1B knockdown protected 16HBEC against CSE-induced 16HBEC injury mentioned above. Moreover, rescue experiments showed that circ_0006872 regulated CSE-induced 16HBEC injury via miR-485-3p/CDKN1B axis. Circ_0006872 silencing protected against CSE-induced bronchial epithelial cell injury via miR-485-3p/CDKN1B axis, suggesting the potential application of circ_0006872 in preventing cigarette smoke-induced COPD.

Associative analysis of multi-omics data indicates that acetylation modification is widely involved in cigarette smoke-induced chronic obstructive pulmonary disease.

We aimed to study the molecular mechanisms of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke more comprehensively and systematically through different perspectives and aspects and to explore the role of protein acetylation modification in COPD. We established the COPD model by exposing C57BL/6J mice to cigarette smoke for 24 weeks, then analyzed the transcriptomics, proteomics, and acetylomics data of mouse lung tissue by RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), and associated these omics data through unique algorithms. This study demonstrated that the differentially expressed proteins and acetylation modification in the lung tissue of COPD mice were co-enriched in pathways such as oxidative phosphorylation (OXPHOS) and fatty acid degradation. A total of 19 genes, namely, ENO3, PFKM, ALDOA, ACTN2, FGG, MYH1, MYH3, MYH8, MYL1, MYLPF, TTN, ACTA1, ATP2A1, CKM, CORO1A, EEF1A2, AKR1B8, MB, and STAT1, were significantly and differentially expressed at all the three levels of transcription, protein, and acetylation modification simultaneously. Then, we assessed the distribution and expression in different cell subpopulations of these 19 genes in the lung tissues of patients with COPD by analyzing data from single-cell RNA sequencing (scRNA-seq). Finally, we carried out the in vivo experimental verification using mouse lung tissue through quantitative real-time PCR (qRT-PCR), Western blotting (WB), immunofluorescence (IF), and immunoprecipitation (IP). The results showed that the differential acetylation modifications of mouse lung tissue are widely involved in cigarette smoke-induced COPD. ALDOA is significantly downregulated and hyperacetylated in the lung tissues of humans and mice with COPD, which might be a potential biomarker for the diagnosis and/or treatment of COPD.

Mechanisms of Lung Damage and Development of COPD Due to Household Biomass-Smoke Exposure: Inflammation, Oxidative Stress, MicroRNAs, and Gene Polymorphisms

Chronic exposure to indoor biomass smoke from the combustion of solid organic fuels is a major cause of disease burden worldwide. Almost 3 billion people use solid fuels such as wood, charcoal, and crop residues for indoor cooking and heating, accounting for approximately 50% of all households and 90% of rural households globally. Biomass smoke contains many hazardous pollutants, resulting in household air pollution (HAP) exposure that often exceeds international standards. Long-term biomass-smoke exposure is associated with Chronic Obstructive Pulmonary Disease (COPD) in adults, a leading cause of morbidity and mortality worldwide, chronic bronchitis, and other lung conditions. Biomass smoke-associated COPD differs from the best-known cigarette smoke-induced COPD in several aspects, such as a slower decline in lung function, greater airway involvement, and less emphysema, which suggests a different phenotype and pathophysiology. Despite the high burden of biomass-associated COPD, the molecular, genetic, and epigenetic mechanisms underlying its pathogenesis are poorly understood. This review describes the pathogenic mechanisms potentially involved in lung damage, the development of COPD associated with wood-derived smoke exposure, and the influence of genetic and epigenetic factors on the development of this disease.

Identification and validation of genetic signature associated with aging in chronic obstructive pulmonary disease.

Aging plays an essential role in the development for chronic obstructive pulmonary disease (COPD). The aim of this study was to identify and validate the potential aging-related genes of COPD through bioinformatics analysis and experimental validation. Firstly, we compared the gene expression profiles of aged and young COPD patients using two datasets (GSE76925 and GSE47460) from Gene Expression Omnibus (GEO), and identified 244 aging-related different expressed genes (DEGs), with 132 up-regulated and 112 down-regulated. Then, by analyzing the data for cigarette smoke-induced COPD mouse model (GSE125521), a total of 783 DEGs were identified between aged and young COPD mice, with 402 genes increased and 381 genes decreased. Additionally, functional enrichment analysis revealed that these DEGs were actively involved in COPD-related biological processes and function pathways. Meanwhile, six genes were identified as the core aging-related genes in COPD after combining the human DEGs and mouse DEGs. Eventually, five out of six core genes were validated to be up-regulated in the lung tissues collected from aged COPD patients than young COPD patients, namely NKG7, CKLF, LRP4, GDPD3 and CXCL9. Thereinto, the expressions of NKG7 and CKLF were negatively associated with lung function. These results may expand the understanding for aging in COPD.

Tanshinone increases Hemopexin expression in lung cells and macrophages to protect against cigarette smoke-induced COPD and enhance antiviral responses

ABSTRACT Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease, while respiratory infections can elicit exacerbations in COPD patients to mediate increased mortality. Administration of Tanshinones (TS) derivatives has been demonstrated to protect against cigarette smoking (CS) and lipopolysaccharide (LPS)-induced COPD progression. However, the underlying molecular mechanisms and the roles of TS in mitigating the severity of viral-mediated exacerbations of COPD have not been elucidated. Here, we found that TS treatments significantly attenuated lung function decline, inflammatory responses and oxidative stress in CS and LPS-induced COPD mice. Subsequent RNA-seq analysis revealed significantly upregulated Hemopexin expression and enriched interferons (IFNs) signaling pathways in lung tissues of COPD mice upon TS treatments. Moreover, TS administration demonstrated Hemopexin-dependent beneficial roles in BEAS-2B lung cells and RAW264.7 macrophages, which was associated with the suppression of oxidative stress and ERK, NF-κB, and NLRP3 inflammasome signaling pathways-mediated inflammation. Furthermore, TS promoted IFN signaling and rescued impaired antiviral responses in CS and LPS-exposed lung cells that were infected by influenza virus. Notably, hemopexin over-expression in lung cells and macrophages recapitulated the pharmacological activities of TS. Taken together, these results indicate that TS administration is a promising and potential therapeutic strategy for treating COPD and preventing COPD exacerbations.

Antiviral Responses of Tissue-resident CD49a+ Lung Natural Killer Cells Are Dysregulated in Chronic Obstructive Pulmonary Disease.

Rationale: Tissue-resident natural killer (trNK) cells have been identified in numerous organs, but little is known about their functional contribution to respiratory immunity, in particular during chronic lung diseases such as chronic obstructive pulmonary disease (COPD). Objectives: To investigate the phenotype and antiviral responses of trNK cells in murine cigarette smoke-induced experimental COPD and in human lung parenchyma from COPD donors. Methods: Mice were exposed to cigarette smoke for 12 weeks to induce COPD-like lung disease. Lung trNK cell phenotypes and function were analyzed by flow cytometry in both murine and human disease with and without challenge with influenza A virus. Measurements and Main Results: In the mouse lung, CD49a+CD49b+EOMES+ and CD49a+CD49b-EOMESlo NK cell populations had a distinct phenotype compared with CD49a- circulating NK cells. CD49a+ NK cells were more extensively altered earlier in disease onset than circulating NK cells, and increased proportions of CD49a+ NK cells correlated with worsening disease in both murine and human COPD. Furthermore, the presence of lung disease delayed both circulating and trNK cell functional responses to influenza infection. CD49a+ NK cells markedly increased their NKG2D, CD103, and CD69 expression in experimental COPD after influenza infection, and human CD49a+ NK cells were hyperactive to ex vivo influenza infection in COPD donors. Conclusions: Collectively, these results demonstrate that trNK cell function is altered in cigarette smoke-induced disease and suggests that smoke exposure may aberrantly prime trNK cell responsiveness to viral infection. This may contribute to excess inflammation during viral exacerbations of COPD.

Immunomodulatory effect of N-acetyl-seryl-aspartyl-proline and vasoactive intestinal peptide on chronic obstructive pulmonary disease pathophysiology.

Chronic obstructive pulmonary disease (COPD) as an inflammatory respiratory system disease is caused by exposure to cigarette smoke and tobacco in long-term. Some anti-inflammatory peptides can control inflammation in COPD. N-acetyl-seryl-aspartyl-proline (Ac-SDKP) and vasoactive intestinal peptide (VIP) as peptide have anti-inflammatory effect, and, in this study, the effect of Ac-SDKP and VIP on COPD inflammation was studied. After producing cigarette smoke-induced COPD mice model, which were treated with VIP and Ac-SDKP, the levels of antioxidant-related factors (malondialdehyde (MDA) and superoxide dismutase (SOD)), fibrotic factors (hydroxyproline (HP) and TGF-β), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and inflammation in histopathological examination were studied. MDA, Remodeling factors, pro-inflammatory cytokines, and inflammation in lung tissue were controlled by VIP and Ac-SDKP treatment. These treatments could enhance SOD. VIP and Ac-SDKP as immuno-regulatory factors had benefit effect in treatment of COPD. The anti-inflammatory, anti-fibrosis, and anti-oxidant properties of VIP and Ac-SDKP may be effective therapy in COPD.

ROS-Responsive miR-150-5p Downregulation Contributes to Cigarette Smoke-Induced COPD via Targeting IRE1α.

MicroRNAs (miRNAs) have been reported in human diseases, in which chronic obstructive pulmonary disease (COPD) is included. Herein, we assessed the role along with the possible mechanisms of miR-150-5p in cigarette smoke- (CS-) induced COPD. The plasma miR-150-5p expression was lower in patients with COPD and acute exacerbation of COPD (AECOPD) and was related to disease diagnosis, disease severity, and lung function. Consistently, exposure to CS for 3 months or 3 days reduced miR-150-5p in the plasma and lung tissues of mice, and CS extract (CSE) inhibited miR-150-5p in human bronchial epithelial cells (HBECs) in a concentration along with time-dependent approach. In vitro, miR-150-5p overexpression decreased the contents of inflammatory factors interleukin- (IL-) 6, IL-8 along with cyclooxygenase-2 (COX-2), and endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) and promoted cell migrate. Mechanistically, miR-150-5p could bind with the 3′-untranslated region (UTR) of inositol requiring enzyme 1α (IRE1α), while IRE1α overexpression obliterated the impacts of miR-150-5p. Besides, N-acetyl-cysteine (NAC) reversed CSE-induced miR-150-5p downregulation and its downstream effects. In vivo, miR-150-5p overexpression counteracted CS-triggered IRE1α upregulation, inflammation, and ER stress in the lung tissues of mice. In conclusion, our findings illustrated that ROS-mediated downregulation of miR-150-5p led to CS-induced COPD by inhibiting IRE1α expression, suggesting to serve as a useful biomarker for diagnosing and treating COPD.

Protective effect of total Saponins from American ginseng against cigarette smoke-induced COPD in mice based on integrated metabolomics and network pharmacology

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease. Aiming at assessing the effect of total saponins from American ginseng on COPD, both the chemical composition and anti-COPD activity of total saponins from wild-simulated American ginseng (TSW) and field-grown American ginseng (TSF) were investigated in this study. Firstly, a HPLC-ELSD chromatographic method was established to simultaneously determine the contents of 22 saponins in TSW and TSF. Secondly, CS-induced COPD mouse model was established to evaluate the activity of TSW and TSF. The results indicated that both TSW and TSF had the protective effect against COPD by alleviating oxidative stress and inflammatory response. TSW showed a stronger effect than TSF. Thirdly, an integrated approach involving metabolomics and network pharmacology was used to construct the "biomarker-reaction-enzyme-target" correlation network aiming at further exploring the observed effects. As the results, 15 biomarkers, 9 targets and 5 pathways were identified to play vital roles in the treatment of TSW and TSF on COPD. Fourthly, based on network pharmacology and the CS-stimulated A549 cell model, ginsenoside Rgl, Rc, oleanolic acid, notoginsenoside R1, Fe, silphioside B were certified to be the material basis for the stronger effect of TSW than TSF. Finally, the molecular docking were performed to visualize the binding modes. Our findings suggested that both TSW and TSF could effectively ameliorate the progression of COPD and might be used for the treatment of COPD.

Seven ferroptosis-specific expressed genes are considered as potential biomarkers for the diagnosis and treatment of cigarette smoke-induced chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by incomplete reversible airway obstruction, with high mortality and disability rates, and smoking is the primary risk factor for COPD. Studies performed to date have confirmed that iron and ferroptosis play crucial roles in the development of cigarette smoke-induced COPD, but the exact mechanisms have not been fully elucidated.MethodsThe microarray datasets GSE10006, GSE11784, and GSE20257 were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between COPD smokers and non-smokers airway epithelial. Protein-protein interaction (PPI) and hub gene networks were constructed using the STRING database and Cytoscape software. At the same time, the 3 datasets were screened for ferroptosis-related genes that were co-differentially expressed. The ferroptosis-related hub genes (FRHGs) that overlapped with the ferroptosis-related genes and hub genes were then identified. Next, the mRNA-miRNA network was constructed, and Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for target genes were performed. Finally, GSE19407, GSE994, and GSE27973 were used to evaluate the expression of hub genes.ResultsWe identified 7 potential FRHGs (NQO1, AKR1C3, AKR1C1, GPX2, TXNRD1, SRXN1, SLC7A11), which showed good diagnostic properties. The molecular functions (MFs) of FRHGs mainly influence biological processes (BPs) responding to oxidative stress. Nrf2 pathways may be the key pathways regulating ferroptosis in cigarette smoke-induced COPD. Meanwhile, co-expressed mRNAs and miRNAs were selected to construct mRNA-miRNA interaction networks. Furthermore, based on the 7 FRHGs mentioned above, we found that benzoic acid showed high drug targeting relevance.ConclusionsThis work identified 7 FRHGs as potential biomarkers for the diagnosis and treatment of COPD and provided insights into the mechanisms of disease development in cigarette smoke-induced COPD at the transcriptome level.

Prediction and enrichment analyses of the Homo sapiens-Drosophila melanogaster COPD-related orthologs: potential for modeling of human COPD genomic responses with the fruit fly.

The significant similarities in airway epithelial cells between mammals and the fruit fly Drosophila melanogaster have rendered the latter an important model organism for studies of chronic inflammatory lung diseases. Focusing on the chronic obstructive pulmonary disease (COPD), we here mapped human gene orthologs associated with this disease in D. melanogaster to identify functionally equivalent genes for immediate, further screening with the fruit fly model. The DIOPT-DIST tool was accessed for the prediction of the COPD-associated orthologs between humans and Drosophila. Enrichment analyses with respect to pathways of the retrieved functional homologs were performed using the ToppFun and FlyMine tools, identifying 73 unique human genes as well as 438 fruit fly genes. The ToppFun analysis verified that the human gene list is associated with COPD phenotypes. Furthermore, the FlyMine investigation highlighted that the Drosophila genes are functionally connected mainly with the "ABC-family proteins mediated transport" and the "β-catenin-independent WNT signaling pathway." These results suggest an evolutionarily conserved role toward responses to inhaled toxicants and CO2 in both species. We reason that the predicted orthologous genes should be further studied in the Drosophila models of cigarette smoke-induced COPD.

Time-resolved proteomic profiling of cigarette smoke-induced experimental chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. We employed quantitative label-based proteomics to map the changes in the lung tissue proteome of cigarette smoke-induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4- and 6-week time points, compared to age-matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy samples. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA-binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.