Smoke-induced Chronic Obstructive Pulmonary Disease Research Articles

Progesterone (P4) ameliorates cigarette smoke-induced chronic obstructive pulmonary disease (COPD)

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with high morbidity and mortality worldwide. Oxidative injury and mitochondrial dysfunction in the airway epithelium are major events in COPD progression.Methods and resultsThe therapeutic effects of Progesterone (P4) were investigated in vivo and in vitro in this study. In vivo, in a cigarette smoke (CS) exposure-induced COPD mouse model, P4 treatment significantly ameliorated CS exposure-induced physiological and pathological characteristics, including inflammatory cell infiltration and oxidative injury, in a dose-dependent manner. The c-MYC/SIRT1/PGC-1α pathway is involved in the protective function of P4 against CS-induced COPD. In vitro, P4 co-treatment significantly ameliorated H2O2-induced oxidative injury and mitochondrial dysfunctions by promoting cell proliferation, increasing mitochondrial membrane potential, decreasing ROS levels and apoptosis, and increasing ATP content. Moreover, P4 co-treatment partially attenuated H2O2-caused inhibition in Nrf1, Tfam, Mfn1, PGR-B, c-MYC, SIRT1, and PGC-1α levels. In BEAS-2B and ASM cells, the c-MYC/SIRT1 axis regulated P4’s protective effects against H2O2-induced oxidative injury and mitochondrial dysfunctions.ConclusionP4 activates the c-MYC/SIRT1 axis, ameliorating CS-induced COPD and protecting both airway epithelial cells and smooth muscle cells against H2O2-induced oxidative damage. PGC-1α and downstream mitochondrial signaling pathways might be involved.

Protective Effect of the Total Alkaloid Extract from Bulbus Fritillariae pallidiflorae in a Mouse Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.

In recent years, the incidence of chronic obstructive pulmonary disease (COPD) has been increasing year by year, but therapeutic drugs has no breakthrough. The total alkaloid extract from Bulbus Fritillariae pallidiflorae (BFP-TA) is widely used in treating lung diseases. Therefore, this study aimed to investigate the protective effect and mechanism of BFP-TA in COPD mice. BFP-TA was prepared by macroporous adsorbent resin, and the material basis of BFP-TA was analyzed by HPLC-ELSD and UHPLC-MS/MS. Then, the COPD mouse model was induced by cigarette smoke (CS) for 12 weeks, administered at weeks 9-12. Subsequently, the body weight, lung-body ratio, pulmonary function, histopathology, and the levels of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and oxidative stress markers in the serum of mice were determined. The expressions of related protein of EMT and MAPK signaling pathways in the lung tissues of mice were detected by Western blot. The alkaloid relative content of BFP-TA is 64.28%, and nine alkaloids in BFP-TA were identified and quantified by UHPLC-MS/MS. Subsequently, the animal experiment showed that BFP-TA could improve pulmonary function, and alleviate inflammatory cell infiltration, pulmonary emphysema, and collagen fiber deposition in the lung of COPD mice. Furthermore, BFP-TA could decrease the levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), MMPs (MMP-9 and MMP-12) and MDA, while increase the levels of TIMP-1 and SOD. Moreover, BFP-TA could decrease the protein expressions of collagen I, vimentin, α-SMA, MMP-9, MMP-9/TIMP-1, Bax, p-JNK/JNK, p-P38/P38, and p-ERK/ERK, while increase the level of E-cadherin. This study is the first to demonstrate the protective effect of BFP-TA in CS-induced COPD mouse model. Furthermore, BFP-TA may improve airway remodeling by inhibiting the EMT process and potentially exert anti-inflammatory effect by inhibiting the MAPK signaling pathway.

NADH Intraperitoneal Injection Prevents Lung Inflammation in a BALB/C Mice Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.

Cigarette smoke is one of the main factors in Chronic Obstructive Pulmonary Disease (COPD), a respiratory syndrome marked by persistent respiratory symptoms and increasing airway obstruction. Perturbed NAD+/NADH levels may play a role in various diseases, including lung disorders like COPD. In our study, we investigated the preventive effect of NADH supplementation in an experimental model of COPD induced by cigarette smoke extract (CSE). N = 64 mice randomly distributed in eight groups were injected with NADH (two doses of 100 mg/kg or 200 mg/kg) or dexamethasone (2 mg/kg) before being exposed to CSE for up to 9 weeks. Additionally, NADH supplementation preserved lung antioxidant defenses by preventing the functional loss of key enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase, and the expression levels of glutathione (GSH) (n = 4, p < 0.001). It also reduced oxidative damage markers, such as malondialdehyde (MDA) and nitrites (n = 4, p < 0.001). A marked increase in tissue myeloperoxidase activity was assessed (MPO), confirming neutrophils implication in the inflammatory process. The latter was significantly ameliorated in the NADH-treated groups (p < 0.001). Finally, NADH prevented the CSE-induced secretion of cytokines such as Tumor Necrosis Factor alpha (TNF-α), IL-17, and IFN-y (n = 4, p < 0.001). Our study shows, for the first time, the clinical potential of NADH supplementation in preventing key features of COPD via its unique anti-inflammatory and antioxidant properties.

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.

SRAGE levels are decreased in plasma and sputum of COPD secondary to biomass-burning smoke and tobacco smoking: Differences according to the rs3134940 AGER variant

The receptor for advanced glycation end products (RAGE) and its gene (AGER) have been related to lung injury and inflammatory diseases, including chronic obstructive pulmonary disease (COPD). We aimed to evaluate the association of rs2071288, rs3134940, rs184003, and rs2070600 AGER single-nucleotide variants and the soluble-RAGE plasma and sputum levels with COPD secondary to biomass-burning smoke (BBS) and tobacco smoking. Four groups, including 2189 subjects, were analyzed: COPD secondary to BBS exposure (COPD-BBS, n = 342), BBS-exposed subjects without COPD (BBES, n = 774), tobacco smoking-induced COPD (COPD-TS, n = 434), and smokers without COPD (SWOC, n = 639). Allelic discrimination assays determined the AGER variants. The sRAGE was quantified in plasma (n = 240) and induced-sputum (n = 72) samples from a subgroup of patients using the ELISA technique. In addition, a meta-analysis was performed for the association of rs2070600 with COPD susceptibility. None of the studied genetic variants were found to be associated with COPD-BBS or COPD-TS. A marginal association was observed for the rs3134940 with COPD-BBS (p = 0.066). The results from the meta-analysis, including six case-control studies (n = 4149 subjects), showed a lack of association of rs2070600 with COPD susceptibility (p = 0.681), probably due to interethnic differences. The sRAGE plasma levels were lower in COPD-BBS compared to BBS and in COPD-TS compared to SWOC. The sRAGE levels were also lower in sputum samples from COPD-BBS than BBES. Subjects with rs3134940-TC genotypes exhibit lower sRAGE plasma levels than TT subjects, mainly from the COPD-BBS and SWOC groups. The AGER variants were not associated with COPD-BBS nor COPD-TS, but the sRAGE plasma and sputum levels are related to both COPD-BBS and COPD-TS and are influenced by the rs3134940 variant.

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.

Chemical profiling and mechanisms of Agarikon pill in a rat model of cigarette smoke-induced chronic obstructive pulmonary disease

Background and aimAgarikon pill (AGKP), a traditional Chinese herbal formula, and has been used for chronic obstructive pulmonary disease (COPD) treatment clinically. However, the active components and exact pharmacological mechanisms are still unclear. We aimed to investigate the therapeutic effects and mechanisms of AGKP on COPD and identify the chemical constituents and active compounds. Experimental procedureThe chemical components of AGKP were identified by ultrahigh-performance liquid chromatography coupled with quadrupole/orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS). Network pharmacology analysis was performed to uncover the potential mechanism of AGKP. The efficiencies and mechanisms of AGKP were further confirmed in COPD animal models. Results and conclusionNinety compounds from AGKP, such as flavonoids, triterpenoids, saponins, anthracenes, derivatives, phenyl propionic acid, and other organic acids, were identified in our study. AGKP improved lung function and pathological changes in COPD model rats. Additionally, inflammatory cell infiltration and proinflammatory cytokine levels were markedly reduced in COPD rats administered AGKP. Network pharmacology analysis showed that the inflammatory response is the crucial mechanism by which AGKP exerts therapeutic effects on COPD rats. WB and PCR data indicated that AGKP attenuated the inflammatory response in COPD model rats. AGKP reduces the pulmonary inflammatory response through the PI3K/AKT and MAPK TLR/NF-κB signaling pathways and exerts therapeutic effects via inhibition of inflammation and mucus hypersecretion on COPD model rats.

MicroRNA-377-3p exacerbates chronic obstructive pulmonary disease through suppressing ZFP36L1 expression and inducing lung fibroblast senescence

Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing is recognized as an early and significant factor for COPD development. Senescent fibroblasts were observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition and senescence-associated secretory phenotype (SASP). On the basis of our previous study, we further investigated the the causes for the increased levels of miR-377-3p in the blood of COPD patients, as well as its regulatory function in the pathological progression of COPD. We found that the majority of up-regulated miR-377-3p was localized in lung fibroblasts. Inhibition of miR-377-3p improved chronic smoking-induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibroblasts, while knockdown of miR-377-3p attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for miR-377-3p that likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that miR-377-3p is crucial for COPD pathogenesis, and may serve as a potential target for COPD therapy.

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.

Protection against cigarette smoke-induced chronic obstructive pulmonary disease via activation of the SIRT1/FoxO1 axis by targeting microRNA-132.

To investigate the biological role of miR-132 in a murine model of chronic obstructive pulmonary disease (COPD) via activation of the SIRT1/FoxO1 axis. COPD was induced in C57BL/6J male mice by exposing them to cigarette smoke (CS) for 8 weeks. A miR-132 knockout mouse model was used to assess the role of miR-132 in CS-induced COPD. Lung tissue apoptosis was evaluated using TUNEL assays and histopathology, along with lung functional tests which were performed to assess CS-induced lung injury. Elevated miR-132 expression was observed in lung tissues and bronchoalveolar lavage fluid in COPD mice. miR-132 depletion improved lung function, restored lung tissue morphology, and reduced apoptosis. Target prediction software identified miR-132 as a potential repressor of SIRT1. In COPD mice, SIRT1 and FoxO1 expression were reduced, but miR-132 knockout restored their levels. Inhibition of miR-132 may serve as a therapeutic strategy for CS-induced COPD.

Effects of advanced nanomaterials on the respiratory system of a murine COPD model

This study assessed the effects of cellulose nanofibrils (CNFs) and multi-walled carbon nanotubes (MWCNTs) on lung inflammation in a cigarette smoke-induced chronic obstructive pulmonary disease (COPD) mouse model. Prior to instillation, COPD model mice displayed distinctive cellular compositions and elevated cytokine levels in bronchoalveolar lavage fluid (BALF). After intratracheal instillation of 80 μg CNFs, no significant histopathological changes, BALF composition alterations, or cytokine level shifts were observed on day 28. This suggests minimal lung impact and no interference with reducing smoke-induced inflammation. In contrast, the instillation of 80 μg MWCNTs resulted in significant histopathological changes, increased cellular composition, and elevated cytokine levels in BALF on day 28. These findings indicate that CNF exposure had little effect on the lungs and did not impede the reduction of smoke-induced inflammation, while MWCNT exposure hindered the attenuation of pulmonary inflammatory response. The study emphasizes the importance of considering diverse cases, including individuals with pre-existing respiratory conditions, when assessing occupational safety and health risks associated with advanced nanomaterial exposure.

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.

Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.

New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung.

Cryptotanshinone alleviates lipopolysaccharide and cigarette smoke-induced chronic obstructive pulmonary disease in mice via the Keap1/Nrf2 axis

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity worldwide. Cigarette smoking, which leads to abnormalities in the airways or alveoli and persistent obstruction of the airway's flow, is a significant risk factor of COPD. Cryptotanshinone (CTS) is the active ingredient in Salvia miltiorrhiza (Danshen) and has many pharmacological properties including anti-inflammatory, antitumor, and antioxidant properties, but its impact on COPD is uncertain. In the present study, the potential effect of CTS on COPD was investigated in a modified COPD mice model induced with cigarette smoke (CS) and lipopolysaccharide (LPS) exposure. CTS significantly reversed the decline in lung function, emphysema, inflammatory cell infiltration, small airway remodeling, pulmonary pathological damage, and airway epithelial cell proliferation in CS- and LPS-exposed mice. Additionally, CTS decreased inflammatory cytokines such as tumor necrosis factor α (TNF α), interleukins IL-6 and IL-1β, and keratinocyte chemoattractant (KC), increased the activities of superoxide dismutase (SOD), Catalase (CAT) and L-Glutathione (GSH), and repressed the expression of protein hydrolases matrix metalloprotein (MMP)− 9 and − 12 in pulmonary tissue and bronchoalveolar lavage fluid (BALF). The protective effects of CTS were also observed in human bronchial epithelial cell line BEAS-2B simulated with cigarette smoke condensate (CSC) and LPS. Mechanistically, CTS can repress the protein level of Keap1, resulting to activation of erythroid 2-related factor (Nrf2), finally alleviating COPD. In summary, the present findings demonstrated that CTS dramatically ameliorates COPD induced by CS and LPS via activating Keap1/Nrf2 pathway.

Mettl3 Mediated m6A Methylation Involved in Epithelial-Mesenchymal Transition by Targeting SOCS3/STAT3/SNAI1 in Cigarette Smoking-Induced COPD.

Persistent inflammation and epithelial-mesenchymal transition are essential pathophysiological processes in chronic obstructive pulmonary disease (COPD) and involve airway remodeling. m6A methylation modification was discovered to play an important role in various diseases. Nevertheless, the regulatory role of m6A methylation has not yet been investigated in cigarette smoking-induced COPD. The study aims to explore the regulatory role of m6A methylation in cigarette smoking-induced COPD. In this study, two Gene Expression Omnibus (GEO) datasets were first utilized to analyze the expression profiles of m6A RNA methylation regulators in COPD. We then established a cell model of COPD by exposing human bronchial epithelial cells (HBECs) to cigarette smoke extract (CSE) in vitro and detected the expression of m6A writer Mettl3 and EMT phenotype markers. RNA interference, cycloleucine, RT-qPCR, western blot, MeRIP-sequencing, and cell migration assay were performed to investigate the potential effect of Mettl3 on the EMT process in CSE-induced HBECs. Our results showed that Mettl3 expression was significantly elevated in cigarette smoking-induced COPD patients and in a cellular model of COPD. Furthermore, Mettl3 silence and cycloleucine treatment inhibited the EMT process of HBECs caused by CSE. Mechanically, Mettl3 silence weakens the m6A methylation of SOCS3 mRNA to enhance the protein expression of SOCS3, inhibiting CSE-induced SOCS3/STAT3/SNAI1 signaling and EMT processes in HBECs. Our study inferred that Mettl3-mediated m6A RNA methylation modification modulates CSE-induced EMT by targeting SOCS3 mRNA and ultimately serves as a crucial regulator in the emergence of COPD. This conclusion reinforces the regulatory role of m6A methylation in COPD.

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.

Akkermansia muciniphila Ameliorates Lung Injury in Smoke-Induced COPD Mice by IL-17 and Autophagy

Objective. Smoking is a primary hazard factor for chronic obstructive pulmonary disease (COPD), which induced a decrease in intestinal Akkermansia muciniphila abundance and Th17 imbalance in COPD. This study analyzed the changes of gut microbiota metabolism and Akkermansia abundance in patients with smoking-related COPD and explored the potential function of Akkermansia muciniphila in smoke-induced COPD mice. Methods. Gut microbiota diversity and metabolic profile were analyzed by 16S rRNA sequence and metabolomics in COPD patients. The IL-1β, IL-17, TNF-α, and IL-6 levels were tested by ELISA. Lung tissue damage was observed by HE staining. The expression of cleave-caspase 3, trophoblast antigen 2 (TROP2), and LC3 in lung tissues were analyzed by IHC or IF. The p-mTOR, mTOR, p62, and LC3 expression in lung tissues were tested by western blot. Results. The levels of IL-17, IL-1β, TNF-α, and IL-6 in the peripheral blood of COPD patients increased significantly. The number and alpha diversity of gut microbiota were decreased in COPD patients. The abundance of Akkermansia muciniphila in gut of COPD patients was decreased, and the metabolic phenotype and retinol metabolism were changed. In the retinol metabolism, the retinol and retinal were significantly changed. Akkermansia muciniphila could improve the alveolar structure and inflammatory cell infiltration in lung tissue, reduce the IL-17, TNF-α, and IL-6 levels in peripheral blood, promote the p-mTOR expression, and inhibit the expression of autophagy-related proteins in smoke-induced COPD mice. Conclusion. The number and alpha diversity of gut microbiota were decreased in patients with smoking-related COPD, accompanied by decreased abundance of Akkermansia muciniphila, and altered retinol metabolism function. Gut Akkermansia muciniphila ameliorated lung injury in smoke-induced COPD mice by inflammation and autophagy.