stilbenes and Pulmonary-Disease--Chronic-Obstructive

Resveratrol, a natural polyphenolic molecule with several biological activities, is a well recognized anti-oxidant, anti-aging and cancer chemopreventive agent. Moreover, resveratrol anti-inflammatory and antifibrotic properties have been demonstrated both in vitro and in different animal models of inflammatory pathologies, including bowel and liver diseases. We review the evidence of resveratrol protective role in respiratory diseases such as acute lung injury, asthma, chronic obstructive pulmonary disease and lung fibrosis. We conclude that resveratrol and its derivatives may act as a therapeutic agents in respiratory diseases and pertinent clinical trials should be performed.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Asthma; Disease Models, Animal; Fibrosis; Humans; Inflammation; Liver Diseases; Lung; Mice; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes

Sirtuin1 (Sirt1) is a NAD-dependent class III histone deacetylase (HDAC), and regulates pulmonary immune/inflammatory system and the aging process mainly through post-translational modification. Sirt1 could become a potential target for treatment of lung diseases due to participating in the development of a variety of lung diseases. In this paper, physiological characteristics, biological activities, modification regulations and its relationship with chronic obstructive pulmonary emphysema, asthma and lung cancer are reviewed.

Topics: Animals; Asthma; Benzamides; Humans; Lung Diseases; Lung Neoplasms; Naphthols; Protein Processing, Post-Translational; Pulmonary Disease, Chronic Obstructive; Resveratrol; Sirtuin 1; Stilbenes

The putative cardiovascular risks and benefits of the ingestion of wine and alcohol-containing spirits have been well publicized; however, less attention has been focused upon the health effects of wine and spirits consumption on the respiratory system. This paper will highlight epidemiologic, clinical and experimental data on the effects of wine and distilled spirits [and the chemical components thereof] on lung function, chronic obstructive pulmonary disease progression, lung cancer risk, risk of developing acute respiratory distress syndrome, high altitude pulmonary edema and wine [sulfite] associated asthma. Several studies have demonstrated a positive [beneficial] effect of light-to-moderate wine consumption on pulmonary function, while chronic ingestion of distilled spirits may have either no effect, or a negative effect. Studies in Scandinavia, Europe and South America have suggested a possible protective effect of wine ingestion against lung cancer, especially adenocarcinoma. Resveratrol [3,5,4'-trihydroxystilbene] a polyphenolic compound found in red wine, has anti-oxidant, anti-inflammatory and estrogen agonist effects and may be responsible for some of the health benefits of wine. The spectrum of potentially beneficial clinical effects of resveratrol and other wine-derived compounds is discussed.

Topics: Adenocarcinoma; Alcohol Drinking; Alcoholic Beverages; Alcoholism; Altitude Sickness; Antioxidants; Asthma; Female; Humans; Lung; Lung Neoplasms; Male; Pulmonary Disease, Chronic Obstructive; Pulmonary Edema; Respiratory Distress Syndrome; Resveratrol; Stilbenes; Sulfites; Wine

The pathophysiology of chronic obstructive pulmonary disease (COPD) features pulmonary inflammation with a predominant alveolar macrophage involvement. Bronchoalveolar macrophages from patients with COPD release increased amounts of inflammatory cytokines in vitro, an effect that is not inhibited by the glucocorticosteroid dexamethasone. Resveratrol (3,5,4'-trihydroxystilbene) is a component of red wine extract that has anti-inflammatory and antioxidant properties. A study was undertaken to determine whether or not resveratrol would inhibit cytokine release in vitro by alveolar macrophages from patients with COPD.. Alveolar macrophages were isolated from bronchoalveolar lavage (BAL) fluid from cigarette smokers and from patients with COPD (n=15 per group). The macrophages were stimulated with either interleukin (IL)-1beta or cigarette smoke media (CSM) to release IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF). The effect of resveratrol was examined on both basal and stimulated cytokine release.. Resveratrol inhibited basal release of IL-8 in smokers and patients with COPD by 94% and 88% respectively, and inhibited GM-CSF release by 79% and 76% respectively. Resveratrol also inhibited stimulated cytokine release. Resveratrol reduced IL-1beta stimulated IL-8 and GM-CSF release in both smokers and COPD patients to below basal levels. In addition, resveratrol inhibited CSM stimulated IL-8 release by 61% and 51% respectively in smokers and COPD patients, and inhibited GM-CSF release by 49% for both subject groups.. Resveratrol inhibits inflammatory cytokine release from alveolar macrophages in COPD. Resveratrol or similar compounds may be effective pharmacotherapy for macrophage pathophysiology in COPD.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Bronchoalveolar Lavage Fluid; Cytokines; Female; Humans; In Vitro Techniques; Interleukin-1; Macrophages, Alveolar; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Resveratrol; Smoke; Smoking; Stilbenes; Wine

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease resulted from airflow obstructions, and there is a driving requirement for novel and effective preventive and therapeutic agents of COPD. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been regarded to be a promising therapeutic target for COPD. Resveratrol is a natural Nrf2 activator with antioxidant and anti-inflammatory properties, however, its application is limited by its relative low efficiency and poor bioavailability. Herein, based on the skeleton of resveratrol, trans-4,4'-dihydroxystilbene (DHS) has been firstly identified to be an Nrf2 activator, which is more potent than the well-known sulforaphane (SF) and resveratrol. Our results indicate that DHS blocks Nrf2 ubiquitylation through specifically reacting with Cys151 cysteine in Keap1 protein to activate Nrf2-regulated defensive response, and thus enhances intracellular antioxidant capability. Furthermore, DHS relieves lipopolysaccharide (LPS)-stimulated inflammatory response via inhibition of NF-κB. Importantly, DHS significantly ameliorates pathological alterations (e.g. infiltration of leukocytes and fibrosis), downregulates the levels of oxidant biomarkers malondialdehyde (MDA) and 8-oxo-7,8-dihydro-2'-deoxyguanosin (8-oxo-dG), and inhibits the overproductions of inflammatory mediators [e.g. tumor necrosis factor α (TNF-α), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9)] in a cigarette smoke (CS)-induced pulmonary impairment mice model. Taken together, this study demonstrates that DHS attenuates the CS-induced pulmonary impairments through inhibitions of oxidative stress and inflammatory response targeting Nrf2 and NF-κB in vitro and in vivo, and could be developed into a preventive agent against pulmonary impairments induced by CS.

Topics: Animals; Kelch-Like ECH-Associated Protein 1; Lung; Mice; NF-E2-Related Factor 2; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Smoking; Stilbenes

Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo.. Primary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague-Dawley rats.. Isorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.

Topics: Administration, Oral; Adrenal Cortex Hormones; Aged; Animals; Anti-Inflammatory Agents; Biological Availability; Cell Survival; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Inflammation; Injections, Intravenous; Male; Molecular Structure; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Respiratory System; Resveratrol; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4'-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Gene Expression Regulation; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Malondialdehyde; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pulmonary Disease, Chronic Obstructive; Rats; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Superoxide Dismutase

Chronic airway inflammation and airway remodeling are the major pathophysiological characteristics of chronic obstructive pulmonary disease (COPD). Resveratrol and genistein have been previously demonstrated to have anti‑inflammatory and antioxidative properties. The present study aimed to measure the inhibitory effects of resveratrol and genistein on tumor necrosis factor (TNF)‑α and matrix metalloproteinase (MMP)‑9 concentration in patients with COPD. Lymphocytes were isolated from the blood of 34 patients with COPD and 30 healthy subjects, then randomly divided into the following four treatment groups: Control, dexamethasone (0.5 µmol/l), resveratrol (12.5 µmol/l) and genistein (25 µmol/l) groups. After 1 h of treatment, 100 µl lymphocytes were collected for nuclear factor (NF)‑κB immunocytochemical staining. After 48 h treatment, the supernatant of the lymphocytes was collected for analysis of TNF‑α and MMP‑9 concentration levels. The percentage of lymphocytes with positive nuclear NF‑κB expression was analyzed by immunocytochemical staining. The concentration levels of TNF‑α and MMP‑9 were measured using radioimmunoassay and enzyme‑linked immunosorbent assay, respectively. The present study demonstrated that the percentage of NF‑κB‑positive cells, and the levels of TNF‑α and MMP‑9 in lymphocytes from patients with COPD patients were significantly higher compared with healthy subjects. Additionally, there were positive correlations between the percentage of NF‑κB‑positive cells, and the concentration levels of TNF‑α and MMP‑9 in patients with COPD. All three factors were significantly reduced in lymphocytes treated with resveratrol and genistein, and the inhibitory effects of resveratrol on NF‑κB, TNF‑α and MMP‑9 were more potent than the effects of genistein. In conclusion, resveratrol and genistein may inhibit the NF‑κB, TNF‑α and MMP‑9‑associated pathways in patients with COPD. It is suggested that resveratrol and genistein may be potential drugs candidates for use in the treatment of COPD.

Topics: Aged; Aged, 80 and over; Female; Genistein; Humans; Lymphocytes; Male; Matrix Metalloproteinase 9; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

This study was designed to examine whether resveratrol exerts the protective effects on LPS and cigarette smoke (LC)-induced COPD in a murine model. In lung histopathological studies, H&E, Masson's trichrome, and AB-PAS staining were performed. The cytokines (IL-6, IL-17, TGF-β, and TNF-α) and inflammatory cells in BALF were determined. The Beclin1 level in the lungs of mouse was analyzed. Compared with the LC-induced mouse, the level of inflammatory cytokines (IL-17, IL-6, TNF-α, and TGF-β) of the BALF in the resveratrol + cigarette smoke-treated mouse had obviously decreased. Histological examination of the lung tissue revealed that the resveratrol treatment attenuated the fibrotic response and mucus hypersecretion. In addition, resveratrol inhibited the expression of the Beclin1 protein in mouse lungs. The presented findings collectively suggest that resveratrol has a therapeutic effect on mouse LC-induced COPD, and its mechanism of action might be related to reducing the production of the Beclin1 protein.

Topics: Animals; Beclin-1; Bronchoalveolar Lavage Fluid; Cytokines; Lipopolysaccharides; Lung; Mice; Mucus; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Resveratrol; Smoke; Stilbenes

The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5 μm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9 ± 1.1% and 3.7 ± 0.1 μm, respectively, when assessed with an Andersen cascade impactor (ACI) at 60 l/min. The cytotoxicity results of resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 μM). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD.

Topics: Administration, Inhalation; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Line; Cell Survival; Chemistry, Pharmaceutical; Desiccation; Dry Powder Inhalers; Epithelial Cells; Free Radical Scavengers; Humans; Interleukin-8; Lipopolysaccharides; Particle Size; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes; Stress, Physiological; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Resveratrol has demonstrated many beneficial effects against aging, including anti-inflammatory and antioxidant roles. The present study was designed to observe the effects of resveratrol on the dysfunction of dendritic cells (DCs) from COPD patients and its possible mechanism and use in the treatment for COPD.. Flow cytometry analysis was used to examine the expression of costimulatory markers CD80 and CD86 and ELISA was used to examine the secretion of IFN-α. Expression of miR-34 was examined by using real-time PCR. Expression vector of miR-34, LV3-miR-34 was also constructed and transfected into DCs to observe the effects on functions of DCs.. The results showed that there was remarkable upregulation of CD80 and CD86 and secretion of cytokines IFN-α in DCs from COPD patients. Resveratrol displayed a dose-dependent cytotoxicity action over 10 µg/mL and pretreatment with resveratrol inhibited upregulation of CD80 and CD86 and secretion of cytokines IFN-α. Further study showed resveratrol upregulated the expression of miR-34, which inhibited the dysfunction of DCs.. These proofs suggest that resveratrol inhibited dysfunction of DCs from COPD patients through promoting miR-34.

Topics: B7-1 Antigen; B7-2 Antigen; Biomarkers; Dendritic Cells; Dose-Response Relationship, Drug; Female; HEK293 Cells; Humans; Interferon-gamma; Male; MicroRNAs; Middle Aged; Pulmonary Disease, Chronic Obstructive; Resveratrol; Signal Transduction; Stilbenes; Transfection; Up-Regulation

During bacterial infections, pathogen-associated molecular patterns (PAMPs) induce cytokine/chemokine release in immunoactive cells. This increases corticosteroid-resistant airway inflammation in chronic obstructive pulmonary disease (COPD) and leads to exacerbations. Anti-inflammatory therapies other than corticosteroids are required and resveratrol is currently under discussion. Resveratrol is an activator of sirtuins, which are class III histone deacetylases (HDACs). We suggested that human airway smooth muscle cells (HASMCs) release COPD-associated cytokines/chemokines in response to lipoteichoic acid (LTA), a major PAMP of gram-positive bacteria and that resveratrol is superior to the corticosteroid dexamethasone in suppressing these cytokines/chemokines. Cultivated HASMCs of patients with COPD were pre-incubated with resveratrol or dexamethasone before stimulation with LTA. CCL2, GM-CSF, IL-6 and IL-8 were analysed in culture supernatants by enzyme-linked immunosorbent assay. Drug effects were investigated in the absence and presence of trichostatin A (TSA), an inhibitor of class I/II HDACs, and EX527, an inhibitor of the sirtuin SIRT1. LTA induced robust cytokine/chemokine release. Resveratrol was superior to dexamethasone in reducing CCL-2, IL-6 and IL-8 in LTA-exposed HASMCs of patients with COPD. Both drugs were equally effective in reducing GM-CSF. Resveratrol effects were partially reversed by EX527 but not by TSA. Dexamethasone effects were partially reversed by TSA but not by EX527. We conclude that HASMCs contribute to the increase in airway inflammation in COPD exacerbations caused by gram-positive bacterial infections. Our data suggest resveratrol as an alternative anti-inflammatory therapy in infection-induced COPD exacerbations. Resveratrol and corticosteroids suppress cytokine/chemokine expression through activation of SIRT1 or interaction with class I/II HDACs, respectively, in HASMCs.

Topics: Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents; Carbazoles; Chemokine CCL2; Cytokines; Dexamethasone; Female; Gram-Positive Bacteria; Granulocyte-Macrophage Colony-Stimulating Factor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Myocytes, Smooth Muscle; Pulmonary Disease, Chronic Obstructive; Respiratory System; Resveratrol; Sirtuin 1; Stilbenes; Teichoic Acids

To investigate alveolar epithelial cell apoptosis induced by endoplasmic reticulum stress in a rat model of chronic obstructive pulmonary disease (COPD) and the potential protective effect of resveratrol.. The COPD rat model was established by intratracheal instillation of lipopolysaccharide (LPS) and exposure to cigarette smoke daily. Forty-eight male Sprague-Dawley rats were randomly divided into 4 groups (n = 12 each): a normal control group, a resveratrol control group (resveratrol 25 mg × kg⁻¹ × d⁻¹ gavage), a COPD group (COPD rat model established), and a resveratrol intervention group (COPD model rats receiving resveratrol 25 mg × kg⁻¹ × d⁻¹ gavage). Spirometry was conducted and the lung pathological changes were observed. The protein expression of CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 were detected by immunohistochemistry and Western blot, and alveolar epithelial apoptosis was analyzed by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL). Statistical analysis among groups were carried out by one way analysis of variance followed by LSD-t test between 2 groups.. Significant decrease of FEV0.3/FVC [(59 ± 4)%] and dynamic lung compliance [(0.154 ± 0.013) ml/cm H₂O, 1 cm H₂O = 0.098 kPa] and increase of airway resistance [(0.651 ± 0.046) cm H₂O × ml⁻¹× s⁻¹] were found in the COPD group when compared with the normal control group [(82 ± 4)%, (0.401 ± 0.033) ml/cm H₂O, (0.404 ± 0.033) cm H₂O × ml⁻¹ × s⁻¹] (t = -14.48, 16.48, P < 0.05). The FEV0.3/FVC [(71 ± 5)%] and dynamic lung compliance [(0.302 ± 0.023) ml/cm H₂O] of the resveratrol intervention group were significantly improved when compared with those of the COPD group, and the airway resistance [(0.442 ± 0.036) cm H₂O × ml⁻¹ × s⁻¹] also decreased (t = -10.02-10.37, P < 0.05). Significant small airway inflammation and emphysema were seen in the lung tissue of COPD group, while significant improvement was observed in the resveratrol intervention group when compared with COPD group. The lung tissue immunohistochemistry integrated optical density (IOD) of CHOP and caspase-12 (9 778 ± 217, 12 009 ± 346) of the COPD group increased significantly when compared with the normal control group (960 ± 94, 1 124 ± 112) (t = -100.43, - 90.43, P < 0.05), while the IODs of the resveratrol intervention group (5 799 ± 177, 6 720 ± 173) decreased significantly when compared with the COPD group (t = 45.32, 43.93, P < 0.05). Western blot results showed that the relative quantification of CHOP (0.910 ± 0.053) and caspase-12 (1.104 ± 0.026) increased in the COPD group when compared with the normal control group (0.204 ± 0.021, 0.133 ± 0.013, t = -36.04, -115.03, P < 0.05), while the ratios of the resveratrol intervention group (0.462 ± 0.037, 0.642 ± 0.011) decreased significantly when compared with COPD group (t = 24.22, 60.59, P < 0.05). Higher apoptosis index was seen in the COPD group [(39.8 ± 1.6)%] when compared with the resveratrol intervention group [(26.3 ± 1.5)%] and the normal control group [(6.4 ± 0.6)%] (t = 20.21, -49.94, P < 0.05).. Endoplasmic reticulum stress, which induced apoptosis of alveolar epithelial cells, was observed in this COPD model. Resveratrol was shown to alleviate endoplasmic reticulum stress and attenuate alveolar epithelial apoptosis.

Topics: Alveolar Epithelial Cells; Animals; Antioxidants; Apoptosis; Caspase 12; Disease Models, Animal; Endoplasmic Reticulum Stress; Lipopolysaccharides; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Resveratrol; Smoke; Stilbenes; Transcription Factor CHOP

Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation and inflammation. Meanwhile, COPD also is associated with metabolic disorders, such as skeletal muscle weakness. Strikingly, activation of AMP-activated protein kinase (AMPK) exerts critical roles in energy metabolism. However, it remains unclear whether and how the expression levels of AMPK are affected in the COPD model rats which may lead to the dysfunction of the skeletal muscle in these rats.. Here we developed a rat model of COPD, and we investigated the morphological changes of peripheral skeletal muscle and measured the levels of tumor necrosis factor -α (TNF-α) and AMPK in skeletal muscle by using approaches that include immunohistochemistry and polymerase chain reaction (PCR).. We found that the expression levels of both AMPK mRNA and protein in skeletal muscles were significantly reduced in the COPD model rats, in comparison to those from the control rats, the COPD model rats that received treatments with AICAR and resveratrol, whereas the expression levels of TNF-α were elevated in COPD rats.. Such findings indicate that AMPK may serve as a target for therapeutic intervention in the treatment of muscle weakness in COPD patients.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Down-Regulation; Gene Expression Regulation, Enzymologic; Male; Muscle Weakness; Muscle, Skeletal; Pulmonary Disease, Chronic Obstructive; Rats, Wistar; Resveratrol; Ribonucleotides; RNA, Messenger; Sirtuin 1; Stilbenes; Time Factors; Tumor Necrosis Factor-alpha

The objective of this study was to investigate left cardiac damage and the cardioprotective effects of resveratrol in old rats with COPD. Rats 22 months old were divided into three groups: control (CTL), smoking and lipopolysaccharides (SM/LPS), and SM/LPS plus resveratrol (SM/LPS-Res). Cardiac function, pathology, oxidative stress, and apoptosis index were measured. Expression of myocardial SIRT1 was studied by real-time quantitative polymerase chain reaction (PCR) and Western blot detection. The heart weight-body weight ratio (LVW/BW) increased in the SM/LPS group compared with the CTL group. Both the LVW/BW and the area of fibrosis in the SM/LPS-Res group decreased compared with those in the SM/LPS group. 8-OHdG expression increased in cardiac tissue of rats in the SM/LPS group, which could be inhibited by resveratrol. Resveratrol significantly increased the activity of superoxide dismutase (SOD) and reduced the cardiac malonyldialdehyde (MDA) level in the SM/LPS-Res group. There was a significant decrease in the extent of cardiomyocyte apoptosis in the SM/LPS-Res group compared with the SM/LPS group. SIRT1 mRNA increased in the SM/LPS-Res group compared with the SM/LPS group. In conclusion, resveratrol attenuated cardiac oxidative damage and left ventricular remodeling and enhanced the decreased expression of SIRT1 in hearts of old rats with emphysema and thus might be a therapeutic modality for cardiac injury complicated in chronic obstructive pulmonary disease (COPD).

Topics: Animals; Apoptosis; Emphysema; Lipopolysaccharides; Male; Malondialdehyde; Myocardium; Myocytes, Cardiac; Nicotiana; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Smoke; Smoking; Stilbenes; Superoxide Dismutase; Ventricular Function, Left; Ventricular Remodeling

Wine intake is associated with a better lung function in the general population, yet the source of this effect is unknown. Resveratrol, a polyphenol in wine, has anti-inflammatory properties in the lung, its effects being partially mediated via induction of Sirtuin (SIRT)1 activity. We assessed the impact of wine and resveratrol intake, and SIRT1 single-nucleotide polymorphisms (SNPs) on lung function in the general population. Effects of red and white wine and resveratrol intake on forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC were analysed in the population-based Doetinchem cohort (n=3,224). Associations of four tagging SIRT1 SNPs with lung function were analysed in the Doetinchem (n=1,152) and Vlagtwedde-Vlaardingen (n=1,390) cohorts. Resveratrol intake was associated with higher FVC levels, and white wine intake with higher FEV(1) levels and lower risk of airway obstruction. SIRT1 SNPs were not significantly associated with level or course of lung function, either directly or indirectly via wine or resveratrol intake. This study shows a positive association of resveratrol intake with lung function in the general population, confirms the previously reported positive association of white wine intake with higher levels of FEV(1), and additionally shows an association with a higher FEV(1)/FVC ratio. These effects probably do not run via SNPs in SIRT1.

Topics: Adult; Aged; Antioxidants; Cohort Studies; Feeding Behavior; Female; Forced Expiratory Volume; Genetic Predisposition to Disease; Humans; Lung; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Resveratrol; Risk Factors; Sirtuin 1; Stilbenes; Vital Capacity; Wine

To appraise the efficacy of Vam3 (Amurensis H), a dimeric derivative of resveratrol, at inhibiting cigarette smoke-induced autophagy.. Human bronchial epithelial cells were treated with cigarette smoke condensates, and a chronic obstructive pulmonary disease (COPD) model was established by exposing male BALB/c mice to cigarette smoke. The protein levels of the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3), Sirtuin 1 (Sirt1), and foxhead box O 3a (FoxO3a) were examined using Western blotting and Immunohistochemistry. LC3 punctae were detected by immunofluorescence. The levels of FoxO3a acetylation were examined by immunoprecipitation. The level of intracellular oxidation was assessed by detecting ROS and GSH-Px.. Vam3 attenuated cigarette smoke condensate-induced autophagy in human bronchial epithelial cells, and restored the expression levels of Sirt1 and FoxO3a that had been reduced by cigarette smoke condensates. Similar protective effects of Vam3, reducing autophagy and restoring the levels of Sirt1 and FoxO3a, were observed in the COPD animal model. Additionally, Vam3 also diminished the oxidative stress that was induced by the cigarette smoke condensates.. Vam3 decreases cigarette smoke-induced autophagy via up-regulating/restoring the levels of Sirt1 and FoxO3a and inhibiting the induced oxidative stress.

Topics: Animals; Antioxidants; Autophagy; Bronchi; Cell Line; Epithelial Cells; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Lung; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Resveratrol; Sirtuin 1; Smoking; Stilbenes

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Chlorofluorocarbons; Clinical Trials as Topic; Human Genome Project; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Resveratrol; Sirtuins; Stilbenes

Airway inflammation in chronic obstructive pulmonary disease (COPD) is believed to be insensitive to corticosteroids. However, corticosteroids are recommended in COPD (GOLD stages III, IV) with frequent exacerbations. Resveratrol has anti-inflammatory properties and could be an alternative to corticosteroids in COPD therapy. We investigated the effect of dexamethasone versus resveratrol on the release of COPD-related inflammatory mediators (IL-6, IL-8, GM-CSF and MCP-1) and matrix-metalloprotease-9 (MMP-9) from alveolar macrophages exposed to gram-negative bacterial endotoxin (lipopolysaccharide, LPS). We compared never-smokers, current smokers without airway obstruction and current smokers with COPD. The cytokines and MMP-9 were measured in cell culture supernatants with ELISA. The release of IL-8 and MMP-9 from LPS-exposed alveolar macrophages was increased in COPD, the release of GM-CSF and IL-6 was decreased in COPD and the release of MCP-1 was without differences between the cohorts. Dexamethasone impaired the release of all cytokines and MMP-9 from LPS-exposed alveolar macrophages of all cohorts, but for IL-8 and GM-CSF this effect was reduced in COPD. In alveolar macrophages of COPD, there was an almost complete reduction in IL-6 release but only a partial reduction in IL-8, GM-CSF, MCP-1 and MMP-9 release demonstrating a partial corticosteroid-insensitivity. In contrast, resveratrol almost completely reduced the release of all cytokines and MMP-9 without significant differences between the cohorts. Our data provide evidence for a corticosteroid resistance of alveolar macrophage-dependent inflammatory responses induced by gram-negative bacteria in COPD and thus question the utility of corticosteroids in COPD therapy. Instead, resveratrol may prove an alternative.

Topics: Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes

Topics: Cachexia; Clinical Trials as Topic; Drug Approval; Drug Discovery; Drug Industry; Growth Hormone-Releasing Hormone; Humans; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Receptors, Retinoic Acid; Research; Retinoic Acid Receptor gamma; Stilbenes; Weight Loss

Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NS > S > COPD. That of resveratrol was NS = S = COPD for IL-8 and NS = S < COPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = S > COPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Bronchi; Cells, Cultured; Cytokines; Dexamethasone; Female; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Respiratory System; Resveratrol; Smoking; Stilbenes; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Topics: Animals; Biotechnology; Clinical Trials as Topic; Genotype; Humans; Industry; Isotretinoin; Nicotine; Nicotinic Agonists; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pyrazoles; Smoking Cessation; Stilbenes

The purpose of this study is to establish COPD animal model by intra-tracheal instillation of bleomycin (BLM) once and exposure to cigarette smoke for continuous 27 d, and to observe the effects of the inhalation on the model. At the 29th day, blood samples were taken from cervical artery for blood-gas analysis and parameters of lung function were recorded. Bronchoalveolar lavage fluid (BALF) was collected to measure intercellular adhesion molecule-1 (ICAM-1) concentration. The results showed that atomization inhaled resveratrol could alleviate rat COPD lung injury accompanied by amelioration of pathological changes, increase the ratio of forced expiratory volume in 0.3 s (FEV0.3) and forced vital capacity (FVC), and decrease the ICAM-1 level in BALF. The ultimate reduction of inflammatory factors was involved, at least in part, in the mechanism of resveratrol effects.

Topics: Animals; Bleomycin; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Forced Expiratory Volume; Intercellular Adhesion Molecule-1; Lung; Lung Compliance; Male; Maximal Midexpiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Smoking; Stilbenes