Experimental therapeutics of Nrf2 as a target for prevention of bacterial exacerbations in COPD.
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ABSTRACT:
SUBMITTER: Biswal S
PROVIDER: S-EPMC3359107 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
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Experimental therapeutics of Nrf2 as a target for prevention of bacterial exacerbations in COPD.
Biswal Shyam S Thimmulappa Rajesh K RK Harvey Christopher J CJ
Proceedings of the American Thoracic Society 20120501 2
A growing body of evidence indicates that oxidative stress plays a central role in the progression of chronic obstructive pulmonary disease (COPD). Chronic oxidative stress caused by cigarette smoke generates damage-associated molecular patterns (DAMPs), such as oxidatively or nitrosatively modified proteins and extracellular matrix fragments, which induce abnormal airway inflammation by activating innate and adaptive immune responses. Furthermore, oxidative stress-induced histone deacetylase 2 ...[more]
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Project description:ObjectivesDrugs for targeted therapy have become a new strategy of adjuvant therapy for treatment of lung cancer. The Keap1 (kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2) pathway is recognized to be critical in regulating genes related to the cellular protective response and protecting cells from oxidative damages and toxic insult.MethodsPubmed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were "Nrf2" or "Keap1" and "Lung cancer".ResultsThe upregulation of Nrf2 had been closely related to tumor protection and drug resistance. The aberrant state of Keap1 or Nrf2 that were frequently found in lung cancer conferred a poor prognosis. Nrf2 could prevent cells from undergoing oncogenesis as a tumor suppressor, while it could also promote cancer progression and resistance to chemotherapeutic drugs as an oncogene, depending on the different stages of tumor progression. Target Nrf2 signaling by specific chemicals showed it could prevent tumor growth or combat chemoresistance.ConclusionsIncreasing evidence has demonstrated the dual roles of the Keap1-Nrf2 pathway in tumor initiation and progression. In this paper, we provide a comprehensive overview of the potency of the Keap1-Nrf2 pathway as an antitumor target, and the current status of Nrf2 activators or inhibitors for therapeutic approaches. Further studies are required to clarify the role of Nrf2 in lung cancer at different tumor stages, in order to maximize the efficacy of Keap1-Nrf2 targeting agents.
| S-EPMC5643752 | biostudies-literature
Project description:BackgroundAcute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.MethodsWe performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.ResultsA total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).ConclusionsAmong selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).
| S-EPMC3220999 | biostudies-literature
Project description:The natural disease course of chronic obstructive pulmonary disease (COPD) is often punctuated by exacerbations: acute events of symptom worsening associated with significant morbidity and healthcare resource utilization; reduced quality of life; and increased risk of hospitalization and death. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that patients at risk of exacerbations (GOLD Groups C and D) receive a long-acting muscarinic antagonist (LAMA) or a long-acting β2-agonist (LABA)/LAMA combination, respectively, as preferred initial treatments. The latter recommendation is based on recent trial evidence demonstrating the superior efficacy of a fixed-dose LABA/LAMA over an inhaled corticosteroid (ICS)/LABA in exacerbation prevention. ICS in combination with a LABA is also indicated for prevention of exacerbations, but the use of ICS is associated with an increased risk of adverse events such as pneumonia, and offers limited benefits beyond those provided by LABA or LAMA monotherapy. In this review, we examine evidence from a number of pivotal studies of LABAs and LAMAs, administered as monotherapy or as part of dual or triple combination therapy, with a specific focus on their effect on exacerbations. We also discuss a new proposed treatment paradigm for the management of COPD that takes into account this recent evidence and adopts a more cautious approach to the use of ICS. In alignment with GOLD 2017, we suggest that ICS should be reserved for patients with concomitant asthma or in whom exacerbations persist despite treatment with LABA/LAMA.
| S-EPMC5477752 | biostudies-literature
Project description:BackgroundObservational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.MethodsIn this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.ResultsA total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.ConclusionsAmong patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).
| S-EPMC7416529 | biostudies-literature
Project description:BackgroundRetrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial.MethodsWe designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers.ResultsA total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89).ConclusionsSimvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).
| S-EPMC4375247 | biostudies-literature
Project description:The changes in the microbial community structure during acute exacerbations of severe chronic obstructive pulmonary disease (COPD) in hospitalized patients remain largely uncharacterized. Therefore, further studies focused on the temporal dynamics and structure of sputum microbial communities during acute exacerbation of COPD (AECOPD) would still be necessary. In our study, the use of molecular microbiological techniques provided insight into both fungal and bacterial diversities in AECOPD patients during hospitalization. In particular, we examined the structure and varieties of lung microbial community in 6 patients with severe AECOPD by amplifying 16S rRNA V4 hyper-variable and internal transcribed spacer (ITS) DNA regions using barcoded primers and the Illumina sequencing platform. Sequence analysis showed 261 bacterial genera representing 20 distinct phyla, with an average number of genera per patient of >157, indicating high diversity. Acinetobacter, Prevotella, Neisseria, Rothia, Lactobacillus, Leptotrichia, Streptococcus, Veillonella, and Actinomyces were the most commonly identified genera, and the average total sequencing number per sputum sample was >10000 18S ITS sequences. The fungal population was typically dominated by Candia, Phialosimplex, Aspergillus, Penicillium, Cladosporium and Eutypella. Our findings highlight that COPD patients have personalized structures and varieties in sputum microbial community during hospitalization periods.
| S-EPMC4493005 | biostudies-literature
Project description:Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea. These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD. Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (≥ 2 per year) independently of disease severity. Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis. The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting β(2)-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS). While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance. Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation. Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations. Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations.
| S-EPMC3511775 | biostudies-literature
Project description:Severe exacerbations of COPD, ie, those leading to hospitalization, have profound clinical implications for patients and significant economic consequences for society. The prevalence and burden of severe COPD exacerbations remain high, despite recognition of the importance of exacerbation prevention and the availability of new treatment options. Severe COPD exacerbations are associated with high mortality, have negative impact on quality of life, are linked to cardiovascular complications, and are a significant burden on the health-care system. This review identified risk factors that contribute to the development of severe exacerbations, treatment options (bronchodilators, antibiotics, corticosteroids [CSs], oxygen therapy, and ventilator support) to manage severe exacerbations, and strategies to prevent readmission to hospital. Risk factors that are amenable to change have been highlighted. A number of bronchodilators have demonstrated successful reduction in risk of severe exacerbations, including long-acting muscarinic antagonist or long-acting β2-agonist mono- or combination therapies, in addition to vaccination, mucolytic and antibiotic therapy, and nonpharmacological interventions, such as pulmonary rehabilitation. Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD. Evidence-based approaches to prevent and manage severe exacerbations should be implemented as part of targeted strategies for disease management.
| S-EPMC5638577 | biostudies-literature
Project description:A review of the most relevant evidence based therapeutic options currently available for the management of exacerbations of COPD.
| S-EPMC2111219 | biostudies-literature
Project description:Background:p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives:These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38? would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods:The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results:The p38 isoform most relevant to lung inflammation was p38?, and AZD7624 specifically inhibited p38? and p38? isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-? by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout. Conclusion:Although p38? is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.
| S-EPMC5877500 | biostudies-literature