Chronic Obstructive Pulmonary Disease Therapy Research Articles

Pulmonology: What You May Have Missed in 2023.

The field of pulmonology saw significant advances in 2023. The publications highlighted in this article address advances and changes in practice related to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pleural disorders, and sleep-disordered breathing. One article reviews data examining the efficacy of vaccination against respiratory syncytial virus, a respiratory viral illness that has had devastating effects globally. Four studies evaluate the role of various therapies in COPD, including dupilumab, ensifentrine, pulmonary rehabilitation programs, and lung volume reduction versus endobronchial valves. Another study explores the effect on vascular events of positive-pressure ventilation in patients with sleep-disordered breathing and recent stroke. The use of combination therapy with rituximab and mycophenolate mofetil on progression-free survival in patients with nonspecific interstitial pneumonia is the topic of another study. We also highlight an update of clinical recommendations for the evaluation of patients with pleural disorders and a systematic review analyzing the effectiveness of inhaled corticosteroids as a supplement to dual therapy for COPD.

Real-World Effectiveness of Single-Inhaler Triple Therapy for COPD: Impact of Diabetes Comorbidity

Background Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment. Methods In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes. Results The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86–1.25) among COPD patients with type 2 diabetes and 0.74 (0.65–0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14–2.75). Conclusion Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.

Sex-differences in COPD: from biological mechanisms to therapeutic considerations.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory condition characterized by symptoms of dyspnea, cough, and sputum production. We review sex-differences in disease mechanisms, structure-function-symptom relationships, responses to therapies, and clinical outcomes in COPD with a specific focus on dyspnea. Females with COPD experience greater dyspnea and higher morbidity compared to males. Imaging studies using chest computed tomography scans have demonstrated that females with COPD tend to have smaller airways than males as well as a lower burden of emphysema. Sex-differences in lung and airway structure lead to critical respiratory mechanical constraints during exercise at a lower absolute ventilation in females compared to males, which is largely explained by sex differences in maximum ventilatory capacity. Females experience similar benefit with respect to inhaled COPD therapies, pulmonary rehabilitation, and smoking cessation compared to males. Ongoing re-assessment of potential sex-differences in COPD may offer insights into the evolution of patterns of care and clinical outcomes in COPD patients over time.

Antioxidant Glutathione Analogues UPF1 and UPF17 Modulate the Expression of Enzymes Involved in the Pathophysiology of Chronic Obstructive Pulmonary Disease.

Increased oxidative stress (OS) and systemic inflammation are key players in the pathophysiology of chronic obstructive pulmonary disease (COPD). We aimed to clarify the effects of synthetic glutathione (GSH) analogue peptides UPF1 and UPF17 on the mRNA levels of enzymes involved in systemic inflammation and GSH metabolism in peripheral blood mononuclear cells (PBMCs) from patients with acute exacerbation of COPD (AE-COPD) and stable COPD along with non-obstructive smokers and non-smokers. UPF1 and UPF17 increased the expression of enzymes involved in the formation of the antioxidant capacity: superoxide dismutase 1 (SOD1) and the catalytic subunit of glutamyl-cysteine ligase (GCLC) in patients with AE-COPD and stable COPD, but also in non-obstructive smokers and non-smokers. Similarly, both UPF1 and UPF17 increased the expression of inflammatory enzymes poly(ADP-ribose) polymerase-1 (PARP-1), dipeptidyl peptidase 4 (DPP4), and cyclooxygenase-2 (COX-2). Both UPF analogues acted in a gender-dependent manner by increasing the expression of certain anti-inflammatory (histone deacetylase 2 (HDAC2)) and GSH metabolism pathway (SOD1 and GSH reductase (GSR))-related enzymes in females and decreasing them in males. UPF1 and UPF17 are able to increase the expression of the enzymes involved in GSH metabolism and could serve as a lead for designing potential COPD therapies against excessive OS.

Bidirectional relationship between chronic obstructive pulmonary disease and oral disease

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that has various comorbid conditions and systemic complications. One of the complications is dental and oral disease, which can occur through systemic inflammatory mechanisms and the long-term side effects of inhaled drugs. Dental and oral diseases can also cause COPD progression, increase the risk of exacerbations, and affect the patient's quality of life. Some mechanisms that may play a role include aspiration of oral pathogens, aspiration of inflammatory proteins, and systemic inflammation. Dysbiosis of the lung microbiome can result from dental and oral conditions, increasing the risk of COPD and pulmonary infections. The association between COPD and oral disease includes the presence of systemic inflammatory conditions, the risk factor of smoking, and the indirect effects of inhaled medication use. Comprehensive management of COPD patients regarding dental and oral health is needed, which includes prevention of dental and oral disease, routine assessment of dental and oral health, provision of specific dental therapy, and personalized treatment in selecting COPD therapy.

Autologous transplantation of P63+ lung progenitor cells for chronic obstructive pulmonary disease therapy.

Adult lung resident stem/progenitor cells, including P63+ progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63+ progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63+ progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 106 to 5.2 × 106 cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, n = 17; control group, n = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: -17.4%; P = 0.008). Furthermore, participants in the intervention group showed >30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of P63 was associated with treatment efficacy. In conclusion, transplantation of cultured P63+ lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.

Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease.

Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.

The cuproptosis-related gene glutaminase promotes alveolar macrophage copper ion accumulation in chronic obstructive pulmonary disease

Cuproptosis, a novel mode of cell death, is strongly associated with a variety of diseases. However, the contribution of cuproptosis to the onset or progression of chronic obstructive pulmonary disease (COPD), the third most common chronic cause of mortality, is not yet clear. To investigate the potential role of cuproptosis in COPD, raw datasets from multiple public clinical COPD databases (including RNA-seq, phenotype, and lung function data) were used. For further validation, mice exposed to cigarette smoke for three months were used as in vivo models, and iBMDMs (immortalized bone marrow-derived macrophages) and RAW264.7 cells stimulated with cigarette smoke extract were used as in vitro models. For the first time, the expression of the cuproptosis-related gene glutaminase (GLS) was found to be decreased in COPD, and the low expression of GLS was significantly associated with the grade of pulmonary function. In vivo experiments confirmed the decreased expression of GLS in COPD, particularly in alveolar macrophages. Furthermore, in vitro studies revealed that copper ions accumulated in alveolar macrophages, leading to a substantially decreased amount of cell activity of macrophages when stimulated with cigarette extract. In summary, we demonstrate the high potential of GLS as an avenue for diagnosis and therapy in COPD.

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.

A perspective current and past modes of inhalation therapy.

Inhalation is the preferred route of delivery for anti-asthma and chronic obstructive pulmonary disease (COPD) drugs. The use of this route has demonstrated efficacy in these and other conditions, it offers rapid onset of action, and is associated with minimal systemic exposure, thereby reducing the risk of adverse effects. Therefore, the current brief covers an interesting collection of inhaler action modes, shedding light on their molecular mechanisms and clinical applications for anti-asthma, COPD and antibacterial inhalation therapy. Hence, not only enriches our understanding of inhalation therapy molecular intricacies but also provides a comprehensive overview of the evolving landscape in clinical and antibacterial inhalation therapy. In doing so, it underscores the pivotal role of microbiology and biotechnology in advancing therapeutic approaches that harness the power of inhalation.

Lung regeneration: diverse cell types and the therapeutic potential.

Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

Development of a disease-specific health utility score for chronic obstructive pulmonary disease from a discrete choice experiment patient preference study.

While patient input to health technology assessment (HTA) has traditionally been of a qualitative nature, there is increasing interest to integrate quantitative evidence from patient preference studies into HTA decision making. Preference data can be used to generate disease-specific health utility data. We generated a health utility score for patients with chronic obstructive pulmonary disease (COPD) and consider its use within HTAs. Based on qualitative research, six symptoms were identified as important to COPD patients: shortness of breath, exacerbations, chronic cough, mucus secretion, sleep disturbance, and urinary incontinence. We employed a discrete choice experiment (DCE) and the random parameter logistic regression technique to estimate utility scores for all COPD health states. The relationship between patients' COPD health utility scores, self-perceived COPD severity, and EQ-5D-3L utility scores was analyzed, with data stratified according to disease severity and comorbidity subgroups. The COPD health utility score had face validity, with utility scores negatively correlated with patients' self-perceived COPD severity. The correlation between the COPD health utility scores and EQ-5D-3L values was only moderate. While patient EQ-5D-3L scores were impacted by comorbidities, the COPD health utility score was less impacted by comorbid conditions. Our COPD utility measure, derived from a DCE, provides a patient-centered health utility score and is more sensitive to the COPD health of the individual and less sensitive to other comorbidities. This disease-specific instrument should be considered alongside generic health-related quality of life instruments when valuing new COPD therapies in submissions to licensing and reimbursement agencies.

The combination of astragalus injection and ambroxol hydrochloride in the adjuvant treatment of COPD: a systematic review and meta-analysis

Chronic obstructive pulmonary disease (COPD) is a severe condition that leads to premature mortality and places a significant financial burden on healthcare systems. An adjunctive therapy in COPD includes the simultaneous administration of astragalus injection and ambroxol hydrochloride. Despite its widespread use, the effectiveness of this combined approach in COPD treatment has not been systematically evaluated. Thus, we conducted a systematic review and meta-analysis to assess the efficacy of combining astragalus injection with ambroxol hydrochloride as an adjuvant treatment for COPD. Six electronic databases were used to search for relevant randomized controlled trials, and data analysis was conducted using Review Manager 5.4. A total of 14 randomized controlled trials were included, involving 1070 patients who met the criteria. The results of the meta-analysis indicated that the combination of astragalus injection with ambroxol hydrochloride as an adjuvant treatment can improve various clinical parameters in patients with COPD compared to conventional treatment alone. These parameters include the clinical effective rate (OR = 5.44, 95% CI 3.51–8.43, I2 = 0%), partial pressure of oxygen in artery (MD = 1.12, 95% CI 0.87–1.36, I2 = 5%), partial pressure of carbon dioxide in artery (MD = − 1.43, 95% CI − 1.65 to − 1.21, I2 = 0%), forced expiratory volume in one second (MD = 0.30, 95% CI 0.18–0.42, I2 = 0%), percentage of forced expiratory volume in one second (MD = 16.18, 95% CI 12.60–19.76, I2 = 82%), forced vital capacity (MD = 0.33, 95% CI 0.21–0.45, I2 = 36%), hemoglobin (MD = − 16.17, 95% CI − 20.84 to − 11.51, I2 = 29%), and the ratio of forced expiratory volume in one second to forced vital capacity (MD = 2.51, 95% CI − 0.05 to 5.06, I2 = 0%). The combination of astragalus injection and ambroxol hydrochloride could be a selection of COPD patients as an adjuvant treatment. However, further validation is required to evaluate the effectiveness of combining astragalus injection and ambroxol hydrochloride as an adjunctive treatment for patients with COPD.

Feasibility, safety and tolerability of CT-guided percutaneous thermal ablation in COPD with malignant pulmonary nodules

For early-stage non-small cell lung cancer, surgical resection was used as the first treatment. However, approximately 20% of patients were not suitable for surgery due to severe comorbidities. We verified the feasibility, safety, and tolerability of percutaneous thermal ablation for patients of chronic obstructive pulmonary disease (COPD) with peripheral high-risk pulmonary nodules in the real world. The patients with peripheral high-risk pulmonary nodules ineligible or unwilling to undergo surgery who were ineligible or unwilling tosurgery underwent CT-guided thermal ablation in our hospital from January 1st, 2019 to May 31th, 2022 were retrospectively collected, and divided into COPD and non COPD group. Incidence, severity, risk factors of complications between in different severity of COPD and non-COPD group were compared. A total of 216 high-risk were enrolled, including 73 in COPD group and 143 in the non-COPD group. The average age, male gender, MMRC score, size of nodules, incidence of confirmed pathological diagnosis, and pneumothorax after thermal ablation were higher in the COPD group than in the non-COPD group. COPD was the only independent risk factor for pneumothorax after ablation. The incidence of pneumothorax increased with the severity of COPD, but no statistical significance. Compared to the baseline, the MMRC score was significantly increased in the COPD group, but there was no significant difference in the discharge time and hospitalization expenses between the COPD patients with or without pneumothorax. CT-guided percutaneous thermal ablation is a safe and feasible therapy for different severities of COPD with high-risk pulmonary nodules, and it is well-tolerated without increasing medical burden.

The role of peak inspiratory flow in the selection of inhalation therapy in patients with chronic obstructive pulmonary disease

Pharmacotherapy for chronic obstructive pulmonary disease (COPD) primarily relies on inhalation therapy. The choice of an appropriate inhalation device is of particular importance as it impacts the frequency of device use errors, patient adherence to treatment, and overall treatment effectiveness. Peak inspiratory flow (PIF) represents the maximum air flow rate generated by a patient during inhalation and is measured in liters per minute. Dry powder inhalers (DPIs) possess internal device resistance that patients must overcome to activate the device. Measuring PIF is an integral component of optimizing COPD therapy when utilizing dry powder inhalers (DPIs). For most DPIs, an optimal PIF value is considered to be no less than 60 L/min, while with a PIF of less than 30 L/min, the medication can’t reach the lower airways. At the same time, the clinical effectiveness of the use of DPI at values of PIF from 30 L/min to 60 L/min may be insufficient, therefore, it is necessary to take into account the value of PIF for the selection of basic COPD therapy. Given the lack of portable fluometers among doctors in real clinical practice, it is important to identify risk factors for suboptimal PIF in patients with COPD. Patients with emphysema, pulmonary hyperinflation, elderly, female, short height, obesity and comorbidity are at risk for insufficient PIF value for further effective use of DPI.This review provides essential information about the role of inspiratory flow for the effective use of DPIs, presents methods for its measurement, discusses predictors of suboptimal PIF, and offers recommendations for selecting inhalation devices for COPD patients based on PIF values.

Clinical efficacy of a triple combination of budesonide/ glycopyrronium bromide/formoterol in the treatment of chronic obstructive pulmonary disease

Chronic Obstructive Pulmonary Disease (COPD) is a chronic condition characterized by persistent airflow limitation, caused by chronic inflammation in response to exposure to inhaled damaging particles or gases. Exacerbations of COPD lead to the progression of symptoms, worsening lung function, reduced physical tolerance, and, as a result, contribute to an increase mortality. Therefore, the prevention of exacerbations is a primary objective in the management of COPD. The foundation of COPD therapy involves prescribing long-acting bronchodilators, and for some patients, the use of anti-inflammatory agents, such as inhaled corticosteroids (ICS). ICS are used in combination with long-acting beta2-agonists (LABA) or as part of triple therapy (ICS/LABA/ LAMA). The choice of triple therapy depends on the patient’s exacerbation history, severity of symptom, level of peripheral blood eosinophilia, risk of infectious complications, and the presence of a concomitant diagnosis of bronchial asthma. Triple therapy offers advantages in terms of improving lung function, disease symptoms, reducing exacerbation frequency, and significantly decreasing mortality compared to other inhaled therapy options for COPD. A significant advantage of this therapy has been shown in patients with eosinophilic COPD. Currently, three combined inhalation medications containing ICS/LABA/LAMA are available for COPD treatment in our country. This review provides basic information on the clinical efficacy and safety profile of one of them, budesonide/glycopyrronium bromide/formoterol, in patients with various COPD phenotypes.

Mitochondrial Dysfunction and Nanocarrier-Based Treatments in Chronic Obstructive Pulmonary Disease (COPD)

Mitochondrial dysfunction significantly contributes to the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). To treat mitochondrial dysfunction in COPD, novel drug delivery systems (DDS) are needed. In this review, we provide a brief overview of the current understanding of the factors in COPD and highlight the trends in novel nanocarriers/nanoparticles for targeting mitochondrial dysfunction. These drug-encapsulated nanoparticles are still in the early stages of clinical application but represent the most promising system for COPD therapy.

Targeting biophysical microenvironment for improved treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is responsible for high disability rates, high death rates, and significant cost to health systems. Growing evidence in recent decades shows significant biophysical microenvironment changes in COPD, impacting lung tissues, cells, and treatment response. Furthermore, such biophysical changes have shown great potential as novel targets for improved therapeutic strategy of COPD, where both pharmacological and non-pharmacological therapies focusing on repairing the biophysical microenvironment of the lung have emerged. We present the first comprehensive review of four distinct biophysical hallmarks [i.e., extracellular matrix (ECM) microarchitecture, stiffness, fluid shear stress, and mechanical stretch] in COPD, the possible involvement of pathological changes, possible effects, and correlated in vitro models and sum up the emerging COPD treatments targeting these biophysical hallmarks.

Chronic obstructive pulmonary disease and modern therapies

Chronic obstructive pulmonary disease and modern therapies

The Effectiveness and Safety of Long-Term Macrolide Therapy for COPD in Stable Status: A Systematic Review and Meta-Analysis.

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition with fewer treatments available as the severity increases. Previous systematic reviews have demonstrated the benefits of long-term macrolide use. However, the therapeutic differences between different macrolides and the optimal duration of use remain unclear. Methods: A systematic review and meta-analysis were conducted to assess the effectiveness of long-term macrolide use in reducing COPD exacerbations, compare the therapeutic differences among macrolides, and determine the appropriate treatment duration. Four databases (PubMed, Cochrane Library, Web of Science, and ICHU-SHI) were searched until 20 March 2023, and a random-effects model was used to calculate the pooled effect. Results: The meta-analysis included nine randomized controlled trials involving 1965 patients. The analysis revealed an odds ratio (OR) of 0.34 (95% confidence interval [CI] 0.19, 0.59, p < 0.001) for the reduction in exacerbation frequency. Notably, only azithromycin or erythromycin showed suppression of COPD exacerbations. The ORs for reducing exacerbation frequency per year and preventing hospitalizations were -0.50 (95% CI: -0.81, -0.19; p = 0.001) and 0.60 (95% CI: 0.3, 0.97; p = 0.04), respectively. Statistical analyses showed no significant differences between three- and six-month macrolide prescriptions. However, studies involving a twelve-month prescription showed an OR of 0.27 (95% CI: 0.11, 0.68; p = 0.005; I2 = 81%). Although a significant improvement in St George's Respiratory Questionnaire (SGRQ) total scores was observed with a mean difference of -4.42 (95% CI: -9.0, 0.16; p = 0.06; I2 = 94%), the minimal clinically important difference was not reached. While no adverse effects were observed between the two groups, several studies have reported an increase in bacterial resistance. Conclusions: Long-term use of azithromycin or erythromycin suppresses COPD exacerbations, and previous studies have supported the advantages of a 12-month macrolide prescription over a placebo.