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Phosphodiesterase-4 (PDE4) inhibitors have the potential to suppress inflammatory cells and structural cells in chronic obstructive pulmonary disease patients, giving a broad spectrum anti-inflammatory profile.
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Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new trea...
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Context 1
... interest in PDE4, which hydolyses cyclic adenosine 5'-monophosphate and is the predominant PDE enzyme expressed in neutrophils, CD4+, CD8 + cells, mono- cytes and is also present in macrophages [163]. PDE4 is also present in airway smooth muscle and epithelial cells, indicat- ing that PDE4 inhibitors could also have effects on structural cells ( fig. 3). Thus, there is compelling scientific rationale for the use of PDE4 inhibitors in COPD, although their clinical development has been slow [164,165]. Selective PDE4 inhibitors, such as rolipram, cilomilast and roflumilast, are active in several animal models of neutrophil inflammation, confirming their anti-inflammatory potential ...
Similar publications
Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtain...
Citations
... The usage of bronchodilators for the management of COPD is an important advance. It has been long acting, but the underlying mechanism for these drugs to deal with the inflammatory process is not known [132]. COPD shows heterogeneous clinical phenotypes, which leads to incongruent groups with unstable disease mechanisms or molecular pathways, leading to inconsistent approaches for the development of new therapies [133]. ...
The global prevalence of chronic obstructive pulmonary disease (COPD) has increased over the last decade and has emerged as the third leading cause of death worldwide. It is characterized by emphysema with prolonged airflow limitation. COPD patients are more susceptible to COVID-19 and increase the disease severity about four times. The most used drugs to treat it show numerous side effects, including immune suppression and infection. This review discusses a narrative opinion and critical review of COPD. We present different aspects of the disease, from cellular and inflammatory responses to cigarette smoking in COPD and signaling pathways. In addition, we highlighted various risk factors for developing COPD apart from smoking, like occupational exposure, pollutants, genetic factors, gender, etc. After the recent elucidation of the underlying inflammatory signaling pathways in COPD, new molecular targeted drug candidates for COPD are signal-transmitting substances. We further summarize recent developments in biomarker discovery for COPD and its implications for disease diagnosis. In addition, we discuss novel drug targets for COPD that could be explored for drug development and subsequent clinical management of cardiovascular disease and COVID-19, commonly associated with COPD. Our extensive analysis of COPD cause, etiology, diagnosis, and therapeutic will provide a better understanding of the disease and the development of effective therapeutic options. In-depth knowledge of the underlying mechanism will offer deeper insights into identifying novel molecular targets for developing potent therapeutics and biomarkers of disease diagnosis.
... 5 The implication of immune pathways in guiding host-directed therapeutics for COPD Immune pathways orchestrating lung tissue damage and fibrosis in tuberculosis or post-tuberculosis disease warrant a careful search into possibilities of using a select group of immune-based therapies optimal for patients diagnosed with tuberculosis-associated COPD (Barnes and Stockley, 2005). This section discusses a select list of immune-based therapies for tuberculosis, traditionally referred to as host-directed therapies (HDTs). ...
Pulmonary tuberculosis is increasingly recognized as a risk factor for COPD. Severe lung function impairment has been reported in post-TB patients. Despite increasing evidence to support the association between TB and COPD, only a few studies describe the immunological basis of COPD among TB patients following successful treatment completion. In this review, we draw on well-elaborated Mycobacterium tuberculosis-induced immune mechanisms in the lungs to highlight shared mechanisms for COPD pathogenesis in the setting of tuberculosis disease. We further examine how such mechanisms could be exploited to guide COPD therapeutics.
... Current treatment strategies for COPD: Although current therapies for COPD have significantly improved the management of the disease, novel therapeutic approaches are still urgently needed, especially for suppressing inflammation in small airways (92). Cigarette smoke is one of the major factors for COPD and smoking cessation has so far been shown to diminish disease progression. ...
... A variety of other interventions can lower the exacerbations in COPD, including influenza vaccination (94), anti-cholinergic bronchodilators (95), long-acting b 2 -agonists (LABAs) (96), and inhaled corticosteroids (ICSs). Further research is needed to understand the cell signaling mechanisms of COPD so that biomarkers can be identified and new therapies can be developed (92). ...
Lungs are important respiratory organs primarily involved in gas exchange. Lungs interact directly with the environment and their primary function is affected by several inflammatory responses caused by allergens, inflammatory mediators, and pathogens, eventually leading to disease. The immune architecture of the lung consists of an extensive network of innate immune cells, which induce adaptive immune responses based on the nature of the pathogen(s). The balance of immune responses is critical for maintaining immune homeostasis in the lung. Infection by pathogens and physical or genetic dysregulation of immune homeostasis result in inflammatory diseases. These responses culminate in the production of a plethora of cytokines such as TSLP, IL-9, IL-25, and IL-33, which have been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Shifting the balance of Th1, Th2, Th9, and Th17 responses have been the targets of therapeutic interventions in the treatment of these diseases. Here, we have briefly reviewed the innate and adaptive i3mmune responses in the lung. Genetic and environmental factors, and infection are the major causes of dysregulation of various functions of the lung. We have elaborated on the impact of inflammatory and infectious diseases, advances in therapies, and drug delivery devices on this critical organ. Finally, we have provided a comprehensive compilation of different inflammatory and infectious diseases of the lungs and commented on the pros and cons of different inhalation devices for the management of lung diseases. The review is intended to provide a summary of the immunology of the lung, with an emphasis on drug and device development.
... Emphysema, a major COPD phenotype, has been independently associated 3 with an increased risk for cardiovascular disease, lung cancer, and mortality (2)(3)(4). While 4 some progress has been made in treating COPD, much work remains in identifying 5 therapeutic targets specifically for emphysema (5). Furthermore, timely diagnosis calls for a 6 ...
... Counts were transformed 3 to log2 CPM values and quantile-normalized to further remove systematic noise from the 4 data. 5 6 Protein measurements and filtering 7 ...
Rationale: Emphysema is a key component of COPD with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and possible development of targeted therapies.
Objectives: Discover blood transcriptomic and proteomic biomarkers for chest computed tomography-quantified emphysema in smokers and develop predictive biomarker panels.
Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training set of 2,370 COPDGene participants with available whole blood RNA sequencing, plasma SomaScan proteomics, and clinical data. Validation was conducted in a testing set of 1,016 COPDGene subjects. Since body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Predictive models were also developed using elastic net to predict quantitative emphysema from cell blood count, RNA sequencing, and proteomic biomarkers. Model accuracy was assessed by area under the receiver-operator-characteristic-curves (AUROC) for subjects stratified into tertiles of emphysema severity.
Measurements and Main Results: 4,913 genes, 1,478 isoforms, 386 exons, and 881 proteins were significantly associated with emphysema (FDR 10%). 75% and 77% of genes and proteins, respectively, were mediated by BMI. The significantly enriched biological pathways were involved in inflammation and cell differentiation, differing between the most and least BMI-mediated genes. The cell blood count plus protein model achieved the highest performance with an AUROC of 0.89.
Conclusions: Blood transcriptome and proteome-wide analyses reveal key biological pathways of emphysema and enhance the prediction of emphysema.
... Indeed, it is known that exacerbations of COPD, which are often triggered by viral or bacterial infection, are associated with a more rapid decline in lung function. The more often exacerbations happen, the more destruction occurs, and full resolution of the inflammation becomes difficult [21,23,65]. Therefore, hindering pathogen entry by protecting the clearance process might halt COPD progression. ...
Airway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes and microRNA-449 (miR449). In vitro, miR449 was strongly increased during airway epithelial mucociliary differentiation. In vivo, miR449 was upregulated during recovery from chemical or infective insults. miR0449−/− mice (both alleles are deleted) showed impaired ciliated epithelial regeneration after naphthalene and Haemophilus influenzae exposure, accompanied by more intense inflammation and emphysematous manifestations of COPD. The latter occurred spontaneously in aged miR449−/− mice. We identified Aurora kinase A and its effector target HDAC6 as key mediators in miR449-regulated ciliary homeostasis and epithelial regeneration. Aurora kinase A is downregulated upon miR449 overexpression in vitro and upregulated in miR449−/− mouse lungs. Accordingly, imaging studies showed profoundly altered cilia length and morphology accompanied by reduced mucociliary clearance. Pharmacological inhibition of HDAC6 rescued cilia length and coverage in miR449−/− cells, consistent with its tubulin-deacetylating function. Altogether, our study establishes a link between miR449, ciliary dysfunction, and COPD pathogenesis.
... Aerobic exercise training is an effective non-pharmacological approach that should be included in pulmonary rehabilitation programs for COPD patients [11][12][13]. Exercise training attenuates cytokine levels potentially via modulation of the cholinergic anti-inflammatory pathway, due to increased vagus nerve activity [14]. Moderate to high levels of regular physical activity can reduce the risk of COPD development and lung function decline among smokers [15] and exercise training attenuated respiratory mechanics impairments and protected against pulmonary emphysema development, due to inhibition of inflammation and oxidative stress induced by exposure to cigarette smoke in mice [16,17]. ...
Lung inflammation is modulated by cholinergic signaling and exercise training protects mice against pulmonary emphysema development; however, whether exercise training engages cholinergic signaling is unknown.
Aims
As cholinergic signaling is directly linked to the vesicular acetylcholine transporter (VAChT) levels, we evaluated whether the effects of aerobic exercise training depend on the VAChT levels in mice with pulmonary emphysema.
Main methods
Wild-type (WT) and mutant (KDHOM) mice (65–70% of reduction in VAChT levels) were exposed to cigarette smoke (30 min, 2×/day, 5×/week, 12 weeks) and submitted or not to aerobic exercise training on a treadmill (60 min/day, 5×/week, 12 weeks). Lung function and inflammation were evaluated.
Key findings
Cigarette smoke reduced body mass in mice (p < 0.001) and increased alveolar diameter (p < 0.001), inflammation (p < 0.001) and collagen deposition (p < 0.01) in lung tissue. Both trained groups improved their performance in the final physical test compared to the initial test (p < 0.001). In WT mice, exercise training protected against emphysema development (p < 0.05), reduced mononuclear cells infiltrate (p < 0.001) and increased MAC-2 positive cells in lung parenchyma (p < 0.05); however, these effects were not observed in KDHOM mice. The exercise training reduced iNOS-positive cells (p < 0.001) and collagen fibers deposition (p < 0.05) in lung parenchyma of WT and KDHOM mice, although KDHOM mice showed higher levels of iNOS-positive cells.
Significance
Our data suggest that the protective effects of aerobic exercise training on pulmonary emphysema are, at least in part, dependent on the integrity of the lung cholinergic signaling.
... Chronic obstructive pulmonary disease (COPD) is a serious health problem in which progressive and irreversible airflow limitations are observed, and it is caused by an abnormal inflammatory response to cigarette smoke (CS) and air pollution. Long-acting β 2 -agonists (LABAs) and muscarinic receptor antagonists (LAMAs) are used clinically for bronchodilation in the treatment of COPD [1,2]. Although steroid therapy is commonly used to treat inflammation associated with COPD, there are some cases in which steroid therapy does not sufficiently suppress COPD disease progression because of resistance to steroid therapy in part of the inflammatory processes [1,3]. ...
... Long-acting β 2 -agonists (LABAs) and muscarinic receptor antagonists (LAMAs) are used clinically for bronchodilation in the treatment of COPD [1,2]. Although steroid therapy is commonly used to treat inflammation associated with COPD, there are some cases in which steroid therapy does not sufficiently suppress COPD disease progression because of resistance to steroid therapy in part of the inflammatory processes [1,3]. Therefore, it is important to discover new proteins that inhibit the onset and exacerbation of COPD and to develop new types of anti-inflammatory compounds for treating COPD. ...
Although the pathogenesis of chronic obstructive pulmonary disease (COPD) is not yet fully understood, recent studies suggest that the disruption of the intracellular balance of oxidative (such as reactive oxygen species (ROS)) and antioxidant molecules plays an important role in COPD development and progression. Metallothionein is an endogenous metal-binding protein with reported ROS scavenging activity. Although there have been many publications on the protective effects of metallothionein in the kidney and liver, its role in COPD models such as elastase- or cigarette smoke (CS)-induced lung injury is unknown. Thus, in the present study, we analyzed the elastase-induced lung injury model using metallothionein-knockout (MT-KO; MT-1 and -2 gene deletion) mice. The expression of MT-1 and MT-2 in the lungs of MT-KO mice was markedly lower compared with that in the lungs of wildtype (WT) mice. Porcine pancreatic elastase (PPE)-induced lung injury (alveolar enlargement and respiratory impairment) was significantly exacerbated in MT-KO mice compared with WT mice. Additionally, PPE-induced increases in the number of inflammatory cells, inflammatory cytokines, and cell death in lung tissue were significantly more pronounced in MT-KO mice compared with WT mice. Finally, using an in vivo imaging system, we also found that PPE-induced ROS production in the lungs was enhanced in MT-KO mice compared with WT mice. These results suggest that metallothionein may act as an inhibitor against elastase-induced lung injury by suppressing ROS production. These results suggest that metallothionein protein, or compounds that can induce metallothionein, could be useful in the treatment of COPD.
... J.F.Macbr. (Fabaceae) contains numerous proteinase inhibitors (Araújo et al., 2005;Barnes and Stockley, 2005) Martins- Olivera et al. (2016). demonstrated that treatment of emphysematous mice with B. bauhinioides kallikrein proteinase inhibitor reduces the count of macrophages, neutrophils, lymphocytes, eosinophils in bronchioalveolar lavage fluid and reduces the MMP-9, MMP-12, TIMP-1 (remodeling factors), iNOS, eNOS, and PGE2α (oxidative stress factors), and TNFα (inflammatory factors) levels in the alveolar walls (Martins-Olivera et al., 2016). ...
Background
: Chronic obstructive pulmonary disease (COPD) is a class of lung diseases including chronic bronchitis, asthma, and emphysema. Long-time smoking is considered the main reason for developing emphysema. Emphysema can be defined as damage to the walls of the air sacs (alveoli) of the lung. It has been demonstrated that natural compounds with antioxidant and anti-inflammatory effects can effectively improve or protect the lung against this disease. This paper is dedicated to systematically review the effective natural compounds in the treatment of pulmonary emphysema.
Purpose
: This is the first systematic and comprehensive review on the role of plant-derived secondary metabolites in managing and/or treating pulmonary emphysema
Study design and Methods
: A systematic and comprehensive review was done based on Scopus, PubMed, and Cochrane Library databases were searched using the "emphysema", "plant", "herb", and "phytochemical" keywords. Non-English, review, and repetitive articles were excluded from the study. Search results were included in the Prisma diagram.
Results
: From a total of 1285 results, finally, 22 articles were included in the present study. The results show that some herbs such as Scutellaria baicalensis Georgi and Monascus adlay and some phytochemicals such as gallic acid and quercetin and blackboard tree indole alkaloids affect more factors in improving the lung emphysema. Also, some natural compounds such as marijuana smoke and humic acid also play an aggravating role in this disease. It also seems that some of the medicinal plants such as PM014 herbal formula, pomegranate juice and açaí berry sometimes have side effects that are inconsistent with their therapeutic effects.
Conclusion
: We concluded that natural compounds can effectively improve pulmonary emphysema due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. However, additional studies are suggested to prove efficacy and side effects.
... These results showed that the pyrolysis smoke-induced inflammatory response via the activation of the NF-κB-dependent inflammatory signaling pathway. 31 Pre-treating of macrophages with A. lactiflora extract and fractions prior to inducing inflammatory response by pyrolysis smoke demonstrated anti-inflammatory activities. All extract and fractions significantly down-regulated expression of pro-inflammatory genes (RelA, TNF, IL6) and decreased secretion of pro-inflammatory cytokines (TNF-α, IL-6), p < 0.0001, compared with pyrolysis smoke-induced macrophage (Figure 4-5). ...
Artemisia lactiflora, a Chinese-origin plant, has been reported to have unique phytochemicals responsible for its medicinal properties. The growth of the agricultural industry emits air pollution, which has adverse effects on health. There are limited scientific reports on the biological activities of A. lactiflora. Studies on its activities and mechanisms may provide insight into its use in medicinal purposes to treat those health problems and conditions. In this study, leaves of A. lactiflora were extracted and fractioned with solvents of different polarities. Total phenolics, total flavonoids DPPH • scavenging, ABTS •+ scavenging, and cytotoxicity of A. lactiflora were assessed. Anti-inflammatory activities were evaluated by pre-treating macrophages with extract or fractions then induced inflammatory response by coconut shell pyrolysis smoke. Inflammatory responses were assessed by measuring pro-inflammatory genes expression and pro-inflammatory cytokines secretion. Among all extract and fractions of A. lactiflora, butanol fraction has the highest phenolic, flavonoid, and DPPH • scavenging activity. All extract and fractions significantly down-regulated pro-inflammatory genes expression ( RelA, TNF, IL6) and decreased pro-inflammatory cytokines secretion (TNF-α, IL-6), p < 0.0001, compared with pyrolysis smoke-induced macrophages. The ethyl acetate fraction showed the highest anti-inflammatory activity in decreasing pro-inflammatory cytokines secretion. These results may prove the anti-inflammatory activities of A. lactiflora through the inhibition of the NF-κB-dependent pathway. Taken together, this study first reported the anti-inflammatory activities of A. lactiflora. Thus, the plant can be used to prevent and treat inflammatory responses caused by highly oxidative pyrolysis smoke released from the re-utilization of agro-industrial leftovers.
... Available medicaments (anti-inflammatory drugs, β2agonists, and anticholinergics) efficiently reduce airflow limitation and improve the quality of life of COPD patients, but they are not able to prevent disease progression and mortality [13]. Since COPD is projected to become the third leading cause of disease mortality worldwide by 2020 [1,2], new therapeutic approaches are urgently needed in order to prevent progression and exacerbation of COPD. ...
Mesenchymal stem cells (MSCs), due to their potential for differentiation into alveolar epithelial cells and their immunosuppressive characteristics, are considered a new therapeutic agent in cell-based therapy of inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD). Since most of the MSC-mediated beneficent effects were the consequence of their paracrine action, herewith, we investigated the effects of a newly designed MSC-derived product "Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)" in the attenuation of chronic airway inflammation by using an animal model of COPD (induced by chronic exposure to cigarette smoke (CS)) and clinical data obtained from Exo-d-MAPPS-treated COPD patients. Exo-d-MAPPS contains a high concentration of immunomodulatory factors which are capable of attenuating chronic airway inflammation, including soluble TNF receptors I and II, IL-1 receptor antagonist, and soluble receptor for advanced glycation end products. Accordingly, Exo-d-MAPPS significantly improved respiratory function, downregulated serum levels of inflammatory cytokines (TNF-α, IL-1β, IL-12, and IFN-γ), increased serum concentration of immunosuppressive IL-10, and attenuated chronic airway inflammation in CS-exposed mice. The cellular makeup of the lungs revealed that Exo-d-MAPPS treatment attenuated the production of inflammatory cytokines in lung-infiltrated macrophages, neutrophils, and natural killer and natural killer T cells and alleviated the antigen-presenting properties of lung-infiltrated macrophages and dendritic cells (DCs). Additionally, Exo-d-MAPPS promoted the expansion of immunosuppressive IL-10-producing alternatively activated macrophages, regulatory DCs, and CD4+FoxP3+T regulatory cells in inflamed lungs which resulted in the attenuation of chronic airway inflammation. In a similar manner, as it was observed in an animal model, Exo-d-MAPPS treatment significantly improved the pulmonary status and quality of life of COPD patients. Importantly, Exo-d-MAPPS was well tolerated since none of the 30 COPD patients reported any adverse effects after Exo-d-MAPPS administration. In summing up, we believe that Exo-d-MAPPS could be considered a potentially new therapeutic agent in the treatment of chronic inflammatory lung diseases whose efficacy should be further explored in large clinical trials.
