Emphysema Phenotype Research Articles

Clinical application and challenges of thermal vapor lung volume reduction

There are major clinical challenges in the management of chronic obstructive pulmonary disease (COPD). Recent studies suggest that thermal vapor lung volume reduction may be an important interventional method in the treatment of emphysema phenotype of COPD. In this article, we reviewed and summarized the research and development, the current situation of clinical application, and the clinical challenges of thermal vapor lung volume reduction, to provide further clinical evidence for the standardized application of thermal vapor lung volume reduction.

Mice with Lymphatic Dysfunction Develop Pathogenic Lung Tertiary Lymphoid Organs that Model an Autoimmune Emphysema Phenotype of COPD.

We have previously shown that mice with loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development of emphysema. TLOs in CLEC2-deficient mice were rich in plasma cells and were a source of a broad array of autoantibodies. Chronic cigarette smoke exposure increased the size and number of lung TLOs in CLEC2-deficient mice, and was associated with increased markers of antigen presentation and maturation, leading to increased autoantibody deposition. Using lung tissue from COPD patients, we found an increase in lymphatic markers in patients with an emphysema phenotype and autoreactive TLOs compared to COPD patients without emphysema that lack prominent TLOs. Taken together, these results demonstrate that emphysema in mice with lymphatic dysfunction can be partially rescued by blocking TLO formation, and that these TLOs are source of autoantibodies that are exacerbated by cigarette smoke. Our work suggests that lymphatic dysfunction in mice may recapitulate some aspects an autoimmune emphysema phenotype that is seen in a subset of patients with COPD.

The severity assessment and nucleic acid turning-negative-time prediction in COVID-19 patients with COPD using a fused deep learning model

BackgroundPrevious studies have shown that patients with pre-existing chronic obstructive pulmonary diseases (COPD) were more likely to be infected with coronavirus disease (COVID-19) and lead to more severe lung lesions. However, few studies have explored the severity and prognosis of COVID-19 patients with different phenotypes of COPD.PurposeThe aim of this study is to investigate the value of the deep learning and radiomics features for the severity evaluation and the nucleic acid turning-negative time prediction in COVID-19 patients with COPD including two phenotypes of chronic bronchitis predominant patients and emphysema predominant patients.MethodsA total of 281 patients were retrospectively collected from Hohhot First Hospital between October 2022 and January 2023. They were divided to three groups: COVID-19 group of 95 patients, COVID-19 with emphysema group of 94 patients, COVID-19 with chronic bronchitis group of 92 patients. All patients underwent chest computed tomography (CT) scans and recorded clinical data. The U-net model was pretrained to segment the pulmonary involvement area on CT images and the severity of pneumonia were evaluated by the percentage of pulmonary involvement volume to lung volume. The 107 radiomics features were extracted by pyradiomics package. The Spearman method was employed to analyze the correlation of the data and visualize it through a heatmap. Then we establish a deep learning model (model 1) and a fusion model (model 2) combined deep learning with radiomics features to predict nucleic acid turning-negative time.ResultsCOVID-19 patients with emphysema was lowest in the lymphocyte count compared to COVID-19 patients and COVID-19 companied with chronic bronchitis, and they have the most extensive range of pulmonary inflammation. The lymphocyte count was significantly correlated with pulmonary involvement and the time for nucleic acid turning negative (r=-0.145, P < 0.05). Importantly, our results demonstrated that model 2 achieved an accuracy of 80.9% in predicting nucleic acid turning-negative time.ConclusionThe pre-existing emphysema phenotype of COPD severely aggravated the pulmonary involvement of COVID-19 patients. Deep learning and radiomics features may provide more information to accurately predict the nucleic acid turning-negative time, which is expected to play an important role in clinical practice.

Features of Intracellular Matrix State during Development and Formation of COPD Clinical Phenotypes

The objective: to evaluate state of extracellular matrix markers and their tissue inhibitors during development and formation of clinical phenotypes of COPD, in patients facing the high risk of developing exacerbations.Subjects and Methods. 96 COPD patients (73% men and 27% women) were examined. Patients were randomized into the following groups: Group 1 included 40 COPD patients with bronchitis phenotype; Group 2 included 38 patients with emphysema phenotype; and Control Group consisted of 18 practically healthy subjects. All patients underwent a comprehensive clinical and laboratory examination. Levels of matrix metalloproteinases (total MMP-9 and MMP-2) and their tissue inhibitors TIMMP1 and TIMMP2 were determined by ELISA.Results. The development of COPD, regardless of the clinical phenotype of the disease, is accompanied by pronounced expression of extracellular matrix markers MMP-9 and MMP-2. Regardless of the COPD clinical phenotype, elevated activity of metalloproteinases is accompanied by inhibition of production of TIMMP2 and dysfunction of the MMP-9/TIMMP1 antiprotease system. In COPD patients with MMP-2 level of 214 ng/ml, the formation of bronchitis phenotype can be predicted, while with MMP-2 level of 214 ng/ml or more, the formation of emphysema phenotype can be predicted.

Role of quantitative planar lung perfusion scintigraphy and tomography in identifying target lobes in patients with emphysematous phenotype of advanced chronic obstructive pulmonary disease: a retrospective cross-sectional study.

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease. Despite optimal medical therapy and pulmonary rehabilitation, bronchoscopic and surgical lung volume reduction may still be necessary. Identifying the target lobe is crucial for the success of these treatments. This study aims to compare the role of quantitative planar lung perfusion scintigraphy (QPLPS) with quantitative lung computed tomography (StratX®), which is used in identifying the target lobe before the Zephyr® endobronchial valve (EBV) placement in patients with the emphysematous phenotype of advanced COPD. A single-center retrospective cross-sectional study was performed in the Department of Pulmonology at the University of Health Sciences Turkey, Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital between June 2019 and June 2022. The study included 46 patients with the emphysematous phenotype of advanced COPD, who were all candidates for Zephyr® EBV therapy. The target lobes were assessed using the QPLPS and StratX® and the agreement between the methods was analyzed by the Kappa statistic method. Additionally, demographic characteristics, respiratory function tests, distributions of emphysema, and 6-minute walk test results of patients were recorded. The median age was 67 (42-80) years and 42 (91.3%) were male. In QPLPS, the perfusion percentages were 7.47%±3.31%, 9.59%±2.67%, and 13.32%±2.59% for the 1st, 2nd and 3rd target lobes, respectively while in StratX®, the voxel densities were 68.28%±9.16%, 63.79%±7.42%, and 60.69%±5.35%. In StratX®, the fissure integrity (FI) at the target lobe was 76.25%±21.18%, 84.68%±17.67%, and 86.19%±13.19%, respectively. There was a significant agreement between the methods in identifying the first, second, and third target lobes in all patients (Kappa coefficient: 0.897, 0.700, and 0.522), and also in identifying the first and second target lobes in patients with heterogeneous (Kappa coefficient: 0.879, and 0.735), and homogeneous subgroups (Kappa coefficient: 0.919, and 0.672). There is an agreement between QPLPS and StratX® in identifying the target lobe in patients with severe emphysema, including those with homogeneous diseases. However, StratX® may be preferred, considering that it also predicts FI.

COPD is associated with increased cardiovascular disease risk independent of phenotype.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide that frequently presents with concomitant cardiovascular diseases. Despite the pathological distinction between individual COPD phenotypes such as emphysema and chronic bronchitis, there is a lack of knowledge about the impact of COPD phenotype on cardiovascular disease risk. Thus, this study aimed to utilize a nationally representative sample to investigate cardiovascular disease prevalence in patients with COPD with emphysema and chronic bronchitis phenotypes. Data from 31,560 adults including 2504 individuals with COPD, collected as part of the National Health and Nutrition Examination Survey (1999-2018), were examined. A significantly increased cardiovascular disease risk, including coronary heart disease, heart failure, myocardial infarction and stroke, was identified in patients with COPD among all disease phenotypes. Particularly, compared to those without COPD, individuals with chronic bronchitis presented with 1.76 (95% CI: 1.41-2.20) times greater odds, individuals with emphysema with 2.31 (95% CI: 1.80-2.96) times greater odds, while those with a concurrent phenotype (combined chronic bronchitis and emphysema) exhibited 2.98 (95% CI: 2.11-4.21) times greater odds of reporting cardiovascular diseases. Our data confirms that patients with COPD present an elevated risk of developing cardiovascular disease among all phenotypes, with the most marked increase being in those with concurrent chronic bronchitis and emphysema phenotypes. These findings emphasize the need for awareness and appropriate cardiovascular screening in COPD.

Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-β/Smad or Wnt/β-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.

Effect of SHP-1 knockout in airway epithelial cells on emphysema phenotype in chronic obstructive pulmonary disease in mice

Objective: To construct and characterize conditional Src homology region 2 protein tyrosine phosphatase 1 (SHP-1) knockout mice in airway epithelial cells and to observe the effect of defective SHP-1 expression in airway epithelial cells on the emphysema phenotype in chronic obstructive pulmonary disease (COPD). Methods: To detect the expression of SHP-1 in the airway epithelium of COPD patients. CRISPR/Cas9 technology was used to construct SHP-1flox/flox transgenic mice, which were mated with airway epithelial Clara protein 10-cyclase recombinase and estrogen receptor fusion transgenic mice (CC10-CreER+/+), and after intraperitoneal injection of tamoxifen, airway epithelial SHP-1 knockout mice were obtained (SHP-1flox/floxCC10-CreER+/-, SHP-1Δ/Δ). Mouse tail and lung tissue DNA was extracted and PCR amplified to discriminate the genotype of the mice; the knockout effect of SHP-1 gene in airway epithelial cells was verified by qRT-PCR, Western blotting, and immunofluorescence. In addition, an emphysema mouse model was constructed using elastase to assess the severity of emphysema in each group of mice. Results: Airway epithelial SHP-1 was significantly downregulated in COPD patients. Genotyping confirmed that SHP-1Δ/Δ mice expressed CC10-CreER and SHP-1-flox. After tamoxifen induction, we demonstrated the absence of SHP-1 protein expression in airway epithelial cells of SHP-1Δ/Δ mice at the DNA, RNA, and protein levels, indicating that airway epithelial cell-specific SHP-1 knockout mice had been successfully constructed. In the emphysema animal model, SHP-1Δ/Δ mice had a more severe emphysema phenotype compared with the control group, which was manifested by disorganization of alveolar structure in lung tissue and rupture and fusion of alveolar walls to form pulmonary alveoli. Conclusions: The present study successfully established and characterized the SHP-1 knockout mouse model of airway epithelial cells, which provides a new experimental tool for the in-depth elucidation of the role of SHP-1 in the emphysema process of COPD and its mechanism.

Mortality prevention as the centre of COPD management.

COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung function and lower diffusing capacity of the lung for carbon monoxide, decreased exercise capacity, belong to the emphysematous phenotype and those who have concomitant bronchiectasis. Mortality risk seems to be greater in patients who experience COPD exacerbations and in those who suffer from concomitant cardiovascular and/or metabolic diseases. To predict the risk of death in COPD patients, several composite scores have been created using different parameters. In previous years, large studies (also called mega-trials) have evaluated the efficacy of different therapies on COPD mortality, but until recently only nonpharmaceutical interventions have proven to be effective. However, recent studies on fixed combinations of triple therapy (long-acting β-agonists, long-acting muscarinic antagonists and inhaled corticosteroids) have provided encouraging results, showing for the first time a reduction in mortality compared to dual therapies. The aim of the present review is to summarise available data regarding mortality risk in COPD patients and to describe pharmacological therapies that have shown effectiveness in reducing mortality.

Respiratory Oscillometry and Functional Performance in Different COPD Phenotypes.

Chronic obstructive pulmonary disease (COPD) phenotypes may introduce different characteristics that need to be known to improve treatment. Respiratory oscillometry provides a detailed analysis and may offer insight into the pathophysiology of COPD. In this paper, we used this method to evaluate the differences in respiratory mechanics of COPD phenotypes. This study investigated a sample of 83 volunteers, being divided into control group (CG = 20), emphysema (n = 23), CB (n = 20) and asthma-COPD overlap syndrome (ACOS, n = 20). These analyses were performed before and after bronchodilator (BD) use. Functional capacity was evaluated using the Glittre‑ADL test, handgrip strength and respiratory pressures. Initially it was observed that oscillometry provided a detailed description of the COPD phenotypes, which was consistent with the involved pathophysiology. A correlation between oscillometry and functional capacity was observed (r=-0.541; p = 0.0001), particularly in the emphysema phenotype (r = -0.496, p = 0.031). BD response was different among the studied phenotypes. This resulted in an accurate discrimination of ACOS from CB [area under the receiver operating curve (AUC) = 0.84] and emphysema (AUC = 0.82). These results offer evidence that oscillatory indices may enhance the comprehension and identification of COPD phenotypes, thereby potentially improving the support provided to these patients.

Comparative study of bone mineral density, phenotypes of emphysema in patients with or without established diagnosis of chronic airway disease

Background: Bone thinning and emphysema are established diseases caused by tobacco-related products proven beyond doubt. A paucity of literature available to establish the association between them. Objectives: To explore the association between the different emphysema subtypes and the presence of low bone mineral density among a population of active or former smokers with and without an established diagnosis of chronic obstructive pulmonary disease (COPD). Methods: 100 active and former smokers with chronic airway disease attending the Pulmonology Outpatient Department were identified, and they were administered clinical questionnaires, pulmonary function tests, chest computed tomography, and DEXA scans. Appropriate statistical tests were performed to analyze the association between the different emphysema subtypes, low bone mineral density, and smoking in the study participants. Results: Out of 100 samples, 80 % of the patients had low BMD (25 had osteoporosis, and 55 had osteopenia). Emphysema was more frequent and severe in patients with osteoporosis (63.2 vs. 36.8%, p=&amp;lt;0.01). For analyzing significant co-factors, a multivariable analysis was done, which yielded Body Mass Index (Odds ratio of 0.89 with a 95% Confidence Interval of 0.67–1.23) and the presence of centrilobular emphysema as most commonly associated with osteoporosis. (Odds ratio of 35.25, with a 95% confidence interval of 3.23 to 401.63). Conclusion: Patients having increased Body Mass Index (BMI) and the presence of centrilobular emphysema are having osteoporosis irrespective of their smoking status, which implicates BMI, and centrilobular emphysema has to be considered while evaluating COPD patients.

Downregulated BMP-Smad1/5/8 signaling causes emphysema via dysfunction of alveolar type II epithelial cells.

Bone morphogenetic protein (BMP)-Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP-Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP-Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP-Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP-Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP-Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP-Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.

Type 1 diabetes contributes to combined pulmonary fibrosis and emphysema in male alpha 1 antitrypsin deficient mice.

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema. Decreased AAT plasma concentrations and anti-protease activity are documented in T1D patients. The objective of this study was to determine whether T1D exacerbates the progression of lung damage in AAT deficiency. First, pulmonary function testing (PFT) and histopathological changes in the lungs of C57BL/6J streptozotocin (STZ)-induced T1D mice were investigated 3 and 6 months after the onset of hyperglycemia. PFT demonstrated a restrictive pulmonary pattern in the lungs of STZ-injected mice, along with upregulation of mRNA expression of pro-fibrotic markers Acta2, Ccn2, and Fn1. Increased collagen deposition was observed 6 months after the onset of hyperglycemia. To study the effect of T1D on the progression of lung damage in AAT deficiency background, C57BL/6J AAT knockout (KO) mice were used. Control and STZ-challenged AAT KO mice did not show significant changes in lung function 3 months after the onset of hyperglycemia. However, histological examination of the lung demonstrated increased collagen accumulation and alveolar space enlargement in STZ-induced AAT KO mice. AAT pretreatment on TGF-β-stimulated primary lung fibroblasts reduced mRNA expression of pro-fibrotic markers ACTA2, CCN2, and FN1. Induction of T1D in AAT deficiency leads to a combined pulmonary fibrosis and emphysema (CPFE) phenotype in male mice.

Analysis of sputum microbial flora in chronic obstructive pulmonary disease patients with different phenotypes during acute exacerbations

BackgroundIncreasing studies have shown that the imbalance of the respiratory microbial flora is related to the occurrence of COPD, the severity and frequency of exacerbations and mortality.However, it remains unclear how the sputum microbial flora differs during exacerbations in COPD patients manifesting emphysema phenotype, chronic bronchitis with emphysema phenotype and asthma-COPD overlap phenotype. MethodsSputum samples were obtained from 29 COPD patients experiencing acute exacerbations who had not received antibiotics or systemic corticosteroids within the past four weeks.Patients were divided into three groups;emphysema phenotype(E);chronic bronchitis with emphysema phenotype(B+E) and asthma-COPD overlap phenotype(ACO).We utilized metagenomic Next Generation Sequencing (mNGS) technology to analyze the sputum microbial flora in COPD patients with different phenotypes during exacerbations. ResultsThere was no significant difference in alpha diversity and beta diversity among three groups.The microbial flora composition was similar in all three groups during exacerbations except for a significant increase in Streptococcus mitis in ACO.Through network analysis,we found Candidatus Saccharibacteria oral taxon TM7x and Fusobacterium necrophorum were the core nodes of the co-occurrence network in ACO and E respectively.They were positively correlated with some species and play a synergistic role.In B+E,Haemophilus pittmaniae and Klebsiella pneumoniae had a synergistic effect.Besides,some species among the three groups play a synergistic or antagonistic role.Through Spearman analysis,we found the relative abundance of Streptococcus mitis was negatively correlated with the number of hospitalizations in the past year(r = −0.410,P = 0.027).We also observed that the relative abundance of Prevotella and Prevotella melaninogenica was negatively correlated with age(r = −0.534,P = 0.003;r = −0.567,P = 0.001),while the relative abundance of Streptococcus oralis and Actinomyces odontolyticus was positively correlated with age(r = 0.570,P = 0.001;r = 0.480,P = 0.008).In addition,the relative abundance of Prevotella melaninogenica was negatively correlated with peripheral blood neutrophil ratio and neutrophil to lymphocyte ratio(r = −0.479,P = 0.009;r = −0.555,P = 0.002),while the relative abundance of Streptococcus sanguinis was positively correlated with peripheral blood neutrophil ratio and neutrophil to lymphocyte ratio (r = 0.450,P = 0.014;r = 0.501,P = 0.006).There was also a significant positive correlation between Oribacterium and blood eosinophil counts(r = 0.491,P = 0.007). ConclusionOverall,we analyzed the sputum microbiota of COPD patients with different phenotypes and its relationship with clinical indicators, and explored the relationships between microbiota and inflammation in COPD.We hope to alter the prognosis of patients by inhibiting specific bacterial taxa related to inflammation and using guide individualized treatment in the future research.

Lung volumes differentiate the predominance of emphysema versus airway disease phenotype in early COPD: an observational study of the COPDGene cohort.

Lung volumes identify the "susceptible smokers" who progress to develop spirometric COPD. However, among susceptible smokers, development of spirometric COPD seems to be heterogeneous, suggesting the presence of different pathological mechanisms during early establishment of spirometric COPD. The objective of the present study was to determine the differential patterns of radiographic pathologies among susceptible smokers. We categorised smokers with preserved spirometry (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0) in the Genetic Epidemiology of COPD (COPDGene) cohort based on tertiles (low, intermediate and high) of lung volumes (either total lung capacity (TLC), functional residual capacity FRC or FRC/TLC) at baseline visit. We then examined the differential patterns of change in spirometry and the associated prevalence of computed tomography measured pathologies of emphysema and airway disease with those categories of lung volumes. The pattern of spirometric change differed when participants were categorised by TLC versus FRC/TLC: those in the high TLC tertile showed stable forced expiratory volume in 1 s (FEV1), but enlarging forced vital capacity (FVC), while those in the high FRC/TLC tertile showed decline in both FEV1 and FVC. When participants from the high TLC and high FRC/TLC tertiles were partitioned into mutually exclusive groups, compared to those with high TLC, those with high FRC/TLC had lesser emphysema, but greater air trapping, more self-reported respiratory symptoms and exacerbation episodes and higher likelihood of progressing to more severe spirometric disease (GOLD stages 2-4 versus GOLD stage 1). Lung volumes identify distinct physiological and radiographic phenotypes in early disease among susceptible smokers and predict the rate of spirometric disease progression and the severity of symptoms in early COPD.

The novel TAK1 inhibitor handelin inhibits NF-κB and AP-1 activity to alleviate elastase-induced emphysema in mice

Emphysema, one of the two major components of chronic obstructive pulmonary disease (COPD), is driven by aberrant inflammatory responses and associated with irreversible lung parenchymal destruction. As effective therapy for preventing or treating COPD/emphysema is yet unavailable, development of molecular targets and therapeutic agents for COPD/emphysema is required. We identified handelin-a guaianolide dimer of sesquiterpene lactones- from a chemical library of 431 natural products as it exhibited potent inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) and reactive oxygen species (ROS) production, LPS-induced activation of nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK)/AP-1, and expression of proinflammatory mediators in macrophage cells. In silico docking and biochemical studies enabled the identification of the ATP-binding pocket of transforming growth factor beta-activated kinase 1 (TAK1), a kinase upstream of NF-κB and MAPK/AP-1 pathways, as a molecular target for handelin. Moreover, oral administration of handelin (10mg/kg) suppressed elastase-induced development of emphysematous phenotypes, including lung function disturbance, airspace enlargement, and increases in the level of neutrophils and CD8+ T cells in lung tissues, without overt toxicity. Consistent with in vitro results, analyses of lung tissues revealed that treatment with handelin suppressed elastase-induced NF-κB and AP-1 activation in the lungs, followed by downregulation of their targets including interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase 9 (MMP9). These findings suggest that handelin, as a TAK1 inhibitor, effectively prevents development of emphysema in an elastase-induced mouse model by inhibiting a proinflammatory mediators mediated by NF-κB and AP-1.

Expression profile of the free radicals metabolism and antioxidant genes in chronic obstructive lung disease

Chronic obstructive pulmonary disease (COPD) is a multifactorial heterogeneous chronic inflammatory disease of the respiratory system. Oxidative stress plays a central role in the pathophysiology of COPD. The goal of the study is the identification of new molecular markers of COPD based on the analysis of the expression profile of genes involved to oxidative stress response and antioxidant protection in peripheral blood mononuclear cells. Methods. To identify differential gene expression in COPD we performed expression profiling of 84 oxidative stress response and antioxidant protection genes in peripheral blood mononuclear cells samples from COPD (N=10 with frequent exacerbation emphysema and bronchitis phenotype, N=10 rare exacerbation emphysema phenotype and N=10 smoking controls). RNA was isolated from PBMCs, and gene expression was assessed using RT2 Profiler PCR Arrays « Human Oxidative Stress Plus PCR Array» (Qiagen). Results. Significant changes were revealed in the expression profile of several genes in frequent exacerbation emphysema and bronchitis phenotype COPD phenotype: decreased expression of BNIP3, GCLC, PRNP, TTN, HSP90AA1 gene; and increased expression of FTH1, PRDX3, SOD2 genes. In the group of COPD patients with rare exacerbation emphysema phenotype, an increase in the transcriptional activity of most genes that play a key role in the mechanisms of cell protection from free radical damage was found: FTH1, PRDX3, SOD2, PTGR1,GPX4, GSR, PTGS1, HSPA1A, NCF1 и NCF2, PRDX5, SIRT2, SQSTM1, SRXN1, TXNRD2, LHPP. We confirmed the assumption that the blood cell transcriptome reflects the pathogenesis and systemic nature of COPD and can be considered as a source of information for assessing the severity of the disease, monitoring the effectiveness of therapy, and searching for new non-invasive biomarkers of the disease and its various phenotypes.

Phenotypes of chronic obstructive pulmonary disease as a factor in the severe course of a new coronavirus infection

Chronic obstructive pulmonary disease (COPD) is the third cause of death in the world, from which 3.23 million people died in 2019 according to the World Health Organization. In 2020, J.M. Leung, C.X. Yang, A. Team et al. demonstrated that the expression of ACE-2 in bronchial epithelial cells was significantly increased in patients with COPD compared to the control group. Current smoking was also associated with higher expression of ACE-2 compared to former smokers and never smokers. A number of studies cite data of negative impact of COPD on the course of a new coronavirus infection. In our work, 99 patients with COPD and a new coronavirus infection were examined: 24 women and 75 men (mean age of 69.1±10.8 years). The aim of the work was to determine the features of radiological patterns and the course of a new coronavirus infection in patients with different phenotypes of chronic obstructive pulmonary disease. At admission to hospital 7.1% of patients had CT-0, 20.2% — CT-1, 41.4% — CT-2, 24.2% — CT-3, and 7.1% — CT-4. The maximum degree of lung tissue damage (for the entire period of hospital stay): 3.0% of patients — CT-0, 18.2% — CT-1, 24.2% — CT-2, 38.4% — CT-3, 16.2% — CT-4. 11.1% of patients developed pulmonary embolism, 2.0% — deep vein thrombosis. 28.3% of patients had secondary infection, 24.2% — sepsis, 13.1% — ARDS, 16.2% — hydrothorax, 3.0% — pneumothorax. 41.4% of patients needed a ventilator, 33.3% of patients had a fatal outcome. Statistical analysis showed that a new coronavirus infection in patients with bronchitis phenotype of COPD was more severe than in patients with emphysematous and mixed phenotypes. Also, patients with bronchitis phenotype had a higher risk of a greater maximum degree of lung tissue damage (for the entire period of hospital stay) compared with patients with emphysematous and mixed COPD phenotype.

Whole-body analysis of TRPML3 (MCOLN3) expression using a GFP-reporter mouse model reveals widespread expression in secretory cells and endocrine glands.

TRPML3 (mucolipin 3, MCOLN3) is an endolysosomal cation channel belonging to the TRPML subfamily of transient receptor potential channels. Gain-of-function mutations in the Trpml3 gene cause deafness, circling behavior and coat color dilution in mice due to cell death of TRPML3-expressing hair cells of the inner ear or skin melanocytes, respectively. Furthermore, TRPML3 was found to play a role in the long term survival of cochlear hair cells (its absence contributing to presbycusis), in specialized giant lysosomes that neonatal (birth to weaning) enterocytes used for the uptake and digestion of maternal milk nutrients, and in the expulsion of exosome-encased bacteria such as uropathogenic E. coli, infecting bladder epithelial cells. Recently, TRPML3 was found to be expressed at high levels in alveolar macrophages and loss of TRPML3 results in a lung emphysema phenotype, confirmed in two independently engineered Trpml3 knockout lines. TRPML3 is not ubiquitously expressed like its relative TRPML1 and thus cellular expression of TRPML3 on a whole-tissue level remains, with the exceptions mentioned above, largely elusive. To overcome this problem, we generated a τGFP reporter mouse model for TRPML3 and compared expression data obtained from this model by immunofluorescence on tissue sections with immunohistochemistry using TRPML3 antibodies and in situ hybridization. We thus uncovered expression in several organs and distinct cell types. We confirmed TRPML3 expression in both neonatal and adult alveolar macrophages, in melanocytes of hair follicles and glabrous skin, in principle cells of the collecting duct of the neonatal and adult kidney, and in olfactory sensory neurons of the olfactory epithelium, including its fibres protruding to the glomeruli of the olfactory bulb. Additionally, we localized TRPML3 in several glands including parathyroid, thyroid, salivary, adrenal, and pituitary gland, testes and ovaries, suggestive of potential roles for the channel in secretion or uptake of different hormones.

Loss of Pleckstrin homology like domain, family A, member 1 promotes type Ⅱ alveolar epithelial cell apoptosis in chronic obstructive pulmonary disease emphysematous phenotype via interaction with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon.

Emphysematous phenotype is the most important phenotypic component of chronic obstructive pulmonary disease and is associated with substantial morbidity and mortality. The current pharmaceutical treatments and therapeutic procedures do not reduce pulmonary damage in patients with emphysematous phenotype. Therefore, it is important to identify effector molecules that can be used as interfering targets in such patients. Apoptosis of type II alveolar epithelial cells plays a key role in the phenotypic formation. This study aimed to further explore the molecular mechanisms involved in this process. The number of type II alveolar epithelial cells was significantly reduced due to increased apoptosis in patients with emphysematous phenotype compared to those with non-emphysematous phenotype. Pleckstrin homology like domain, family A, member 1 (PHLDA1) was mainly distributed in type II alveolar epithelial cells in both groups but was markedly reduced in patients with emphysematous phenotype. Overexpression of PHLDA1 prevented cigarette smoke extract-stimulated apoptosis of type II alveolar epithelial cells, whereas its knockdown worsened the apoptosis. PHLDA1 binding ability to tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) was weakened after exposure to cigarette smoke extract, with decreased PHLDA1 level lowering the abundance of YWHAE and attenuating the binding ability of YWHAE to p-Bad. These results demonstrate that considerable apoptosis of type II alveolar epithelial cells occurs in patients with emphysematous phenotype, and PHLDA1 may act as an effective antiapoptotic factor via YWHAE. Moreover, PHLDA1 may serve as a potential interfering target, providing insights into therapeutic strategies for emphysematous phenotype.