Apoptosis In Chronic Obstructive Pulmonary Disease Research Articles

Aucubin Alleviates Chronic Obstructive Pulmonary Disease by Activating Nrf2/HO-1 Signaling Pathway.

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease with high death rates. Aucubin is an iridoid glycoside extracted from Eucommia ulmoides with antioxidative and anti-inflammatory properties in human diseases. This study aimed to investigate its specific function in mouse and cell models of COPD. The COPD mouse model was established by exposing mice to a long-term cigarette smoke (CS). The number of inflammatory cells and the contents of inflammatory factors tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-8 in bronchoalveolar lavage fluid (BALF) of CS-exposed mice were measured. The levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and myeloperoxidase (MPO) in the lung tissues were estimated. Masson staining and hematoxylin-eosin (H&E) staining were utilized to evaluate pulmonary fibrosis and emphysema in CS-treated mice. Cell apoptosis in the lung tissues was estimated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Western blot was applied to quantify protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and apoptotic markers. COPD cell model was established by exposing mouse lung epithelial cells (MLE12) with cigarette smoke extract to further verify the properties of aucubin in vitro. Aucubin reduced the number of inflammatory cells and decreased the contents of TNF-α, IL-6, and IL-8 in BALF of CS-treated mice. The oxidative stress, lung emphysema, fibrosis, and lung cell apoptosis induced by CS exposure were ameliorated by aucubin administration. Aucubin activated the Nrf2/HO-1 signaling pathway in vitro and in vivo. Pretreatment with ML385, a specific Nrf2 inhibitor, antagonized the protective effects of aucubin on inflammation, oxidative stress, fibrosis, and cell apoptosis in COPD. Aucubin alleviates inflammation, oxidative stress, apoptosis, and pulmonary fibrosis in COPD mice and CSE-treated MLE12 cells by activating the Nrf2/HO-1 signaling pathway.

Disease-specific transcriptional programs govern airway goblet cell metaplasia

Hypersecretion of airway mucus caused by goblet cell metaplasia is a characteristic of chronic pulmonary inflammatory diseases including asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Goblet cells originate from airway progenitor club cells. However, the molecular mechanisms and features of goblet cell metaplasia in lung disease are poorly understood. Herein, public single-cell RNA sequencing datasets of human lungs were reanalyzed to explore the transitional phase as club cells differentiate into goblet cells in asthma, CF, and COPD. We found that changes in club and goblet cells during pathogenesis and cellular transition were associated with signalling pathways related to immune response, oxidative stress, and apoptosis. Moreover, other key drivers of goblet cell specification appeared to be pathologically specific, with interleukin (IL)-13 and hypoxia inducible factor 1 (HIF-1)-induced genetic changes in asthma, cystic fibrosis transmembrane conductance regulator (CFTR) mutation being present in CF, and interactions with CD8+ T cells, mitophagy, and mitochondria-induced apoptosis in COPD. In conclusion, this study revealed the similarities and differences in goblet cell metaplasia in asthma, CF, and COPD at the transcriptome level, thereby providing insights into possible novel therapeutic approaches for these diseases.

Notch1 regulates endothelial apoptosis via the ERK pathway in chronic obstructive pulmonary disease.

The Notch signaling pathway plays critical role for determining cell fate by controlling proliferation, differentiation, and apoptosis. In the current study, we investigated the roles of the Notch signaling pathway in cigarette smoke (CS)-induced endothelial apoptosis in chronic obstructive pulmonary disease (COPD). We obtained surgical specimens from 10 patients with COPD and 10 control participants. Notch1, 2, and 4 express in endothelial cells, whereas Notch3 mainly localizes in smooth muscle cells. Compared with control groups, we found that the expression of Notch1, 3, and 4 decreased, as well as their target genes Hes1 and Hes2, while the expression of Notch2 and extracellular signal-regulated kinase (ERK)1/2 increased in COPD patients compared with controls, as well as in human pulmonary microvascular endothelial cells (HPMECs) when exposed to CS extract (CSE). Overexpression of Notch1 with N1ICD in HPMECs markedly alleviated the cell apoptosis induced by CSE. The ERK signaling pathway was significantly activated by CSE, which correlated with CSE-induced apoptosis. However, this activation can be abolished by N1ICD overexpression. Furthermore, treatment of PD98059 (ERK inhibitor) significantly alleviated CSE-induced apoptosis, as well as reduced the methylation of mitochondrial transcription factor A (mtTFA) promoter, which was correlated with CS-induced endothelial apoptosis. These results suggest that CS alters Notch signaling in pulmonary endothelial cells. Notch1 protects against CS-induced endothelial apoptosis in COPD through inhibiting the ERK pathway, while the ERK pathway further regulates the methylation of mtTFA promotor.

Hypoxia‐induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.

AP-2α expression and cell apoptosis of the lung tissue of rats with COPD and ECV304 cells stimulated by cigarette smoke extract

An increasing body of evidence suggests that apoptosis of structural cells in the lung might be an important upstream event in the pathogenesis of chronic obstructive pulmonary disease (COPD). AP-2α is one of the important transcription factors involved in the modulation of apoptosis in carcinogenesis and idiopathic-dilated cardiomyopathy. The relationship between AP-2α and apoptosis in COPD remains to be elucidated. The aim of the present study was to investigate the expression of AP-2α in the lung tissues of rats with COPD induced by smoking and its possible protective effect on cigarette smoke extract (CSE) induced endothelial cell apoptosis. Sprague-Dawley rats (n = 24) were randomly assigned to normal and COPD groups. The COPD group was exposed to smoke from 20 commercial unfiltered cigarettes for 80 d before morphological assessment of the lung tissue was performed. The expression of AP-2α in lung tissues was measured by Western blotting. To demonstrate the relationship between apoptosis and AP-2α, in vitro cell experiments were carried out. Cells were treated with different concentrations of CSE before proliferation was measured by MTT. Apoptosis was then determined by Hoechst staining and the expression of cleaved caspase-3 and AP-2α by Western blotting over time following treatment with 5% CSE. Cells were then infected with an AP-2α adenovirus vector and the expression of cleaved caspase-3 and AP-2α was compared to the control groups by Western blotting. The COPD group showed larger air spaces and significant decrease of FEV0.3/FVC compared with the rats in the control group (P<0.05). The expression of AP-2α was significantly higher in the lung tissue of rats with COPD compared with those of controls (P<0.05). In the ECV304 cells, CSE induced apoptosis (P<0.01) and caspase-3 activation in a time-dependent manner and reduced the cell proliferation rate in a dose-dependent manner (P<0.005). Moreover, 5% CSE treatment increased endogenous AP-2α protein expression. AP-2α overexpression inhibited 5% CSE-induced cell apoptosis and activated caspase-3 expression (P<0.05) AP-2α protects ECV304 cells against CSE-induced apoptosis and may play an important role in smoking induced-apoptosis in COPD.

Increased peripheral blood T‐cell apoptosis and decreased Bcl‐2 in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease, usually associated with cigarette smoking. Stimulated peripheral blood T cells from patients with COPD have an increased propensity to undergo apoptosis. The mitochondrial apoptotic pathway is regulated by pro-apoptotic proteins (including p53 and Bax) as well as anti-apoptotic proteins (e.g. Bcl-2) and cytokines (IL-2, IL-4 and IL-7). We hypothesized that alterations in expression of these apoptosis-related proteins, cytokines and cytokine receptors may be important in determining the susceptibility of T cells to undergoing apoptosis in COPD. We further hypothesized that inhaled corticosteroids (GCS) contribute to the increased rates of T-cell apoptosis observed in COPD. The process of apoptosis (assessed by Annexin V and ssDNA staining), as well as Bcl-2, Bax, p53, IL-2, IL-4 and receptors IL-7R, IL-4R and IL-2Rgamma were investigated in PHA-stimulated peripheral blood-derived T cells, using flow cytometry. Fifteen patients with COPD receiving inhaled GCS (four of who received additional prednisolone), eight patients with COPD receiving symptom control medication, and 16 control subjects were studied. T cells (CD4(+) and CD8(+)) from GCS-treated COPD patients showed an increased propensity to undergo apoptosis, associated with significantly decreased Bcl-2 and IL-7 receptor expression. No significant differences were observed for the COPD patients who were receiving symptom control medication. These findings may suggest a negative peripheral effect of inhaled GCS on the immune system in COPD, although the clinical significance of these effects remains uncertain.

Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation

There is heterogeneity in the propensity of smokers to develop chronic obstructive pulmonary disease (COPD), and improved treatment strategies are hindered by limited understanding of COPD pathogenesis, especially as distinct from the effects of smoking per se. Although apoptosis is essential for tissue homeostasis, increased apoptosis may cause tissue damage and inflammation. This study addressed whether airway T-lymphocytes and airway epithelial cells (AEC) show an increased likelihood of undergoing apoptosis in COPD and if this was related to smoking. Apoptosis (7-amino-actinomycin D, Annexin, single-stranded DNA and caspase), Bcl-2, Bax and p53 were assessed in cells obtained from bronchial bushing and bronchoalveolar lavage from ex- and continuing smokers with COPD, and nonsmoking controls, using flow cytometry. A mean 87% increase in apoptosis of AEC and a 103% increase in T-lymphocyte apoptosis were found in COPD. There were no significant differences in apoptosis of AEC between current and ex-smokers with COPD. Apoptosis may contribute to chronic obstructive pulmonary disease pathogenesis, and continued excess apoptosis after smoking cessation may offer a new target for therapeutic interventions. Whether the persistence of increased apoptosis after smoking cessation results from changes in the pulmonary milleau after years of noxious insult, or whether some individuals have a natural predisposition toward increased apoptosis and possible development of chronic obstructive pulmonary disease remains to be determined.

Apoptosis in COPD

Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease that causes serious morbidity and mortality. Despite its importance, the cellular and molecular mechanisms that contribute to COPD pathogenesis have only recently been investigated. COPD is characterised by chronic inflammation, and loss of structural integrity throughout the lung from conducting airways, to the alveolar walls. Apoptosis is an active biochemical process, associated with minimal inflammation or disruption of neighbouring tissue. Apoptosis is considered to play an important role in effective repair of an injured airway epithelium, and resolution of inflammation. However, disorders in the apoptotic process, including increased rates of epithelial cell apoptosis or defective clearance of apoptotic cells by neighbouring phagocytes, are associated with tissue injury in several conditions, including liver injury and heart disease. Increasingly, the role of apoptosis in the pathogenesis of COPD is being recognised. Several studies have reported increased apoptosis of airway epithelial cells, and defective clearance of these cells by alveolar macrophages in COPD, although how this relates to the disease process is still largely unknown. Cigarette smoking directly induces apoptosis of airway epithelial cells. However, the increased rate of apoptosis does not appear to diminish with cessation of cigarette smoking. In this regard, factors that relate to perpetuation of the chronic inflammatory response in COPD may also contribute to increased apoptosis in the airways. These include the high level of oxidative stress, release of proteolytic enzymes as a result of increased numbers of neutrophils, cytotoxic T-cells, activation of TNF-α, TGF-β and Fas pathways, and inflammatory responses to colonisation of the airways with bacteria. Understanding the role of apoptosis and phagocytosis in the airways in COPD is likely to lead to novel therapeutic approaches for this extremely common, yet, often neglected disease. Keywords: apoptosis, copd, bronchial epithelial cell, alveolar macrophage