Chronic obstructive pulmonary disease (COPD) ranks among the leading causes of morbidity and mortality worldwide. COPD rarely occurs in isolation and is often combined with various diseases. It is considered that systemic inflammation underlies the comorbid course of COPD. The data obtained in recent years have shown the importance of violations of the cross-links of lipid metabolism and the immune response, which are links in the pathogenesis of both COPD and atherosclerosis. The role of lipid metabolism disorders in the pathogenesis of the comorbid course of COPD and atherosclerosis and the participation of ATP-binding cassette (ABC) transporters in these processes is discussed in this article. It is known that about 20 representatives of a large family of ABC transporters provide lipid homeostasis of cells by moving lipids inside the cell and in its plasma membrane, as well as removing lipids from the cell. It was shown that some representatives of the ABC-transporter family are involved in various links of the pathogenesis of COPD and atherosclerosis, which can determine their comorbid course.
Exacerbations largely determine the character of the progression and prognosis of chronic obstructive pulmonary disease (COPD). Exacerbations are connected with changes in the microbiological landscape in the bronchi due to a violation of their immune homeostasis. Many metabolic and immune processes involved in COPD progression are associated with bacterial colonization of the bronchi. The objective of this review is the analysis of the molecular mechanisms of lipid metabolism and immune response disorders in the lungs in COPD exacerbations. The complex role of lipid metabolism disorders in the pathogenesis of some infections is only beginning to be understood, however, there are already fewer and fewer doubts even now about its significance both in the pathogenesis of infectious exacerbations of COPD and in general in the progression of the disease. It is shown that the lipid rafts of the plasma membranes of cells are involved in many processes related to the detection of pathogens, signal transduction, the penetration of pathogens into the cell. Smoking disrupts the normally proceeded processes of lipid metabolism in the lungs, which is a part of the COPD pathogenesis.
Smoking is a key modifiable risk factor for developing the chronic obstructive pulmonary disease (COPD). When smoking, many processes, including the reverse transport of cholesterol mediated by the ATP binding cassette transporter A1 (ABCA1) protein are disrupted in the lungs. Changes in the cholesterol content in the lipid rafts of plasma membranes can modulate the function of transmembrane proteins localized in them. It is believed that this mechanism participates in increasing the inflammation in COPD. Methods: Bioinformatic analysis of datasets from Gene Expression Omnibus (GEO) was carried out. Gene expression data from datasets of alveolar macrophages and the epithelium of the respiratory tract in smokers and COPD patients compared with non-smokers were used for the analysis. To evaluate differentially expressed genes, bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2), and the GEO2R and Phantasus tools (v. 1.11.0). Results: The conducted bioinformatic analysis showed changes in the expression of the ABCA1 gene associated with smoking. In the alveolar macrophages of smokers, the expression levels of ABCA1 were lower than in non-smokers. At the same time, in most of the airway epithelial datasets, gene expression did not show any difference between the groups of smokers and non-smokers. In addition, it was shown that the expression of ABCA1 in the epithelial cells of the trachea and large bronchi is higher than in small bronchi. Conclusions: The conducted bioinformatic analysis showed that smoking can influence the expression of the ABCA1 gene, thereby modulating lipid transport processes in macrophages, which are part of the mechanisms of inflammation development.
Lipid metabolism plays an important role in many lung functions. Disorders of lipid metabolism are part of the pathogenesis of chronic obstructive pulmonary disease (COPD). Lipids are involved in numerous cross-linkages with inflammation. Recent studies strongly support the involvement of fatty acids as participants in inflammation. They are involved in the initiation and resolution of inflammation, including acting as a substrate for the formation of lipid mediators of inflammation resolution. Specialized pro-inflammatory mediators (SPMs) belonging to the classes of lipoxins, resolvins, maresins, and protectins, which are formed enzymatically from unsaturated fatty acids, are now described. Disorders of their production and function are part of the pathogenesis of COPD. SPMs are currently the subject of active research in order to find new drugs. Short-chain fatty acids are another important participant in metabolic and immune processes, and their role in the pathogenesis of COPD is of great clinical interest.
ABC transporters are a large family of membrane proteins that transport chemically diverse substrates across the cell membrane. Disruption of transport mechanisms mediated by ABC transporters causes the development of various diseases, including atherosclerosis. Methods: A bioinformatic analysis of a dataset from Gene Expression Omnibus (GEO) was performed. A GEO dataset containing data on gene expression levels in samples of atherosclerotic lesions and control arteries without atherosclerotic lesions from carotid, femoral, and infrapopliteal arteries was used for analysis. To evaluate differentially expressed genes, a bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2) and the GEO2R and Phantasus tools (v. 1.11.0). Results: The obtained data indicate the differential expression of many ABC transporters belonging to different subfamilies. The differential expressions of ABC transporter genes involved in lipid transport, mechanisms of multidrug resistance, and mechanisms of ion exchange are shown. Differences in the expression of transporters in tissue samples from different arteries are established. Conclusions: The expression of ABC transporter genes demonstrates differences in atherosclerotic samples and normal arteries, which may indicate the involvement of transporters in the pathogenesis of atherosclerosis.
Funding Acknowledgements Type of funding sources: None. Main funding source(s): no OnBehalf no Atherosclerosis is one of the key medical problems, as it contributes greatly to the structure of morbidity and mortality. Atherosclerosis rarely occurs in isolation, and is often combined with other diseases, including chronic obstructive pulmonary disease (COPD). The study of the significance of atherosclerosis and other key risk factors in the prognosis of COPD was carried out. Materials and methods a study of the nature of the course of COPD for 15 years was carried out at three time control points (2005, 2008 and 2020). The presence of diseases associated with atherosclerosis in history, the severity of dyspnea according to the modified MRC scale and body mass index were taken into account. To assess the significance of the factors, a long-term survival analysis was performed using the Kaplan-Meier method. The statistical significance of the differences between the curves was assessed using the Log-rank test and the Breslow (Generalized Wilcoxon) and Tarone-Ware tests. To assess the influence of various factors and their combinations on long-term survival, a multivariate analysis was carried out using the Cox regression model (proportional hazards model). Results and discussion The study included 170 men, with an average age of 60.09 ± 1.31 years. All patients smoked, the pack-years index was 43.78 ± 1.02. Of the 170 patients included in the study, 119 died by the third time point, which was 70%. The life expectancy of deceased patients averaged 70.48 ± 0.63 years. The main causes of death in patients with COPD are cardiovascular diseases caused by atherosclerosis, cancer, and respiratory failure. The most common cause of death in patients with COPD (68%) is diseases of the circulatory system associated with atherosclerosis. It was found that the presence of atherosclerosis in the anamnesis decreases the survival rate over a 15-year period. The graphs of the Kaplan-Meier survival curve depending on the presence of concomitant cardiovascular diseases in the anamnesis confirm the significance of the differences (p = 0.0194). It was also shown that an increase in the severity of dyspnea is associated with an increased risk of adverse outcomes (p <0.001; ROC analysis, AUC = 0.737 ± 0.038). The analysis of survival using the construction of Kaplan-Meier curves showed that BMI <21 is associated with a poor prognosis (p <0.001; ROC analysis, AUC = 0.827 ± 0.043). The results of the Cox regression model showed that a history of atherosclerosis is a significant predictor of a poor prognosis in patients with COPD in a 15-year follow-up. It was shown that a history of atherosclerosis increases the risk of death in patients with COPD by 1.734 times. Thus, concomitant cardiovascular diseases of atherosclerotic genesis, severe dyspnea and low body weight are a significant factor in the poor prognosis of COPD and should be taken into account when monitoring patients.
Despite all achievements of the modern medicine, the problem of chronic obstructive pulmonary disease (COPD) does not lose its relevance. The current paradigm suggests a key role of macrophages in inflammation in COPD. Macrophages are known to be heterogeneous in their functions. This heterogeneity is determined by their immunometabolic profile and also by peculiarities of lipid homeostasis of cells. Aim. To analyze the role of the ABCA1 transporter, a member of the ABC A subfamily, in the pathogenesis of COPD. The expression of ABCA1 in lung tissues is on the second place after the liver, which shows the important role of the carrier and of lipid homeostasis in the function of lungs. Analysis of the literature shows that participation of the transporter in inflammation consists in regulation of the content of cholesterol in the lipid rafts of the membranes, in phagocytosis and apoptosis. Conclusion. Through regulation of the process of reverse transport of cholesterol in macrophages of lungs, ABCA1 can change their inflammatory response, which makes a significant contribution to the pathogenesis of COPD.
Systemic inflammation makes a significant contribution to the pathogenesis of atherosclerosis and has been the subject of numerous studies. Works aiming to analyze the mechanisms of atherosclerosis development often include experiments on animals. A primary task of such research is the characterization, justification, and selection of an adequate model. Aim. To evaluate the peculiarities of lipid metabolism and systemic inflammation in chronic obstructive pulmonary disease (COPD) in the development of atherosclerosis in animal models. Materials and Methods. Analyses of cross-links between species-specific peculiarities of lipid metabolism and the immune response, as well as a bioinformatic analysis of differences in Toll-like receptor 4 (TLR4) in mice, rats, and rabbits in comparison with its human homolog, were carried out. A search for and analysis of the amino acid sequences of human, mouse, rat, and rabbit TLR4 was performed in the International database GenBank of National Center of Biotechnical Information and in The Universal Protein Resource (UniProt) database. Multiple alignments of the TLR4 amino acid sequences were implemented in the Clustal Omega program, version 1.2.4. Reconstruction and visualization of molecular phylogenetic trees were performed using the MEGA7 program according to the Neighbor-Joining and Maximum Parsimony methods. Results. Species-specific differences of the peculiarities of lipid metabolism and the innate immune response in humans, mice, and rabbits were shown that must be taken into account in analyses of study results. Conclusion.Disorders in lipid metabolism and systemic inflammation mediated by the innate immune system participating in the pathogenesis of atherosclerosis in COPD possess species-specific differences that should be taken into account in analyses of study results.
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