Materiały źródłowe

• #1 Pathology, pathogenesis, and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1463976/

  Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airflow obstruction and an abnormal inflammatory response in the lungs. The latter represents the innate and adaptive immune responses to long term exposure to noxious particles and gases, particularly cigarette smoke. […] This amplified response may result in mucous hypersecretion (chronic bronchitis), tissue destruction (emphysema), and disruption of normal repair and defence mechanisms causing small airway inflammation and fibrosis (bronchiolitis). […] We have good understanding of the cellular and molecular mechanisms underlying the pathological changes found in COPD. […] Inflammation is present in the lungs, particularly the small airways, of all people who smoke. This normal protective response to the inhaled toxins is amplified in COPD, leading to tissue destruction, impairment of the defence mechanisms that limit such destruction, and disruption of the repair mechanisms.

• #1 Pathology, pathogenesis, and pathophysiology | The BMJ

  https://www.bmj.com/content/332/7551/1202

  Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airflow obstruction and an abnormal inflammatory response in the lungs. The latter represents the innate and adaptive immune responses to long term exposure to noxious particles and gases, particularly cigarette smoke. […] Inflammation is present in the lungs, particularly the small airways, of all people who smoke. This normal protective response to the inhaled toxins is amplified in COPD, leading to tissue destruction, impairment of the defence mechanisms that limit such destruction, and disruption of the repair mechanisms. In general, the inflammatory and structural changes in the airways increase with disease severity and persist even after smoking cessation. Besides inflammation, two other processes are involved in the pathogenesis of COPD – an imbalance between proteases and antiproteases and an imbalance between oxidants and antioxidants (oxidative stress) in the lungs.

• #1 Pathology, pathogenesis, and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1463976/

  In general, the inflammatory and structural changes in the airways increase with disease severity and persist even after smoking cessation. […] Besides inflammation, two other processes are involved in the pathogenesis of COPD – an imbalance between proteases and antiproteases and an imbalance between oxidants and antioxidants (oxidative stress) in the lungs. […] COPD is characterised by increased numbers of neutrophils, macrophages, and T lymphocytes (CD8 more than CD4) in the lungs. […] In general, the extent of the inflammation is related to the degree of the airflow obstruction. These inflammatory cells release a variety of cytokines and mediators that participate in the disease process. […] Increased production (or activity) of proteases and inactivation (or reduced production) of antiproteases results in imbalance. […] Cigarette smoke, and inflammation itself, produce oxidative stress, which primes several inflammatory cells to release a combination of proteases and inactivates several antiproteases by oxidation.

• #1 Pathology, pathogenesis, and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1463976/

  The main proteases involved are those produced by neutrophils (including the serine proteases elastase, cathepsin G, and protease 3) and macrophages (cysteine proteases and cathepsins E, A, L, and S), and various matrix metalloproteases (MMP-8, MMP-9, and MMP-12). […] The main antiproteases involved in the pathogenesis of emphysema include 1 antitrypsin, secretory leucoprotease inhibitor, and tissue inhibitors of metalloproteases. […] The oxidative burden is increased in COPD. […] Sources of oxidants include cigarette smoke and reactive oxygen and nitrogen species released from inflammatory cells. This creates an imbalance in oxidants and antioxidants of oxidative stress. […] Many markers of oxidative stress are increased in stable COPD and are further increased in exacerbations. […] Oxidative stress can lead to inactivation of antiproteases or stimulation of mucous production. It can also amplify inflammation by enhancing transcription factor activation (such as nuclear factor B) and hence gene expression of pro-inflammatory mediators.

• #1 Pathology, pathogenesis, and pathophysiology | The BMJ

  https://www.bmj.com/content/332/7551/1202

  Increased production (or activity) of proteases and inactivation (or reduced production) of antiproteases results in imbalance. Cigarette smoke, and inflammation itself, produce oxidative stress, which primes several inflammatory cells to release a combination of proteases and inactivates several antiproteases by oxidation. […] The oxidative burden is increased in COPD. Sources of oxidants include cigarette smoke and reactive oxygen and nitrogen species released from inflammatory cells. This creates an imbalance in oxidants and antioxidants of oxidative stress. Many markers of oxidative stress are increased in stable COPD and are further increased in exacerbations. Oxidative stress can lead to inactivation of antiproteases or stimulation of mucous production. It can also amplify inflammation by enhancing transcription factor activation (such as nuclear factor B) and hence gene expression of pro-inflammatory mediators.

• #1 Pathology, pathogenesis, and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1463976/

  The above pathogenic mechanisms result in the pathological changes found in COPD. […] These in turn result in physiological abnormalities – mucous hypersecretion and ciliary dysfunction, airflow obstruction and hyperinflation, gas exchange abnormalities, pulmonary hypertension, and systemic effects.

• #1 Pathogenesis of Chronic Obstructive Pulmonary Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2713323/

  Studies of lung or bronchial biopsies and induced sputum have shown evidence of lung inflammation in all cigarette smokers. […] However, it appears that an enhanced or abnormal inflammatory response to inhaled particles or gases, beyond the normal protective inflammatory response in the lungs, is a characteristic feature of COPD and has the potential to produce lung injury. […] The mechanism by which CD8+ T lymphocytes accumulate in the airways of the lungs in COPD is not fully understood. […] The role of T cells in the pathogenesis of COPD is not fully understood. […] Increased numbers of activated neutrophils are found in sputum from patients with COPD. […] The role that neutrophils play in the pathogenesis of COPD is not entirely clear. […] Cigarette smoking is known to increase circulating neutrophil leukocyte count and to cause sequestration of neutrophils in the lung capillaries.

• #1 Novel aspects of pathogenesis and regeneration mechanisms in COPD | COPD

  https://www.dovepress.com/novel-aspects-of-pathogenesis-and-regeneration-mechanisms-in-copd-peer-reviewed-fulltext-article-COPD

  Tissue resident macrophages are now recognized as a multifunctional cell, central for tissue maintenance. […] It is becoming increasingly evident that T-cells reside at the epithelial surfaces throughout the human organism, including lungs, and mediate the host defense. […] The importance of T-cells in emphysema development was recently proven in mice model with the demonstration that T-cells from cigarette smoke-exposed mice are able to transfer the diseased process, ie, tissue destruction, to unexposed mice. […] Unbalanced proteolysis is a long-lived and simplified explanatory mechanism to explain processes within emphysematous lung. […] The role of proteolysis is proven and recognized from the very beginning, when emphysema was first described as an antiprotease deficiency-associated disease.

• #1 Novel aspects of pathogenesis and regeneration mechanisms in COPD | COPD

  https://www.dovepress.com/novel-aspects-of-pathogenesis-and-regeneration-mechanisms-in-copd-peer-reviewed-fulltext-article-COPD

  In addition to factors mentioned earlier, accelerated cell senescence has been implicated in the pathogenesis of COPD. […] COPD pathogenesis evolves with the disease exacerbations that are main drivers of health deterioration in patients with COPD. […] Major mechanisms described in COPD are further upregulated during exacerbations, including inflammatory process exaggeration and obstruction in the airways with a subsequent hyperinflation. […] It is well proven that lung tissue in every smoker is inflamed. […] In COPD, inflammatory tissue damage is endless, ie, inflammation perpetuates further on long after patients have quit smoking. […] Participating cells: neutrophils […] Neutrophils are known as the major destructors of the elastic matrix of the alveoli. […] Macrophages play a crucial role in COPD and are regarded as major producers of MMPs in the COPD lung.

• #1 Pathogenesis of Chronic Obstructive Pulmonary Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2713323/

  There is a 5- to 10-fold increase in the numbers of macrophages in the airways, lung parenchyma, and bronchoalveolar lavage fluid (BALF) in patients with COPD. […] Cigarette smoke activates macrophages to release inflammatory mediators, including tumor necrosis factor, IL-8 and other CXC chemokines, monocyte chemotactic peptide-1, leukotriene B4, and reactive oxygen species. […] Many of the inflammatory mediators that are expressed in COPD are controlled by the transcription factor nuclear factor (NF)-B, which is upregulated in alveolar macrophages in patients with COPD and in airway cells in patients with mild/moderate COPD in comparison with control nonsmokers. […] It is likely that interactions occur between different mechanisms. For example, there are probably interrelationships between the proteaseantiprotease balance, oxidative stress, and apoptosis as destructive processes in emphysema.

• #1 Pathological mechanism and targeted drugs of COPD | COPD

  https://www.dovepress.com/pathological-mechanism-and-targeted-drugs-of-copd-peer-reviewed-fulltext-article-COPD

  Activation of NF-kB is achieved by activating protein inhibitor kappa B (IkB) to make ubiquitination of IkB. […] All of these suggest that activation of the NF-B pathway drives the release of inflammatory factors, leads to further enhancement of the oxidative stress response and exacerbates lung injury in patients. […] The pathogenesis of COPD is complex, mainly related to oxidative stress, inflammatory factors and over-expression or activation of signaling pathways. […] NLRP3 is highly correlated with the development of COPD and achieves therapeutic effects in COPD by controlling inflammation to inhibit the production of inflammatory factors by blocking the activation of related pathways.

• #1 Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-7-53

  Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. […] Recently, an increasing number of data suggest a fourth important mechanism involved in the development of COPD: apoptosis of structural cells in the lung might possibly be an important upstream event in the pathogenesis of COPD. There is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients. Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development of emphysema. […] Recent data from both animal models of COPD as well as from studies in human subjects suggest that a fourth mechanism might be involved in the pathogenesis of COPD: disruption of the balance between apoptosis and replenishment of structural cells in the lung might contribute to the destruction of lung tissue in response to cigarette smoke, leading to emphysema.

• #1 Pathogenesis of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke – Hikichi – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/32744/html

  Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is characterized by functional and structural alterations primarily caused by long-term inhalation of harmful particles. Cigarette smoke (CS) induces airway inflammation in COPD, which is known to persist even after smoking cessation. This review discusses the basic pathogenesis of COPD, with particular focus on an endogenous protective mechanism against oxidative stress via Nrf2, altered immune response of the airway inflammatory cells, exaggerated cellular senescence of the lung structural cells, and cell death with expanded inflammation. Recently, CS-induced mitochondria autophagy is reported to initiate programmed necrosis (necroptosis). Necroptosis is a new concept of cell death which is driven by a defined molecular pathway along with exaggerated inflammation. This new cell death mechanism is of importance due to its ability to produce more inflammatory substances during the process of epithelial death, contributing to persistent airway inflammation that cannot be explained by apoptosis-derived cell death. Significant evidence shows that oxidative stress damages the lungs and contributes to COPD pathogenesis. It is possible that therapeutic administration of multiple antioxidants will be effective in the management of COPD. The molecular pathology underlying chronic obstructive pulmonary disease (COPD) is influenced by genetic background, cellular senescence, and chronic inhalation of harmful particles, such as those present in CS. Toxic particles of inhaled smoke induce airway inflammation that is exacerbated in COPD patients; such chronic inflammation is known to persist even after smoking cessation. The importance of Nrf2 is confirmed by CS-exposed Nrf2-deficient mice demonstrating a development of emphysematous lesion in the lungs. The disruption of the epithelial barrier and the reduction in E-cadherin expression induces epithelial-mesenchymal transition, consequently inducing the aberrant production of MMPs and growth factors, airway destruction, and remodeling. Cellular senescence also occurs in stem cells. In normal stem cells, the preservation of a quiescent state is essential to maintain replication competence. Many stem cells prevent oxidative phosphorylation by mitochondria and are often dependent on metabolism via the anaerobic glycolytic pathway to avoid cellular senescence induced by the intracellularly produced ROS. The most probable explanation for the age-associated changes in COPD is the intracellular and extracellular production of ROS. Appropriate ROS levels are necessary for normal aging, while excessive ROS levels lead to cell cycle arrest and cell senescence via activation of the tumor suppressor protein p53. The relationship between autophagy and programmed necrosis (necroptosis) involved in CS-induced cell death is a novel finding that reveals the mechanism of exaggerated inflammatory response that is not explained by apoptosis-derived cell death.

• #1 Pathogenesis of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke – Hikichi – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/32744

  Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is characterized by functional and structural alterations primarily caused by long-term inhalation of harmful particles. Cigarette smoke (CS) induces airway inflammation in COPD, which is known to persist even after smoking cessation. This review discusses the basic pathogenesis of COPD, with particular focus on an endogenous protective mechanism against oxidative stress via Nrf2, altered immune response of the airway inflammatory cells, exaggerated cellular senescence of the lung structural cells, and cell death with expanded inflammation. Recently, CS-induced mitochondria autophagy is reported to initiate programmed necrosis (necroptosis). Necroptosis is a new concept of cell death which is driven by a defined molecular pathway along with exaggerated inflammation. This new cell death mechanism is of importance due to its ability to produce more inflammatory substances during the process of epithelial death, contributing to persistent airway inflammation that cannot be explained by apoptosis-derived cell death. Autophagy is an auto-cell component degradation system executed by lysosomes that controls protein and organelle degradation for successful homeostasis. As well as in the process of necroptosis, autophagy is also observed during cellular senescence. Aging of the lungs results in the acquisition of senescence-associated secretory phenotypes (SASP) that are known to secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases resulting in chronic low-grade inflammation. This review provides insights into CS-induced COPD pathogenesis, which contributes to a very complex disease. Investigating the mechanism of developing COPD, along with the availability of the particular inhibitors, will lead to new therapeutic approaches in COPD treatment.

• #1

  https://www.jci.org/articles/view/60324

  The relentless lung injury due to oxidant exposure, along with the potential exhaustion of lung protective responses, ultimately leads to lung aging, with increased expression of markers of cellular senescence. Again, a common denominator for aging and cellular senescence is oxidative stress, resulting in macromolecular damage, including the increased expression of markers of DNA damage and adduct-modified proteins. The ultimate biological clock of cell turnover is controlled by telomerase, which preserves the shortening of ends of chromosomes during every round of mitosis. Lungs of patients with advanced emphysema have decreased telomere lengths in alveolar cells, which are paralleled by decreased telomere lengths in peripheral blood mononuclear cells. The contribution of shortened telomeres was recently unraveled in investigations with the telomerase reverse transcriptase-knockout mice, which showed increased sensitivity to alveolar injury and airspace enlargement due to cigarette smoke, notably in late intercrosses compared with early intercrosses and wild-type mice.

• #1 COPD – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/copd/symptoms-causes/syc-20353679

  In about 1% of people with COPD, the condition results from a gene change passed down in families. This is a genetic form of emphysema. This gene lessens the levels of a protein called alpha-1-antitrypsin (AAT) in the body. […] Low levels of this protein, a condition called alpha-1-antitrypsin (AAT) deficiency, can cause liver damage, lung conditions such as COPD or both.

• #1

  https://www.jci.org/articles/view/60324

  The stage of progression of alveolar injury has attracted most of the research efforts in the COPD field. For more than 30 years, initiation and progression have been linked to extracellular matrix proteolysis, notably degradation of elastin by elastases, largely of inflammatory cell source. Key to this paradigm were the landmark discoveries of emphysema in 1-antitrypsin-deficient patients and the induction of emphysema by intratracheal instillation of pancreatic elastase, as well as the finding that MMP-12-deficient mice are resistant to cigarette smoke-induced mouse emphysema. While extracellular matrix proteolysis is a central event in emphysema, it is apparent that it cannot explain the complexity of alveolar destruction in COPD. […] We believe that mechanisms involved in the progression stage of COPD may be distinctly engaged in generating variable intermediate and clinically relevant disease phenotypes, such as emphysema, chronic airway disease (including chronic bronchitis and bronchiolitis), and systemic disease.

• #1 COPD Pathogenesis and Alterations in the Oral, Lung, and Gut Microbiomes

  https://www.mdpi.com/2036-7481/15/3/106

  Chronic obstructive pulmonary disease (COPD) is a respiratory and systemic disease affecting more than 300 million people globally every year, and it also becomes a substantial economic burden. […] The pathogenesis of chronic respiratory disorders correlates with lung and gut microbiome, and dysbiosis can affect disease progression in COPD patients. […] The lung microbiome plays an essential role in the pathogenesis of COPD. […] Previous studies documented that the respiratory microbiome detected by Bronchoalveolar lavage fluid (BALF) and sputum in COPD patients were quite different from that of healthy control, with an increased relative abundance of Moraxella, Streptococcus, Proteobacteria, Veillonella, Eubacterium, and Prevotella spp. […] This discrepancy can happen due to the different methods of analyzing the microbiome.

• #1 COPD Pathogenesis and Alterations in the Oral, Lung, and Gut Microbiomes

  https://www.mdpi.com/2036-7481/15/3/106

  These results suggest that the gut–lung axis can influence disease progression in COPD patients, and modulating the lung and gut microbiome can be targeted and potentially become a proper preventive strategy for COPD. […] The progression and pathogenesis of COPD are linked to the altered respiratory microbiome, which correlates with gut dysbiosis. […] It has been reported that some species with anti-inflammatory effects, such as Faecalibacterium prausnitzii and Akkermansia muciniphila, were decreased in chronic respiratory diseases and cancer patients.

• #1 Novel aspects of pathogenesis and regeneration mechanisms in COPD | COPD

  https://www.dovepress.com/novel-aspects-of-pathogenesis-and-regeneration-mechanisms-in-copd-peer-reviewed-fulltext-article-COPD

  Chronic obstructive pulmonary disease (COPD), a major cause of death and morbidity worldwide, is characterized by expiratory airflow limitation that is not fully reversible, deregulated chronic inflammation, and emphysematous destruction of the lungs. […] Several clinical features comprise COPDs such as chronic bronchitis, destruction of small airways, and enlargement/disorganization of alveoli, ie, loss of alveolar tissue. […] Several generally recognized mechanisms will be discussed shortly herein, ie, unregulated inflammation, proteolysis/antiproteolysis imbalance, and destroyed repair mechanisms, while novel topics such as deviated microbiota, air pollutants-related damage, and autoimmune process within the lung tissue will be discussed more extensively. […] Autoimmunity also plays a role in COPD as it becomes increasingly accepted. Autoimmune mechanisms can explain the unregulated inflammatory process perpetuation that continues after smoking cessation, since the initial inflammation and environmental insults in lungs expose certain epitopes for the autoimmune attack.

• #1 Novel aspects of pathogenesis and regeneration mechanisms in COPD | COPD

  https://www.dovepress.com/novel-aspects-of-pathogenesis-and-regeneration-mechanisms-in-copd-peer-reviewed-fulltext-article-COPD

  The increased recruitment of monocytes from the circulation in response to monocyte-selective chemokines that are increased in COPD airways and local proliferation of lung macrophages may contribute to increase in lung macrophages numbers. […] All these data stimulate discussion if autoimmune process in COPD is a causative process or just a consequence or even a coincidence.

• #1 Clinical physiology of chronic obstructive pulmonary disease | British Columbia Medical Journal

  https://bcmj.org/articles/clinical-physiology-chronic-obstructive-pulmonary-disease

  Expiratory airflow limitation is the principal physiological defect in COPD. Intrinsic airway factors relate to bronchial wall inflammation and include mucosal inflammation/edema, bronchial wall remodeling/fibrosis, and increased mucosal secretions. […] Extrinsic factors involve the loss of elastic tissue support for small airways and the dynamic expiratory compression of these airways. Other factors such as respiratory muscle dysfunction can further limit airflow in some patients. Hyperinflation can also occur in COPD, leading to an increase in functional residual capacity (FRC) the amount of air that remains in the lungs at the end of tidal exhalation. […] This can lead to gas trapping and an increase in residual volume (RV). As a consequence, there is an augmentation of the inspiratory work of breathing, which is an important factor in producing dyspnea.

• #1 Clinical physiology of chronic obstructive pulmonary disease | British Columbia Medical Journal

  https://bcmj.org/articles/clinical-physiology-chronic-obstructive-pulmonary-disease

  Perturbations in gas exchange are caused primarily by regional inequalities of ventilation and perfusion (VQ mismatching). This process commonly produces hypoxemia, but in more advanced disease can also contribute to hypercapnia and chronic respiratory acidosis. Other contributing factors to gas exchange disturbances in advanced COPD are pulmonary hypertension and impaired cardiac function, which can lead to reduced mixed venous oxygenation. […] A number of factors contribute to ventilatory muscle dysfunction in COPD. A major factor is a consequence of hyperinflation, which limits force generation and endurance, and places the inspiratory muscles at a mechanical disadvantage. […] Recently it has been proposed that lung inflammation may directly affect atherogenesis by driving systemic inflammation.

• #1 Clinical physiology of chronic obstructive pulmonary disease | British Columbia Medical Journal

  https://bcmj.org/articles/clinical-physiology-chronic-obstructive-pulmonary-disease

  Pulmonary hypertension is a late complication of COPD and independently worsens its prognosis. A major factor is chronic hypoxia, which can result in pulmonary vasoconstriction. Other factors include endothelial dysfunction, remodeling of pulmonary arteries, and pulmonary capillary bed destruction. […] COPD is an inflammatory airway disease with a complex pathophysiology. This disorder leads to airway obstruction and often to hyperinflation, which along with gas exchange abnormalities interact to cause dyspnea and functional limitation. Spirometry is a widely available tool that quantifies the abnormalities in COPD and can be fundamental in diagnosing, monitoring, and establishing the prognosis of individuals with this condition.

• #1 Chronic Obstructive Pulmonary Disease (COPD) – Pulmonary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pulmonary-disorders/chronic-obstructive-pulmonary-disease-and-related-disorders/chronic-obstructive-pulmonary-disease-copd

  The inflammation in COPD increases as disease severity increases, and, in severe (advanced) disease, inflammation does not resolve completely despite smoking cessation. […] Mechanical stress on alveoli from over-distension may make them susceptible to proteases, leading to alveolar septal destruction and progressive emphysema. […] The cardinal pathophysiologic feature of COPD is airflow limitation caused by airway narrowing and/or obstruction, loss of elastic recoil, or both. […] Airway narrowing and obstruction are caused by inflammation-mediated mucus hypersecretion, mucus plugging, mucosal edema, bronchospasm, peribronchial fibrosis, and remodelling of small airways or a combination of these mechanisms. […] Enlarged alveolar spaces sometimes consolidate into bullae, defined as airspaces 1 cm in diameter. […] Chronic alveolar hypoxia increases pulmonary vascular tone, which, if diffuse, causes pulmonary hypertension and cor pulmonale. […] The increase in pulmonary vascular pressure may be augmented by the destruction of the pulmonary capillary bed due to destruction of alveolar septa.

• #1 Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis | Nature Communications

  https://www.nature.com/articles/s41467-019-10991-7

  Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

• #1 Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis | Nature Communications

  https://www.nature.com/articles/s41467-019-10991-7

  Here, we show that CS promotes labile iron accumulation via NCOA4-mediated ferritinophagy, leading to phospholipid peroxidation and ferroptosis in human lung epithelial cells. Using genetic manipulation, including GPx4 transgenic mice and heterozygous GPx4-deficient mice, we verify the crucial role of ferroptosis in cigarette smoke-induced mouse models of COPD. […] To elucidate the potential involvement of GPx4 in COPD pathogenesis, we evaluated GPx4 expression levels in human bronchial epithelial cells isolated from never smoker, smoker non-COPD, and COPD patient lung. Western blotting demonstrated that GPx4 expression was significantly lower in HBECs from COPD lungs than in never smokers and non COPD smokers lungs. Furthermore, GPx4 expression levels were positively correlated with percentage of FEV1/FVC.

• #1 Investigating COPD Pathogenesis: Abnormal Iron Homeostasis in Alveolar Macrophages

  https://www.hcplive.com/view/investigating-copd-pathogenesis-abnormal-iron-homeostasis-in-alveolar-macrophages

  Disruptions in iron metabolism within alveolar macrophages may play a key role in the progression and exacerbation of chronic obstructive pulmonary disease (COPD), according to ongoing research led by William Zhang, MD, Assistant Professor of Medicine at Weill Cornell Medicine. […] Zhang and his team used murine models of cigarette smoke exposure and single-cell RNA sequencing to investigate how dysregulated iron metabolism in alveolar macrophages contributes to COPD pathogenesis and exacerbation risk. […] He found that cigarette smoke induces iron loading in these immune cells, impairing their function, and that disrupting iron regulation may reduce emphysema development but could also weaken infection response.

• #1 Abnormal Iron Homeostasis in Alveolar Macrophages: Implications for COPD Pathogenesis

  https://www.hcplive.com/view/abnormal-iron-homeostasis-alveolar-macrophages-implications-copd-pathogenesis

  Elevated iron levels in airspace macrophages are associated with COPD exacerbation and may drive pathobiology. […] Although cigarette smoke (CS) exposure is known to trigger COPD development, many other biological aspects of COPD pathogenesis are unknown, preventing the development of personalized therapies that target specific mechanistic endotypes. […] We hypothesized that this AM abnormal iron metabolism may be a critical driver of COPD pathobiology, and specific to this proposal, that AM iron accumulation contributes to the well-known phenomenon of AM dysfunction in COPD, resulting in an increased risk for infection and infection-triggered COPD exacerbation. […] This supports our hypothesis that disruption of AM iron homeostasis from smoke may potentiate respiratory infections. […] This highlights the critical importance of maintaining iron homeostasis as while CS-induced iron overload may have adverse effects on macrophage function, the inability to access ferritin-stored iron during an acute infection may limit AMs energetically and metabolically, preventing efficient bacterial clearance. […] Whether this difference is due to fundamental biological differences or due to inadequate dosing and bioavailability is the subject of ongoing studies.

• #1 Cellular Mechanism Impaired by Cigarette Smoke, Affected in COPD Patients

  https://respiratory-therapy.com/disorders-diseases/chronic-pulmonary-disorders/copd/cellular-mechanism-impaired-by-cigarette-smoke-affected-in-copd-patients/

  Cigarette smoke reduces the activity of the immunoproteasome and impacts its levels in COPD patients. […] The immunoproteasome is a defined structure in mammalian cells that is specialized to degrade protein molecules that are foreign to the cell, such as upon virus infection. […] Smoking crucially impairs this protective response of the immune system. […] We observed that cigarette smoke reduces the activity of the immunoproteasome in human cells, explains first author Ilona Kammerl. […] Importantly, lungs of COPD patients displayed reduced immunoproteasome activity. […] This suggests that the specific immune response to viral pathogens is reduced in COPD patients. […] Our data provide the first indications that this is due to cigarette smoke-induced reductions in immunoproteasome activity, emphasizes study leader Silke Meiners. […] Cigarette smoke is a primary risk factor for COPD.

• #1 Chronic obstructive pulmonary disease (COPD) – Aetiology | BMJ Best Practice

  https://bestpractice.bmj.com/topics/en-gb/7/aetiology

  Evidence suggests that the host response to inhaled stimuli generates the inflammatory reaction responsible for the changes in the airways, alveoli, and pulmonary blood vessels. Activated macrophages, neutrophils, and leukocytes are the core cells in this process. Oxidative stress and an excess of proteases amplify the effects of chronic inflammation. […] Growing evidence implicates eosinophils, a leukocyte usually involved in allergic disease, in the COPD inflammatory cascade. […] Elastin breakdown and subsequent loss of alveolar integrity causes emphysema. […] Increased airway resistance is the physiological definition of COPD. Decreased elastic recoil, fibrotic changes in lung parenchyma, and luminal obstruction of airways by secretions all contribute to increased airways resistance. […] Systemic inflammatory mediators may contribute to skeletal muscle wasting or cachexia, and initiate or worsen cardiac, metabolic, and skeletal comorbidities.

• #2 COPD Pathogenesis – Dr. Frank Hull

  https://browardsleepdisorders.com/copd-pathogenesis/

  Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow limitation and a complex inflammatory response in the airways and lung parenchyma. This review examines the molecular and cellular mechanisms underlying COPD pathogenesis, with particular focus on inflammatory pathways, immune responses, and tissue remodeling. […] Understanding these pathways is crucial for developing effective therapeutic strategies. The heterogeneity of COPD suggests that personalized approaches targeting specific pathogenic mechanisms may be necessary for optimal treatment outcomes.

• #2 Pathology, pathogenesis, and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1463976/

  In general, the inflammatory and structural changes in the airways increase with disease severity and persist even after smoking cessation. […] Besides inflammation, two other processes are involved in the pathogenesis of COPD – an imbalance between proteases and antiproteases and an imbalance between oxidants and antioxidants (oxidative stress) in the lungs. […] COPD is characterised by increased numbers of neutrophils, macrophages, and T lymphocytes (CD8 more than CD4) in the lungs. […] In general, the extent of the inflammation is related to the degree of the airflow obstruction. These inflammatory cells release a variety of cytokines and mediators that participate in the disease process. […] Increased production (or activity) of proteases and inactivation (or reduced production) of antiproteases results in imbalance. […] Cigarette smoke, and inflammation itself, produce oxidative stress, which primes several inflammatory cells to release a combination of proteases and inactivates several antiproteases by oxidation.

• #2 Pathogenesis of Chronic Obstructive Pulmonary Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2713323/

  The current paradigm for the pathogenesis of chronic obstructive pulmonary disease is that chronic airflow limitation results from an abnormal inflammatory response to inhaled particles and gases in the lung. […] Airspace inflammation appears to be different in susceptible smokers and involves a predominance of CD8+ T lymphocytes, neutrophils, and macrophages. […] The first is a proteaseantiprotease imbalance, which has been linked to the pathogenesis of emphysema. […] The second process, oxidative stress, has a role in many of the pathogenic processes of chronic obstructive pulmonary disease and may be one mechanism that enhances the inflammatory response. […] It has been proposed that the development of emphysema may involve alveolar cell loss through apoptosis. […] Studies have shown that there are structural abnormalities in small airways in smokers with and without COPD.

• #2 Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

  https://www.mdpi.com/1424-8247/14/10/979

  The imbalance between proteases and their inhibitors plays a crucial role in COPD pathogenesis. Proteases, including neutrophil elastase (NE) and proteinase 3, degrade connective tissue components, especially elastin, leading to emphysema. […] The increase in elastolytic enzymes, such as MMPs, induces ECM degradation and alveolar wall destruction. Alveolar macrophages are pivotal to COPD development, because even after smoking cessation, their dysfunction may continue to contribute to disease progression.

• #2 Progress in the mechanism and targeted drug therapy for COPD | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00345-x

  Oxidative stress is an important factor in COPD pathogenesis. An increased oxidative burden occurs in the lungs of patients with COPD, and oxidative stress may be involved in various the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases and enhancing lung inflammation through activation of redox-sensitive transcription factors. […] The pathogenesis of COPD is closely related to the imbalance of protease/anti-protease, which leads to the destruction of the elastin framework. […] The inflammatory process of COPD is characterised by a continued migration of inflammatory cells (mainly neutrophils) from the blood vessel to the lungs. […] The transcription factor NF-B is studied in systemic inflammation and has been noticed in COPD patients.

• #2 Pathological mechanism and targeted drugs of COPD | COPD

  https://www.dovepress.com/pathological-mechanism-and-targeted-drugs-of-copd-peer-reviewed-fulltext-article-COPD

  Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis, emphysema, and small airway obstruction. Incompletely reversible airflow limitation, inflammation, excessive mucus secretion and bronchial mucosal epithelial lesions are the main pathological basis of the disease. […] This paper summarizes the pathogenesis of COPD and clarifies the effect and mechanism of the latest targeted drugs for COPD. […] Oxidative stress is involved in the development of several inflammatory conditions and is an important pathogenetic factor in COPD. […] The aggregation of neutrophils also leads to activation of a large number of inflammatory factors to produce more ROS, and aggravates the oxidative stress response. […] The oxidative system involves the secretion of the airway epithelial mucus, and the stimulation of noxious gases such as cigarettes generates oxidative stress, which causes a large accumulation of ROS and regulates the relevant mucus genes, such as Muc5b and Mu5ac.

• #2 COPD: Pathogenesis and Natural History | Thoracic Key

  https://thoracickey.com/copd-pathogenesis-and-natural-history/

  The development of structural changes in the pulmonary arterioles leads to persistent pulmonary hypertension and right ventricular hypertrophy/enlargement and dysfunction (cor pulmonale). […] A summary of the pathologic changes in the lungs in COPD is given in Table 43-1. […] An overview of the pathogenic mechanisms in COPD is given in Figure 43-3. […] Studies of lung or bronchial biopsies and induced sputum have shown that lung inflammation is present in all cigarette smokers. However, an enhanced or abnormal inflammatory response to inhaled particles or gases, beyond the normal protective inflammatory response, is a characteristic feature of COPD and has the potential to produce lung injury. […] The mechanism by which CD8 + T lymphocytes accumulate in the airways in COPD is not fully understood.

• #2 COPD: Pathogenesis and Natural History | Thoracic Key

  https://thoracickey.com/copd-pathogenesis-and-natural-history/

  The role of T cells in the pathogenesis of COPD is not fully understood. […] Increased numbers of activated neutrophils are found in both bronchoalveolar lavage (BAL) fluid and sputum from patients with COPD. […] The role of neutrophils in the pathogenesis of COPD is not entirely clear. […] There is a 5- to 10-fold increase in the numbers of macrophages in the airways, lung parenchyma, and BAL in patients with COPD. […] The expression of many of the inflammatory mediators implicated in the inflammatory response in the lungs in COPD is controlled by the transcription factor nuclear factor (NF)-B. […] In general, with increasing severity of COPD there is a further increase in the inflammatory response. […] The most compelling data in support of the causal role of oxidative stress in the pathogenesis of emphysema have been provided by studies outlining the role of the master antioxidant transcription factor nuclear erythroid-related factor 2 (NRF2) in the disease.

• #2 Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-7-53

  Apoptosis is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation. There is increasing evidence that disturbance of the balance between apoptosis and proliferation in lung tissue contributes to the pathogenesis of COPD. […] An increasing number of data, both from animal models and studies on human subjects, supports an important role for apoptosis in the pathogenesis of COPD.

• #2 COPD: Pathogenesis and Natural History | Thoracic Key

  https://thoracickey.com/copd-pathogenesis-and-natural-history/

  Oxidative stress is linked to cell death, including alveolar cell apoptosis in the setting of human and experimental emphysema. […] The aggregate of these data led to the concept of an alveolar maintenance program that was required for structural preservation of the lungs. […] No single mechanism can account for the complex pathology in COPD. It is likely that interactions transpire between different mechanisms.

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