Materiały źródłowe

• #1 Emphysema: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/298283-overview

  Emphysema is pathologically defined as an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis. This process leads to reduced gas exchange, changes in airway dynamics that impair expiratory airflow, and progressive air trapping. […] The complex mechanism thought to be responsible is the interplay between Notch and Wnt, two signaling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation. […] Macrophages are found to be 5- to 10-fold higher in the bronchoalveolar lavage fluid of emphysematous patients. Also, along with macrophages, the release of proteases and free radical hydrogen peroxide from neutrophils adds to the epithelial ruination, specifically with emphasis on the basement membrane. This is why neutrophils are thought to be highly important in the pathogenesis of emphysema at the tissue level, a differentiator to the mainly eosinophilic inflammatory response in airways affected by asthma.

• #2 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  Pulmonary emphysema, a progressive form of chronic obstructive pulmonary disease (COPD), is characterized by persistent respiratory symptoms and airflow limitation resulting from airway or alveolar damage. […] Emphysema, specifically, is a pathological diagnosis that affects the air spaces distal to the terminal bronchiole. It is characterized by abnormal and permanent enlargement of lung air spaces, the destruction of the air space walls without fibrosis, and a loss of elasticity in the lung parenchyma. […] The clinical manifestations of emphysema arise from damage to the airways distal to the terminal bronchiole, including the respiratory bronchioles, alveolar sacs, alveolar ducts, and alveoli, collectively known as the acinus. In emphysema, there is abnormal permanent dilatation of the airspaces and destruction of their walls due to the proteinase activity. This dilatation decreases the alveolar and capillary surface area, impairing gas exchange.

• #3 Emphysema: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/298283-overview

  Emphysema is pathologically defined as an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis. This process leads to reduced gas exchange, changes in airway dynamics that impair expiratory airflow, and progressive air trapping. […] The complex mechanism thought to be responsible is the interplay between Notch and Wnt, two signaling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation. […] Macrophages are found to be 5- to 10-fold higher in the bronchoalveolar lavage fluid of emphysematous patients. Also, along with macrophages, the release of proteases and free radical hydrogen peroxide from neutrophils adds to the epithelial ruination, specifically with emphasis on the basement membrane. This is why neutrophils are thought to be highly important in the pathogenesis of emphysema at the tissue level, a differentiator to the mainly eosinophilic inflammatory response in airways affected by asthma.

• #4 Pathogenesis of Emphysema

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2645322/

  Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. […] The pathogenesis of emphysema is an arena of ongoing, active research, and new developments continue to arise. Emphysema can result from increased alveolar wall cell death and/or failure of alveolar wall maintenance. […] The literature indicates that chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. […] Ongoing inflammation and oxidative stress results in damage to airspace structure and disturbance of the normal maintenance of alveolar structure. Data strongly support a role for proteaseantiprotease imbalance in the development of emphysema. Furthermore, recent studies support the additional role of apoptosis in emphysema. Identification of the cellular and molecular mechanisms involved in the development of emphysema may have important implications for the development of new targets for therapeutic intervention.

• #5 SciELO Brazil – Pathogenesis of pulmonary emphysema – cellular and molecular events Pathogenesis of pulmonary emphysema – cellular and molecular events

  https://www.scielo.br/j/eins/a/QTydSTYJn7VhBzZTDKhH7bk

  Pulmonary emphysema is a chronic obstructive disease, resulting from important alterations in the whole distal structure of terminal bronchioles, either by enlargement of air spaces or by destruction of the alveolar wall, leading to loss of respiratory surface, decreased elastic recoil and lung hyperinflation. […] For many years, the hypothesis of protease-antiprotease unbalance prevailed as the central theme in the pathogenesis of pulmonary emphysema. According to this hypothesis, the release of active proteolytic enzymes, produced mainly by neutrophils and macrophages, degrades the extracellular matrix, affecting the integrity of its components, especially collagen and elastic fibers. […] Many processes seem to be involved in the pathogenesis of pulmonary emphysema. However, the hypothesis of the proteinase-antiproteinase enzymatic unbalance has prevailed as central theme in the last few years. According to this hypothesis, the destruction of the alveolar wall results from the action of active proteolytic enzymes that degrade the extracellular matrix (ECM) and affect the integrity of its components, specially the collagen and elastic fibers.

• #6 The Role of Proteases in the Pathogenesis of Lung Emphysema | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4419-9082-2_5

  Pulmonary emphysema, defined as permanent abnormal enlargement of peripheral airspaces of the lung is a major component of chronic obstructive pulmonary diseases (COPD). […] Despite the increasing importance of emphysema its pathogenesis remains poorly understood. […] The association between emphysema and a hereditary deficiency of l-antitrypsin led to the development of the protease-antiprotease hypothesis in emphysema. […] The concept is that activated inflammatory cells in the lung release several serine proteinases and matrix metalloproteinases, which destroy the lung tissue, overwhelming local antiprotease activities. […] Since the protease-antiprotease hypothesis may not be able to explain all conditions that lead to airspace enlargement new concepts have emerged in the last years that might explain the vanishing of lung structure.

• #7 SciELO Brazil – Pathogenesis of pulmonary emphysema – cellular and molecular events Pathogenesis of pulmonary emphysema – cellular and molecular events

  https://www.scielo.br/j/eins/a/QTydSTYJn7VhBzZTDKhH7bk

  Pulmonary emphysema is a chronic obstructive disease, resulting from important alterations in the whole distal structure of terminal bronchioles, either by enlargement of air spaces or by destruction of the alveolar wall, leading to loss of respiratory surface, decreased elastic recoil and lung hyperinflation. […] For many years, the hypothesis of protease-antiprotease unbalance prevailed as the central theme in the pathogenesis of pulmonary emphysema. According to this hypothesis, the release of active proteolytic enzymes, produced mainly by neutrophils and macrophages, degrades the extracellular matrix, affecting the integrity of its components, especially collagen and elastic fibers. […] Many processes seem to be involved in the pathogenesis of pulmonary emphysema. However, the hypothesis of the proteinase-antiproteinase enzymatic unbalance has prevailed as central theme in the last few years. According to this hypothesis, the destruction of the alveolar wall results from the action of active proteolytic enzymes that degrade the extracellular matrix (ECM) and affect the integrity of its components, specially the collagen and elastic fibers.

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

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

  The breakdown of elastic fibers, so-called elastolysis, is one of the hallmarks of emphysema, an important phenotype contributing to COPD. 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.

• #9 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  After prolonged exposure to harmful smoke, inflammatory cells such as macrophages, neutrophils, and T lymphocytes are recruited, playing a crucial role in the development of emphysema. The process begins with macrophage activation, which releases neutrophil chemotactic factors like leukotriene B4 and interleukin-8. As neutrophils are recruited, they and macrophages release various proteinases that contribute to mucus hypersecretion. […] An imbalance between elastase and anti-elastase imbalance increases susceptibility to lung destruction, resulting in airspace enlargement. Cathepsins and neutrophil-derived proteases, such as elastase and proteinase, degrade elastin, damaging the connective tissue of the lung parenchyma. […] Cytotoxic T cells also contribute to alveolar wall destruction by releasing TNF-a and perforins, which target and destroy epithelial cells. […] A deficiency in alpha-1 antitrypsin compromises these protective mechanisms, increasing the risk of developing panacinar emphysema.

• #10 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  After prolonged exposure to harmful smoke, inflammatory cells such as macrophages, neutrophils, and T lymphocytes are recruited, playing a crucial role in the development of emphysema. The process begins with macrophage activation, which releases neutrophil chemotactic factors like leukotriene B4 and interleukin-8. As neutrophils are recruited, they and macrophages release various proteinases that contribute to mucus hypersecretion. […] An imbalance between elastase and anti-elastase imbalance increases susceptibility to lung destruction, resulting in airspace enlargement. Cathepsins and neutrophil-derived proteases, such as elastase and proteinase, degrade elastin, damaging the connective tissue of the lung parenchyma. […] Cytotoxic T cells also contribute to alveolar wall destruction by releasing TNF-a and perforins, which target and destroy epithelial cells. […] A deficiency in alpha-1 antitrypsin compromises these protective mechanisms, increasing the risk of developing panacinar emphysema.

• #11 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Emphysema-Pathogenesis.aspx

  Emphysema refers to the irreversible damage caused to the delicate air sacs in the lungs called alveoli. The exact pathogenesis of emphysema has been an important subject of research, although the exact mechanisms is still not clear. […] AAT is a protein circulated in the blood that prevents leukocytes from damaging normal body tissue. […] Research has suggested that AAT is the main inhibitor of neutrophil elastase, a concept that is referred to as the protease-antiprotease theory. […] In emphysema, the damage caused to the alveoli eventually leads to their decreased elasticity and over-inflation. […] One of the most significant causes of emphysema is cigarette smoking. […] Oxidative stress is another purported contributor in the pathology of emphysema. The main mechanism here is thought to be activation of the transcription factor nuclear factor-kB, which, in turn, activates proinflammatory cytokine transcription and leads to destruction of the lung tissue.

• #12

  https://journals.lww.com/lungindia/fulltext/2006/23010/copd_etiopathogenesis__interplay_of_environmental.4.aspx

  One of the important manifestations of AAT deficiency is COPD. Many risk factors play a role in the development of COPD in persons having PiZZ phenotype. AAT deficiency can cause emphysema in non-smokers but this risk is increased dramatically in patients with AAT who smoke. […] Emphysema develops as a result of a protease-antiprotease imbalance. The imbalance is noted between the anti-elastase defenses of the lung and the relatively increased action of neutrophil elastase. The result is degradation of elastin of the gas exchanging regions of the lung. AAT is the major anti-elastase defense. Its absence results in destruction of the architecture of the lung leading to emphysema. […] AAT gets inactivated, by the action of oxidants found in tobacco smoke. An increased number of neutrophils are recruited into the alveoli by cigarette smoke and it further aggravates the concentration of NE. Alveolar macrophages and neutrophils release a number of metalloproteinases that are capable of degrading the components of extracellular matrix.

• #13 Emphysema: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/298283-overview

  AATD lung disease is due to the relative deficiency in the blood and lungs of the alpha-1 antitrypsin (AAT) protein. Although evidence suggests a more complicated cascade of proteolytic and inflammatory factors as the cause of emphysema in AATD, unopposed neutrophil elastase activity within the pulmonary interstitium with resultant connective tissue destruction remains an important contributor to the pathogenesis of emphysema. […] Pathologically defined as permanent enlargement of airspaces distal to the terminal bronchioles, emphysema creates an environment leading to a dramatic decline in the alveolar surface area available for gas exchange. Loss of individual alveoli with septal wall destruction leads to airflow limitation via two mechanisms. First, loss of alveolar wall results in a decrease in elastic recoil, which subsequently limits airflow. Second, loss of alveolar supporting structures is indirectly responsible for airway narrowing, again limiting airflow.

• #14 Emphysema – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/emphysema/symptoms-causes/syc-20355555

  In emphysema, the inner walls of the lungs’ air sacs called alveoli are damaged, causing them to eventually rupture. This creates one larger air space instead of many small ones and reduces the surface area available for gas exchange. […] Over time, the condition damages the thin walls of the air sacs in the lungs called alveoli. […] But when the air sacs are damaged in emphysema, it’s hard to move air out of your lungs. […] Smoking is the leading cause of emphysema. […] Rarely, emphysema results from a gene change passed down in families. This gene change causes low levels of a protein called alpha-1-antitrypsin (AAT). […] AAT is made in the liver and is passed into the bloodstream to help protect the lungs from damage caused by smoke, fumes and dust. […] Low levels of AAT, a condition called alpha-1-antitrypsin deficiency, can cause liver damage, lung conditions such as emphysema or both.

• #15 Pulmonary Emphysema: Diagnosis and Treatment | RT

  https://respiratory-therapy.com/disorders-diseases/chronic-pulmonary-disorders/copd/pulmonary-emphysema/

  The pathogenesis of emphysema is grounded in the protease and protease-inhibitor theory. […] The a1-PI molecule is susceptible to oxidative injury during smoking, rendering a1-PI ineffective in neutralizing proteolytic enzymes. […] Research data challenge the protease and protease-inhibitor theory’s ability to describe the sole or primary pathogenesis for emphysema. […] Recent evidence reveals that the degradation of elastin is not solely responsible for the development of emphysema from cigarette smoking. Collagen breakdown in the lungs appears to play a contributory role.

• #16 The role of collagenase in emphysema | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/rr85

  The extracellular matrix is essential for the integrity of the lung and when disrupted can lead to the architectural changes seen in emphysema. […] Studies have focused on elastolytic enzymes as the primary agents in disease pathogenesis, however, recent data suggest that collagenases may also be involved in the destruction of lung tissue in emphysema. […] The importance of collagen in this disease was raised when it was shown that a transgenic mouse line that expressed human MMP-1 (collagenase) in the lung developed emphysema with no effect on lung elastin content. […] Over the past several years, additional studies have emerged to implicate collagenase and collagen breakdown in this disease process. […] These studies suggest that collagenase is involved in the pathogenesis of emphysema in animal models.

• #17 The role of collagenase in emphysema | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/rr85

  The extracellular matrix is essential for the integrity of the lung and when disrupted can lead to the architectural changes seen in emphysema. […] Studies have focused on elastolytic enzymes as the primary agents in disease pathogenesis, however, recent data suggest that collagenases may also be involved in the destruction of lung tissue in emphysema. […] The importance of collagen in this disease was raised when it was shown that a transgenic mouse line that expressed human MMP-1 (collagenase) in the lung developed emphysema with no effect on lung elastin content. […] Over the past several years, additional studies have emerged to implicate collagenase and collagen breakdown in this disease process. […] These studies suggest that collagenase is involved in the pathogenesis of emphysema in animal models.

• #18 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Emphysema-Pathogenesis.aspx

  Emphysema refers to the irreversible damage caused to the delicate air sacs in the lungs called alveoli. The exact pathogenesis of emphysema has been an important subject of research, although the exact mechanisms is still not clear. […] AAT is a protein circulated in the blood that prevents leukocytes from damaging normal body tissue. […] Research has suggested that AAT is the main inhibitor of neutrophil elastase, a concept that is referred to as the protease-antiprotease theory. […] In emphysema, the damage caused to the alveoli eventually leads to their decreased elasticity and over-inflation. […] One of the most significant causes of emphysema is cigarette smoking. […] Oxidative stress is another purported contributor in the pathology of emphysema. The main mechanism here is thought to be activation of the transcription factor nuclear factor-kB, which, in turn, activates proinflammatory cytokine transcription and leads to destruction of the lung tissue.

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

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

  Significant evidence shows that oxidative stress damages the lungs and contributes to COPD pathogenesis. […] The importance of Nrf2 is confirmed by CS-exposed Nrf2-deficient mice demonstrating a development of emphysematous lesion in the lungs. […] The most probable explanation for the age-associated changes in COPD is the intracellular and extracellular production of ROS. […] The PI3K/AKT/mTOR pathway is at the core of the accelerated aging observed in COPD. […] 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. […] Understanding the mechanism of cell death signaling, along with the availability of inhibitors, is now focused as a new therapeutic target in COPD.

• #20 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Emphysema-Pathogenesis.aspx

  Emphysema refers to the irreversible damage caused to the delicate air sacs in the lungs called alveoli. The exact pathogenesis of emphysema has been an important subject of research, although the exact mechanisms is still not clear. […] AAT is a protein circulated in the blood that prevents leukocytes from damaging normal body tissue. […] Research has suggested that AAT is the main inhibitor of neutrophil elastase, a concept that is referred to as the protease-antiprotease theory. […] In emphysema, the damage caused to the alveoli eventually leads to their decreased elasticity and over-inflation. […] One of the most significant causes of emphysema is cigarette smoking. […] Oxidative stress is another purported contributor in the pathology of emphysema. The main mechanism here is thought to be activation of the transcription factor nuclear factor-kB, which, in turn, activates proinflammatory cytokine transcription and leads to destruction of the lung tissue.

• #21 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Emphysema-Pathology-and-Function.aspx

  Apart from chronic inflammation caused by irritation there is also a theory of increased oxidative stress that can contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. […] The major consequence of the oxidative stress is thought to be the activation of the transcription factor nuclear factor-kB. This in turn activates proinflammatory cytokine transcription that causes destruction of the lungs. Cigarette smoking also inhibits histone deacetylase. This also promotes the release of proinflammatory cytokines. […] A theory goes that there is an imbalance between proteases (protein break down enzymes) and antiproteases in emphysema. A delicate balance between protease and antiprotease activity is required for proper lung maintenance. When this balance changes there is increased destruction and inappropriate repair of lungs leading to emphysema.

• #22 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Emphysema-Pathology-and-Function.aspx

  Apart from chronic inflammation caused by irritation there is also a theory of increased oxidative stress that can contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. […] The major consequence of the oxidative stress is thought to be the activation of the transcription factor nuclear factor-kB. This in turn activates proinflammatory cytokine transcription that causes destruction of the lungs. Cigarette smoking also inhibits histone deacetylase. This also promotes the release of proinflammatory cytokines. […] A theory goes that there is an imbalance between proteases (protein break down enzymes) and antiproteases in emphysema. A delicate balance between protease and antiprotease activity is required for proper lung maintenance. When this balance changes there is increased destruction and inappropriate repair of lungs leading to emphysema.

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

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

  Significant evidence shows that oxidative stress damages the lungs and contributes to COPD pathogenesis. […] The importance of Nrf2 is confirmed by CS-exposed Nrf2-deficient mice demonstrating a development of emphysematous lesion in the lungs. […] The most probable explanation for the age-associated changes in COPD is the intracellular and extracellular production of ROS. […] The PI3K/AKT/mTOR pathway is at the core of the accelerated aging observed in COPD. […] 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. […] Understanding the mechanism of cell death signaling, along with the availability of inhibitors, is now focused as a new therapeutic target in COPD.

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

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

  Trx effectively prevents the progression of COPD by regulating redox status and protease/anti-protease balance, blocking the NF-B and MAPK signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the cAMP-PKA and PI3K/Akt signalling pathways. […] The mechanism by which Trx affects COPD is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses. […] Trx also improves the insensitivity of COPD to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (MIF). […] Trx plays an important role in maintaining the body’s redox balance.

• #25 Pathogenesis of Emphysema

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2645322/

  Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. […] The pathogenesis of emphysema is an arena of ongoing, active research, and new developments continue to arise. Emphysema can result from increased alveolar wall cell death and/or failure of alveolar wall maintenance. […] The literature indicates that chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. […] Ongoing inflammation and oxidative stress results in damage to airspace structure and disturbance of the normal maintenance of alveolar structure. Data strongly support a role for proteaseantiprotease imbalance in the development of emphysema. Furthermore, recent studies support the additional role of apoptosis in emphysema. Identification of the cellular and molecular mechanisms involved in the development of emphysema may have important implications for the development of new targets for therapeutic intervention.

• #26

  https://www.jci.org/articles/view/31811

  The presence of inflammatory cells that can release oxidants and proteases has now been well documented, one is reminded that a number of acute lung diseases that manifest with massive inflammation (such as bacterial pneumonia and acute lung injury) develop and resolve entirely without emphysematous parenchyma destruction. […] The activity of inflammatory cell-released proteases is inhibited by antiproteases, while other proteases in alveolar septal structure cells are engaged in the ongoing work of repair and angiogenic remodeling and join the neutrophil and macrophage elastases in support of the innate immune response. […] The loss of alveolar capillary endothelial cells and of small capillaries de facto makes emphysema also a vascular disease. […] The pleiotropic archgrowth factor, VEGF (its role in the lung has been recently reviewed), is normally abundantly expressed in the adult lung tissue. Its receptor, VEGFR2, is, at least in the rat, expressed on both epithelial and endothelial cells, and VEGFR blockade or conditional knockout of the VEGF gene causes lung cell apoptosis and emphysema.

• #27 The Role of Proteases in the Pathogenesis of Lung Emphysema | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4419-9082-2_5

  One concept is based on the vascular atrophy model for emphysema, proposed by Liebow in the 1950s. […] The disappearance of lung alveoli in emphysema is thought to be related to epithelial and endothelial alveolar septal death due to a decrease of endothelial cell maintenance factors. […] This review describes the role of proteases and outlines the apoptosis initiated model leading to pulmonary emphysema.

• #28 Critical role of tumor necrosis factor receptor 1 in the pathogenesis | COPD

  https://www.dovepress.com/critical-role-of-tumor-necrosis-factor-receptor-1-in-the-pathogenesis–peer-reviewed-fulltext-article-COPD

  COPD is a major cause of chronic morbidity and mortality throughout the world. […] Although tumor necrosis factor- (TNF-) has a critical role in the development of COPD, the role of different TNF receptors (TNFRs) in pulmonary emphysema has not been resolved. […] Pulmonary emphysema-like changes disappeared with deletion of TNFR1. […] The apoptotic signals through TNFR1 appear critical for the pathogenesis of pulmonary emphysema. […] In contrast, the inflammatory process has a less important role for the development of emphysema. […] TNF- has been considered to be an important factor for the pathogenesis of pulmonary fibrosis. […] Presently, TNF- is considered to play a central role in the pathogenesis of COPD. […] The main difference between TNFR1 and TNFR2 is the transduction of apoptotic signals, whereby TNFR1 can transduce a death signal.

• #29 Critical role of tumor necrosis factor receptor 1 in the pathogenesis | COPD

  https://www.dovepress.com/critical-role-of-tumor-necrosis-factor-receptor-1-in-the-pathogenesis–peer-reviewed-fulltext-article-COPD

  This study provides direct evidence that alveolar wall apoptosis is sufficient to cause pulmonary emphysema, even without the accumulation of inflammatory cells. […] Taking these data into consideration, we hypothesize that apoptosis has a critical role in the pathogenesis of COPD. […] Although the present data indicated a critical role for TNFR1 in the pathogenesis of COPD, TNFR2/ mice also demonstrated a slight attenuation in COPD development. […] Signals through TNFR1 have critical roles for the pathogenesis in this model.

• #30

  https://www.jci.org/articles/view/31811

  In addition, VEGF signaling leads to endothelial prostacyclin synthesis, and loss of prostacyclin synthase expression in the endothelial monolayers of small pulmonary arteries in emphysematous lungs and decreased prostacyclin synthesis may put these cells into double jeopardy and may remove yet another lung capillary endothelial cell survival factor. […] In addition to outright cell death, we have to consider a role of cellular senescence (not to be confused with the normal aging process of the lung) a process of replication fatigue in emphysema, as there is mounting evidence that cellular senescence may contribute to emphysema pathogenesis. […] The loss of the densely woven, well-organized network of collagen and elastin fibers on which alveolar epithelial and endothelial cell sit may be critical and repair-limiting.

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

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

  Significant evidence shows that oxidative stress damages the lungs and contributes to COPD pathogenesis. […] The importance of Nrf2 is confirmed by CS-exposed Nrf2-deficient mice demonstrating a development of emphysematous lesion in the lungs. […] The most probable explanation for the age-associated changes in COPD is the intracellular and extracellular production of ROS. […] The PI3K/AKT/mTOR pathway is at the core of the accelerated aging observed in COPD. […] 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. […] Understanding the mechanism of cell death signaling, along with the availability of inhibitors, is now focused as a new therapeutic target in COPD.

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

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

  Significant evidence shows that oxidative stress damages the lungs and contributes to COPD pathogenesis. […] The importance of Nrf2 is confirmed by CS-exposed Nrf2-deficient mice demonstrating a development of emphysematous lesion in the lungs. […] The most probable explanation for the age-associated changes in COPD is the intracellular and extracellular production of ROS. […] The PI3K/AKT/mTOR pathway is at the core of the accelerated aging observed in COPD. […] 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. […] Understanding the mechanism of cell death signaling, along with the availability of inhibitors, is now focused as a new therapeutic target in COPD.

• #33 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. […] 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). […] 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.

• #34 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. […] 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). […] 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.

• #35 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. […] 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). […] 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.

• #36 Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD | Applied Chest Imaging Laboratory

  https://acil.bwh.harvard.edu/mitophagy-dependent-necroptosis-contributes-pathogenesis-copd.html

  The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. […] Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. […] These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.

• #37 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  After prolonged exposure to harmful smoke, inflammatory cells such as macrophages, neutrophils, and T lymphocytes are recruited, playing a crucial role in the development of emphysema. The process begins with macrophage activation, which releases neutrophil chemotactic factors like leukotriene B4 and interleukin-8. As neutrophils are recruited, they and macrophages release various proteinases that contribute to mucus hypersecretion. […] An imbalance between elastase and anti-elastase imbalance increases susceptibility to lung destruction, resulting in airspace enlargement. Cathepsins and neutrophil-derived proteases, such as elastase and proteinase, degrade elastin, damaging the connective tissue of the lung parenchyma. […] Cytotoxic T cells also contribute to alveolar wall destruction by releasing TNF-a and perforins, which target and destroy epithelial cells. […] A deficiency in alpha-1 antitrypsin compromises these protective mechanisms, increasing the risk of developing panacinar emphysema.

• #38 Emphysema: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/298283-overview

  Emphysema is pathologically defined as an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis. This process leads to reduced gas exchange, changes in airway dynamics that impair expiratory airflow, and progressive air trapping. […] The complex mechanism thought to be responsible is the interplay between Notch and Wnt, two signaling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation. […] Macrophages are found to be 5- to 10-fold higher in the bronchoalveolar lavage fluid of emphysematous patients. Also, along with macrophages, the release of proteases and free radical hydrogen peroxide from neutrophils adds to the epithelial ruination, specifically with emphasis on the basement membrane. This is why neutrophils are thought to be highly important in the pathogenesis of emphysema at the tissue level, a differentiator to the mainly eosinophilic inflammatory response in airways affected by asthma.

• #39 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  After prolonged exposure to harmful smoke, inflammatory cells such as macrophages, neutrophils, and T lymphocytes are recruited, playing a crucial role in the development of emphysema. The process begins with macrophage activation, which releases neutrophil chemotactic factors like leukotriene B4 and interleukin-8. As neutrophils are recruited, they and macrophages release various proteinases that contribute to mucus hypersecretion. […] An imbalance between elastase and anti-elastase imbalance increases susceptibility to lung destruction, resulting in airspace enlargement. Cathepsins and neutrophil-derived proteases, such as elastase and proteinase, degrade elastin, damaging the connective tissue of the lung parenchyma. […] Cytotoxic T cells also contribute to alveolar wall destruction by releasing TNF-a and perforins, which target and destroy epithelial cells. […] A deficiency in alpha-1 antitrypsin compromises these protective mechanisms, increasing the risk of developing panacinar emphysema.

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

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

  We had previously shown that there are elevated levels of iron and iron proteins in the airways of smokers and subjects with COPD which associate with clinical COPD parameters including exacerbation frequency. […] 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.

• #41 Emphysema: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/298283-overview

  Emphysema is pathologically defined as an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis. This process leads to reduced gas exchange, changes in airway dynamics that impair expiratory airflow, and progressive air trapping. […] The complex mechanism thought to be responsible is the interplay between Notch and Wnt, two signaling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation. […] Macrophages are found to be 5- to 10-fold higher in the bronchoalveolar lavage fluid of emphysematous patients. Also, along with macrophages, the release of proteases and free radical hydrogen peroxide from neutrophils adds to the epithelial ruination, specifically with emphasis on the basement membrane. This is why neutrophils are thought to be highly important in the pathogenesis of emphysema at the tissue level, a differentiator to the mainly eosinophilic inflammatory response in airways affected by asthma.

• #42 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  After prolonged exposure to harmful smoke, inflammatory cells such as macrophages, neutrophils, and T lymphocytes are recruited, playing a crucial role in the development of emphysema. The process begins with macrophage activation, which releases neutrophil chemotactic factors like leukotriene B4 and interleukin-8. As neutrophils are recruited, they and macrophages release various proteinases that contribute to mucus hypersecretion. […] An imbalance between elastase and anti-elastase imbalance increases susceptibility to lung destruction, resulting in airspace enlargement. Cathepsins and neutrophil-derived proteases, such as elastase and proteinase, degrade elastin, damaging the connective tissue of the lung parenchyma. […] Cytotoxic T cells also contribute to alveolar wall destruction by releasing TNF-a and perforins, which target and destroy epithelial cells. […] A deficiency in alpha-1 antitrypsin compromises these protective mechanisms, increasing the risk of developing panacinar emphysema.

• #43

  https://www.jci.org/articles/view/31811

  The presence of inflammatory cells that can release oxidants and proteases has now been well documented, one is reminded that a number of acute lung diseases that manifest with massive inflammation (such as bacterial pneumonia and acute lung injury) develop and resolve entirely without emphysematous parenchyma destruction. […] The activity of inflammatory cell-released proteases is inhibited by antiproteases, while other proteases in alveolar septal structure cells are engaged in the ongoing work of repair and angiogenic remodeling and join the neutrophil and macrophage elastases in support of the innate immune response. […] The loss of alveolar capillary endothelial cells and of small capillaries de facto makes emphysema also a vascular disease. […] The pleiotropic archgrowth factor, VEGF (its role in the lung has been recently reviewed), is normally abundantly expressed in the adult lung tissue. Its receptor, VEGFR2, is, at least in the rat, expressed on both epithelial and endothelial cells, and VEGFR blockade or conditional knockout of the VEGF gene causes lung cell apoptosis and emphysema.

• #44

  https://www.jci.org/articles/view/31811

  The presence of inflammatory cells that can release oxidants and proteases has now been well documented, one is reminded that a number of acute lung diseases that manifest with massive inflammation (such as bacterial pneumonia and acute lung injury) develop and resolve entirely without emphysematous parenchyma destruction. […] The activity of inflammatory cell-released proteases is inhibited by antiproteases, while other proteases in alveolar septal structure cells are engaged in the ongoing work of repair and angiogenic remodeling and join the neutrophil and macrophage elastases in support of the innate immune response. […] The loss of alveolar capillary endothelial cells and of small capillaries de facto makes emphysema also a vascular disease. […] The pleiotropic archgrowth factor, VEGF (its role in the lung has been recently reviewed), is normally abundantly expressed in the adult lung tissue. Its receptor, VEGFR2, is, at least in the rat, expressed on both epithelial and endothelial cells, and VEGFR blockade or conditional knockout of the VEGF gene causes lung cell apoptosis and emphysema.

• #45

  https://www.jci.org/articles/view/31811

  In addition, VEGF signaling leads to endothelial prostacyclin synthesis, and loss of prostacyclin synthase expression in the endothelial monolayers of small pulmonary arteries in emphysematous lungs and decreased prostacyclin synthesis may put these cells into double jeopardy and may remove yet another lung capillary endothelial cell survival factor. […] In addition to outright cell death, we have to consider a role of cellular senescence (not to be confused with the normal aging process of the lung) a process of replication fatigue in emphysema, as there is mounting evidence that cellular senescence may contribute to emphysema pathogenesis. […] The loss of the densely woven, well-organized network of collagen and elastin fibers on which alveolar epithelial and endothelial cell sit may be critical and repair-limiting.

• #46 Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/66804

  This chapter describes endothelium-related and neuro-mediated mechanisms of emphysema development in chronic obstructive pulmonary disease (COPD) and smoking on the basis of previously completed studies, literature data, and own researches. […] New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. […] The participation of endothelial dysfunction and injury in emphysema development in COPD has been described since 2000 and early. […] It was proven that vascular endothelium actively participates in inflammatory reactions in COPD.

• #47 Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/66804

  This chapter describes endothelium-related and neuro-mediated mechanisms of emphysema development in chronic obstructive pulmonary disease (COPD) and smoking on the basis of previously completed studies, literature data, and own researches. […] New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. […] The participation of endothelial dysfunction and injury in emphysema development in COPD has been described since 2000 and early. […] It was proven that vascular endothelium actively participates in inflammatory reactions in COPD.

• #48 Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/66804

  This chapter describes endothelium-related and neuro-mediated mechanisms of emphysema development in chronic obstructive pulmonary disease (COPD) and smoking on the basis of previously completed studies, literature data, and own researches. […] New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. […] The participation of endothelial dysfunction and injury in emphysema development in COPD has been described since 2000 and early. […] It was proven that vascular endothelium actively participates in inflammatory reactions in COPD.

• #49 Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/66804

  This chapter describes endothelium-related and neuro-mediated mechanisms of emphysema development in chronic obstructive pulmonary disease (COPD) and smoking on the basis of previously completed studies, literature data, and own researches. […] New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. […] The participation of endothelial dysfunction and injury in emphysema development in COPD has been described since 2000 and early. […] It was proven that vascular endothelium actively participates in inflammatory reactions in COPD.

• #50 Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/66804

  Chronic exposure to cigarette smoke has been shown to increase SP expression in neurons of the central nervous system and simultaneously inhibits the activity of enzymes that metabolize neurokinins. […] The established pattern of changes in NK1-positive structures can be explained by the ability of SP to cause mast cell degranulation and NK1 receptor-dependent release of histamine and serotonin involved in local inflammatory answer. […] Prolonged pathological effects of tobacco combustion products entail the formation of structural changes with the active involvement of the neurokinin innervation apparatus localized in the mucous membranes of the respiratory system. […] In this way, from the presented data of experimental modeling of emphysema associated with long-term smoking, as well as studies in people with pulmonary emphysema and long-term tobacco smoking experience, neurogenic inflammation takes an active part in the processes of remodeling of lung tissue.

• #51 Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms | IntechOpen

  https://www.intechopen.com/chapters/66804

  Chronic exposure to cigarette smoke has been shown to increase SP expression in neurons of the central nervous system and simultaneously inhibits the activity of enzymes that metabolize neurokinins. […] The established pattern of changes in NK1-positive structures can be explained by the ability of SP to cause mast cell degranulation and NK1 receptor-dependent release of histamine and serotonin involved in local inflammatory answer. […] Prolonged pathological effects of tobacco combustion products entail the formation of structural changes with the active involvement of the neurokinin innervation apparatus localized in the mucous membranes of the respiratory system. […] In this way, from the presented data of experimental modeling of emphysema associated with long-term smoking, as well as studies in people with pulmonary emphysema and long-term tobacco smoking experience, neurogenic inflammation takes an active part in the processes of remodeling of lung tissue.

• #52 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  Pulmonary emphysema, a progressive form of chronic obstructive pulmonary disease (COPD), is characterized by persistent respiratory symptoms and airflow limitation resulting from airway or alveolar damage. […] Emphysema, specifically, is a pathological diagnosis that affects the air spaces distal to the terminal bronchiole. It is characterized by abnormal and permanent enlargement of lung air spaces, the destruction of the air space walls without fibrosis, and a loss of elasticity in the lung parenchyma. […] The clinical manifestations of emphysema arise from damage to the airways distal to the terminal bronchiole, including the respiratory bronchioles, alveolar sacs, alveolar ducts, and alveoli, collectively known as the acinus. In emphysema, there is abnormal permanent dilatation of the airspaces and destruction of their walls due to the proteinase activity. This dilatation decreases the alveolar and capillary surface area, impairing gas exchange.

• #53 Emphysema – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482217/

  Pulmonary emphysema, a progressive form of chronic obstructive pulmonary disease (COPD), is characterized by persistent respiratory symptoms and airflow limitation resulting from airway or alveolar damage. […] Emphysema, specifically, is a pathological diagnosis that affects the air spaces distal to the terminal bronchiole. It is characterized by abnormal and permanent enlargement of lung air spaces, the destruction of the air space walls without fibrosis, and a loss of elasticity in the lung parenchyma. […] The clinical manifestations of emphysema arise from damage to the airways distal to the terminal bronchiole, including the respiratory bronchioles, alveolar sacs, alveolar ducts, and alveoli, collectively known as the acinus. In emphysema, there is abnormal permanent dilatation of the airspaces and destruction of their walls due to the proteinase activity. This dilatation decreases the alveolar and capillary surface area, impairing gas exchange.

• #54 Emphysema – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/emphysema/symptoms-causes/syc-20355555

  In emphysema, the inner walls of the lungs’ air sacs called alveoli are damaged, causing them to eventually rupture. This creates one larger air space instead of many small ones and reduces the surface area available for gas exchange. […] Over time, the condition damages the thin walls of the air sacs in the lungs called alveoli. […] But when the air sacs are damaged in emphysema, it’s hard to move air out of your lungs. […] Smoking is the leading cause of emphysema. […] Rarely, emphysema results from a gene change passed down in families. This gene change causes low levels of a protein called alpha-1-antitrypsin (AAT). […] AAT is made in the liver and is passed into the bloodstream to help protect the lungs from damage caused by smoke, fumes and dust. […] Low levels of AAT, a condition called alpha-1-antitrypsin deficiency, can cause liver damage, lung conditions such as emphysema or both.

• #55 COPD – Symptoms and causes – Mayo Clinic

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

  In emphysema, the inner walls of the lungs’ air sacs called alveoli are damaged, causing them to eventually rupture. This creates one larger air space instead of many small ones and reduces the surface area available for gas exchange. […] The damaged inner walls of the alveoli may be destroyed, creating one large air space that is hard to empty compared with the many healthy small ones. The alveoli now have less surface area that can be used to exchange oxygen and carbon dioxide. Also, old air gets trapped in the large alveoli so there isn’t room for enough new air to get in.

• #56 COPD – Symptoms and causes – Mayo Clinic

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

  In emphysema, the inner walls of the lungs’ air sacs called alveoli are damaged, causing them to eventually rupture. This creates one larger air space instead of many small ones and reduces the surface area available for gas exchange. […] The damaged inner walls of the alveoli may be destroyed, creating one large air space that is hard to empty compared with the many healthy small ones. The alveoli now have less surface area that can be used to exchange oxygen and carbon dioxide. Also, old air gets trapped in the large alveoli so there isn’t room for enough new air to get in.

• #57 Emphysema – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/emphysema/symptoms-causes/syc-20355555

  Emphysema may cause high blood pressure in the arteries that bring blood to the lungs. This serious condition is called pulmonary hypertension. […] Large air spaces called bullae form in the lungs when the inner walls of the alveoli are destroyed. […] These bullae can become very large, even as large as half the lung. […] The bullae lessen the space available for the lung to expand. […] A collapsed lung called pneumothorax can be life-threatening in people who have severe emphysema because their lungs are already damaged. […] People with emphysema have a higher risk of getting lung cancer.

• #58 Emphysema – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/emphysema/symptoms-causes/syc-20355555

  Emphysema may cause high blood pressure in the arteries that bring blood to the lungs. This serious condition is called pulmonary hypertension. […] Large air spaces called bullae form in the lungs when the inner walls of the alveoli are destroyed. […] These bullae can become very large, even as large as half the lung. […] The bullae lessen the space available for the lung to expand. […] A collapsed lung called pneumothorax can be life-threatening in people who have severe emphysema because their lungs are already damaged. […] People with emphysema have a higher risk of getting lung cancer.

• #59 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

  Enlarged alveolar spaces sometimes consolidate into bullae, defined as airspaces 1 cm in diameter. Bullae may be entirely empty or have strands of lung tissue traversing them in areas of locally severe emphysema; they occasionally occupy an entire hemithorax. These changes lead to loss of elastic recoil and lung hyperinflation.

• #60 Emphysema: In-Depth Analysis of Pathogenesis Diagnostic Methods and Treatment Strategies | Open Access Journals

  https://www.rroij.com/open-access/emphysema-indepth-analysis-of-pathogenesis-diagnostic-methods-and-treatment-strategies.php?aid=94877

  Emphysema is a form of Chronic Obstructive Pulmonary Disease (COPD) that primarily results from long-term exposure to irritants that damage the lungs. […] The condition leads to the progressive destruction of alveoli, which reduces the surface area available for gas exchange. […] This damage causes the lungs to lose their elasticity, making it difficult for individuals to expel air effectively. […] The primary cause of emphysema is cigarette smoking. […] Tobacco smoke contains a myriad of harmful chemicals that inflame and damage the airways and alveoli. […] Long-term exposure to air pollution, industrial dust and fumes also contributes to the development of emphysema. […] Additionally, a rare genetic disorder known as Alpha-1 Antitrypsin Deficiency can lead to emphysema by impairing the body’s ability to protect the lungs from damage.

• #61 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Emphysema-Pathogenesis.aspx

  Emphysema refers to the irreversible damage caused to the delicate air sacs in the lungs called alveoli. The exact pathogenesis of emphysema has been an important subject of research, although the exact mechanisms is still not clear. […] AAT is a protein circulated in the blood that prevents leukocytes from damaging normal body tissue. […] Research has suggested that AAT is the main inhibitor of neutrophil elastase, a concept that is referred to as the protease-antiprotease theory. […] In emphysema, the damage caused to the alveoli eventually leads to their decreased elasticity and over-inflation. […] One of the most significant causes of emphysema is cigarette smoking. […] Oxidative stress is another purported contributor in the pathology of emphysema. The main mechanism here is thought to be activation of the transcription factor nuclear factor-kB, which, in turn, activates proinflammatory cytokine transcription and leads to destruction of the lung tissue.

• #62 Pathogenesis of Emphysema | Open Access Journals

  https://www.rroij.com/open-access/pathogenesis-of-emphysema.php?aid=90011

  Panlobular emphysema również zwany panacinar emphysema can include the whole lung or basically the lower projections. This sort of emphysema jest związany z alpha-1 antitrypsin insufficiency (A1AD or AATD), and isn’t związany z paleniem. […] Paracicatricial emphysema, in any case called inconsistent emphysema, jest widoczny w pobliżu przestrzeni włóknistych (bliznowacenie) jako ogromne przestrzenie.

• #63

  https://journals.lww.com/lungindia/fulltext/2006/23010/copd_etiopathogenesis__interplay_of_environmental.4.aspx

  COPD is characterized by a fall in expiratory flow and lung hyperinflation. These changes are due to loss of lung elasticity and inflammatory narrowing of the small airways of the lung. A number of genes in conjunction with environmental factors, are likely to influence the development of airway inflammation and parenchymal destruction, in other words the susceptibility to COPD. […] At present, most of the genes that contribute to the genetic component to COPD remain undetermined. The genes that are implicated in the pathogenesis of COPD are divided into 4 categories based on their functions: antiproteolysis, xenobiotic metabolism of the toxic substances in the cigarette smoke, inflammatory response to cigarette smoke, and mucociliary clearance in the lung. […] Imbalances in relative amounts of proteases and antiproteases are thought to play a major role in the pathogenesis of COPD especially emphysema. Deficiencies or abnormalities in antiproteases could lead to enhanced lung parenchymal destruction. Among the genes, alpha-1 antitrypsin deficiency has proved an important risk factor for COPD.

• #64 Emphysema: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/298283-overview

  Emphysema is pathologically defined as an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis. This process leads to reduced gas exchange, changes in airway dynamics that impair expiratory airflow, and progressive air trapping. […] The complex mechanism thought to be responsible is the interplay between Notch and Wnt, two signaling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation. […] Macrophages are found to be 5- to 10-fold higher in the bronchoalveolar lavage fluid of emphysematous patients. Also, along with macrophages, the release of proteases and free radical hydrogen peroxide from neutrophils adds to the epithelial ruination, specifically with emphasis on the basement membrane. This is why neutrophils are thought to be highly important in the pathogenesis of emphysema at the tissue level, a differentiator to the mainly eosinophilic inflammatory response in airways affected by asthma.

• #65 Pathogenesis of Emphysema

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2645322/

  Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. […] The pathogenesis of emphysema is an arena of ongoing, active research, and new developments continue to arise. Emphysema can result from increased alveolar wall cell death and/or failure of alveolar wall maintenance. […] The literature indicates that chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. […] Ongoing inflammation and oxidative stress results in damage to airspace structure and disturbance of the normal maintenance of alveolar structure. Data strongly support a role for proteaseantiprotease imbalance in the development of emphysema. Furthermore, recent studies support the additional role of apoptosis in emphysema. Identification of the cellular and molecular mechanisms involved in the development of emphysema may have important implications for the development of new targets for therapeutic intervention.

• #66 SciELO Brazil – Pathogenesis of pulmonary emphysema – cellular and molecular events Pathogenesis of pulmonary emphysema – cellular and molecular events

  https://www.scielo.br/j/eins/a/QTydSTYJn7VhBzZTDKhH7bk

  Even though the hypothesis of proteinase-antiproteinase enzyme unbalance prevails in the pathogenesis of pulmonary emphysema, it is not clear yet whether the development of the disease is due to excessive proteases or alpha-1-antiprotease deficiency, or both. Nevertheless, the cellular and molecular and autoimmune phenomena, alveolar cell apoptosis and genetic factors must also be considered, since together or isolate they contribute to understanding of the pathophysiology of pulmonary emphysema.

• #67 CELLULAR AND MOLECULAR MECHANISMS OF EMPHYSEMA PATHOGENESIS

  https://jscholarship.library.jhu.edu/items/b2bf6fb4-963a-4f29-87fb-c419ad3a14a6

  Emphysema is a progressive disease characterized by alveolar degradation, irreversible airway enlargement, and impaired gas exchange over time. […] We and others have theorized that innate immune cells, such as macrophages, become dysregulated in the emphysematous lung and ultimately cause long-term damage to tissue and airways. […] Herein, we applied several next-generation techniques for studying lung cell phenotypes and molecular mechanisms of disease pathogenesis in mice with elastase-induced emphysema. […] By the end of this Thesis, we suggest that severe damage post-elastase is likely orchestrated by a network of dysregulated immune cells; but CD63+ alveolar macrophages, specifically, were identified as a candidate cell type with the functional capacity to damage lung tissue over time. […] Future consideration and characterization of CD63+ alveolar macrophages may shed light on how dysregulated immune cells drive emphysema pathogenesis or the progression of related, degenerative diseases.

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

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

  Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure causes an imbalance favoring pro- over antioxidants (oxidative stress), leading to transcription factor activation and increased expression of inflammatory mediators and proteases. The inflammatory process can alter the bronchi, bronchioles, and pulmonary parenchyma, leading to progressive restriction of airflow, resulting in emphysema and chronic bronchitis. The pathogenesis of emphysema includes destruction of alveolar septa, increased air space, and loss of elastic recoil due to hyperinflammation and oxidative stress. […] COPD is characterized by progressive airflow limitation that is not fully reversible, associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Emphysema is the result of destruction of alveolar walls, which leads to reduced gas exchange, permanent airspace enlargement, loss of elastic recoil, hyperinflation, and expiratory flow limitation. As a consequence of fiber destruction by metalloproteinases, there are changes in collagen- and elastic-fiber organization. These features affect the lung’s tissue stability and mechanical properties, contributing to lung function decline over time and accelerating disease progression.

• #69 Pathogenesis of Emphysema

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2645322/

  Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. […] The pathogenesis of emphysema is an arena of ongoing, active research, and new developments continue to arise. Emphysema can result from increased alveolar wall cell death and/or failure of alveolar wall maintenance. […] The literature indicates that chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. […] Ongoing inflammation and oxidative stress results in damage to airspace structure and disturbance of the normal maintenance of alveolar structure. Data strongly support a role for proteaseantiprotease imbalance in the development of emphysema. Furthermore, recent studies support the additional role of apoptosis in emphysema. Identification of the cellular and molecular mechanisms involved in the development of emphysema may have important implications for the development of new targets for therapeutic intervention.

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