The copper dependent-lysyl oxidases contribute to the pathogenesis of pulmonary emphysema in chronic obstructive pulmonary disease patients

Besiktepe, Neziha; Kayalar, Özgecan; Erşen, Ezel; Öztay, Füsun

doi:10.1016/j.jtemb.2017.08.011

Cited by 24 publications

(24 citation statements)

References 32 publications

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“…However, in contrast to fibulin-5, 33 LOXL1 activity is not upregulated but downregulated in patients with emphysema. 39 The reason for this difference may well lay in the fact that LOXL1, unlike fibulin-5, depends on a cofactor, i.e., copper. 40 Whereas synthesis of repair proteins can be autonomically upregulated following proteolytic insults, tissues are dependent on exogenous supply to provide them with extra copper.…”

Section: Oxidase-like Protein 1 During Elastin Repairmentioning

confidence: 99%

“…44 This pattern of gene expression in copper-deficient rats reminisces to upregulation of fibulin-5 and downregulation of LOX enzymes in human COPD lungs. 33,39 Given that copper is also the essential cofactor of the cytosolic enzyme superoxide dismutase (SOD), activity of this protein was quantified as well. 43 In contrast to LOX, SOD activity was significantly diminished in the copperdeficient lungs.…”

Section: Changes In Pulmonary Extracellular Matrix Of Copper-deficienmentioning

confidence: 99%

“…Whether deficiency of copper relates to the development of emphysema in humans is currently unknown; however, some data may provide a rationale to explore this possibility. 39,62 Copper In Exhaled Breath Condensate…”

Section: Human Data Suggesting That Copper Deficiency Induces Emphysemamentioning

confidence: 99%

See 2 more Smart Citations

<p>Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale</p>

Janssen

Wouters

Janssens

et al. 2019

COPD

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Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.

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Section: Oxidase-like Protein 1 During Elastin Repairmentioning

confidence: 99%

Section: Changes In Pulmonary Extracellular Matrix Of Copper-deficienmentioning

confidence: 99%

See 1 more Smart Citation

<p>Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale</p>

Janssen

Wouters

Janssens

et al. 2019

COPD

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“…Second harmonic generation microscopy can be used to detect fibrillar collagens without labelling and has recently been used to demonstrate significant changes in collagen organisation of COPD lung compared to non-diseased tissue [8]. The collagen fibril cross-linking enzymes, including lysyl oxidase, are reduced in COPD [9], while transglumatminase 2 levels are increased [10], suggesting that an imbalance in enzyme cross-linking may contribute to ECM structural changes in COPD. In addition, accessory ECM cross-linking components including decorin, biglycan and lumican modulate collagen fibril assembly, determining size, shape and collagen content [11].…”

Section: The Interstitial Ecm In Copdmentioning

confidence: 99%

The consequence of matrix dysfunction on lung immunity and the microbiome in COPD

et al. 2018

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The pulmonary extracellular matrix (ECM) is a complex network of proteins which primarily defines tissue architecture and regulates various biochemical and biophysical processes. It is a dynamic system comprising two main structures (the interstitial matrix and the basement membrane) which undergo continuous, yet highly regulated, remodelling. This remodelling process is essential for tissue homeostasis and uncontrolled regulation can lead to pathological states including chronic obstructive pulmonary disease (COPD). Altered expression of ECM proteins, as observed in COPD, can contribute to the degradation of alveolar walls and thickening of the small airways which can cause limitations in airflow. Modifications in ECM composition can also impact immune cell migration and retention in the lung with migrating cells becoming entrapped in the diseased airspaces. Furthermore, ECM changes affect the lung microbiome, aggravating and advancing disease progression. A dysbiosis in bacterial diversity can lead to infection, inducing epithelial injury and pro-inflammatory reactions. Here we review the changes noted in the different ECM components in COPD and discuss how an imbalance in microbial commensalism can impact disease development.

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“…It is characterized by inflated alveoli with excessive air, irreversible loss of alveoli, damage of the pulmonary epithelium, and reduced respiratory surface area depending on the extent of injury (2). The destruction of the alveolar structure can occur due to the protease-antiprotease imbalance, degradation of elastic fibers and loss of the tissue elasticity (3,4). Pulmonary epithelial cell loss, failure to achieve pulmonary epithelium integrity, chronic inflammation, and deterioration of repair mechanisms following pulmonary epithelial injury can result in emphysema (3,5,6).…”

Section: Introductionmentioning

confidence: 99%

Alterations at the Synthesis and Degradation of E-cadherin in the Human Lungs with Emphysema

Gogus¹,

Kayalar²,

Ongen³

et al. 2017

Eur J Biol

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Pulmonary emphysema leads to a cascade of events starting with enlarged alveoli, loss of alveoli and, subsequently to the damage and disruption of pulmonary epithelium. The integrity of the pulmonary epithelium, which is constituted by pneumocytes linked to each other through E-cadherin proteins, is important for respiration. The aim of the present study was to detect the content and destruction of E-cadherin protein and to investigate the contribution of E-cadherin to pulmonary emphysema pathogenesis. The structural changes, reparative capacity of the pulmonary epithelium, amount of E-cadherin protein and, the immunoreactivity of neural precursor cell expressed developmentally down-regulated protein 9 (NEDD9) were evaluated in emphysematous (n=7) and non-emphysematous (n=6) areas of lung samples taken from patients with chronic obstructive pulmonary disease. Emphysematous areas are characterized by enlarged alveoli, disrupted alveolar walls and epithelium, increased type 2 pneumocytes and NEDD9 immunoreactivity, and reduced E-cadherin proteins. Our data shows that E-cadherin levels are decreased in emphysematous areas due to its degradation by NEDD9. Decreased E-cadherin levels also lead to the disintegration of the pulmonary epithelium by causing the presence of weakness intercellular connections or the absence of intercellular connections. The repair of the pulmonary epithelium could not complete due to the reduced E-cadherin, because type 2 pneumocytes could not differentiate into type 1 pneumocytes. In conclusion, the reduced E-cadherin levels lead to emphysematous alterations in human lungs and contributes to pulmonary emphysema pathogenesis.

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The copper dependent-lysyl oxidases contribute to the pathogenesis of pulmonary emphysema in chronic obstructive pulmonary disease patients

Cited by 24 publications

References 32 publications

<p>Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale</p>

<p>Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale</p>

The consequence of matrix dysfunction on lung immunity and the microbiome in COPD

Alterations at the Synthesis and Degradation of E-cadherin in the Human Lungs with Emphysema

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