The relationship between elastin cross linking and alveolar wall rupture in human pulmonary emphysema

Fagiola, Michael; Reznik, Sandra E.; Riaz, Muhammad; Qyang, Yibing; Lee, Seo Yeon; Avella, Joseph; Turino, Gerard M.; Cantor, Jerome O.

doi:10.1152/ajplung.00284.2022

Cited by 4 publications

(2 citation statements)

References 38 publications

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“…We found that Dp16 mice showed a significant 1.3-fold increase in MLI, suggesting an increased alveolar airspace size comparable to mild-moderate emphysematous change in humans [ 50 ]. It is unclear whether increased MLI is associated with increased susceptibility to severe lung infection, although the links between acute exacerbations in COPD patients, bacterial infection, and worsening disease progression are well established [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease

Colvin,

Nguyen,

Boncella

et al. 2023

Genes

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(1) Background: We sought to investigate the baseline lung and heart biology of the Dp16 mouse model of Down syndrome (DS) as a prelude to the investigation of recurrent respiratory tract infection. (2) Methods: In controls vs. Dp16 mice, we compared peripheral blood cell and plasma analytes. We examined baseline gene expression in lungs and hearts for key parameters related to susceptibility of lung infection. We investigated lung and heart protein expression and performed lung morphometry. Finally, and for the first time each in a model of DS, we performed pulmonary function testing and a hemodynamic assessment of cardiac function. (3) Results: Dp16 mice circulate unique blood plasma cytokines and chemokines. Dp16 mouse lungs over-express the mRNA of triplicated genes, but not necessarily corresponding proteins. We found a sex-specific decrease in the protein expression of interferon α receptors, yet an increased signal transducer and activator of transcription (STAT)-3 and phospho-STAT3. Platelet-activating factor receptor protein was not elevated in Dp16 mice. The lungs of Dp16 mice showed increased stiffness and mean linear intercept and contained bronchus-associated lymphoid tissue. The heart ventricles of Dp16 mice displayed hypotonicity. Finally, Dp16 mice required more ketamine to achieve an anesthetized state. (4) Conclusions: The Dp16 mouse model of DS displays key aspects of lung heart biology akin to people with DS. As such, it has the potential to be an extremely valuable model of recurrent severe respiratory tract infection in DS.

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Section: Discussionmentioning

confidence: 99%

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease

Colvin,

Nguyen,

Boncella

et al. 2023

Genes

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“…The results showed a significant correlation between free lung DID and increasing airspace size, supporting the concept that these crosslinks may serve as a biomarker for airspace enlargement. This study was followed by measurements of free lung DID in both normal and emphysematous postmortem human lungs, which showed that elastin breakdown was greatly accelerated when mean airspace diameter exceeded 400 μm ( Figure 2 ) ( 29 ). The density of DID in lung tissue sections also increased markedly beyond 300 μm and leveled off at 400 μm.…”

Section: Introductionmentioning

confidence: 99%

Desmosine as a biomarker for the emergent properties of pulmonary emphysema

Cantor

2023

Front. Med.

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Developing an effective treatment for pulmonary emphysema will require a better understanding of the molecular changes responsible for distention and rupture of alveolar walls. A potentially useful approach to studying this process involves the concept of emergence in which interactions at different levels of scale induce a phase transition comprising a spontaneous reorganization of chemical and physical systems. Recent studies in our laboratory provide evidence of this phenomenon in pulmonary emphysema by relating the emergence of airspace enlargement to the release of elastin-specific desmosine and isodesmosine (DID) crosslinks from damaged elastic fibers. When the mean alveolar diameter exceeded 400 μm, the level of peptide-free DID in human lungs was greatly increased, reflecting rapid acceleration of elastin breakdown, alveolar wall rupture, and a phase transition to an active disease state that is less responsive to treatment. Based on this finding, it is hypothesized that free DID in urine and other body fluids may serve as a biomarker for early detection of airspace enlargement, thereby facilitating timely therapeutic intervention and reducing the risk of respiratory failure.

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The Role of the Extracellular Matrix in the Pathogenesis and Treatment of Pulmonary Emphysema

Cantor

2024

IJMS

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Pulmonary emphysema involves progressive destruction of alveolar walls, leading to enlarged air spaces and impaired gas exchange. While the precise mechanisms responsible for these changes remain unclear, there is growing evidence that the extracellular matrix plays a critical role in the process. An essential feature of pulmonary emphysema is damage to the elastic fiber network surrounding the airspaces, which stores the energy needed to expel air from the lungs. The degradation of these fibers disrupts the mechanical forces involved in respiration, resulting in distension and rupture of alveolar walls. While the initial repair process mainly consists of elastin degradation and resynthesis, continued alveolar wall injury may be associated with increased collagen deposition, resulting in a mixed pattern of emphysema and interstitial fibrosis. Due to the critical role of elastic fiber injury in pulmonary emphysema, preventing damage to this matrix component has emerged as a potential therapeutic strategy. One treatment approach involves the intratracheal administration of hyaluronan, a polysaccharide that prevents elastin breakdown by binding to lung elastic fibers. In clinical trials, inhalation of aerosolized HA decreased elastic fiber injury, as measured by the release of the elastin-specific cross-linking amino acids, desmosine, and isodesmosine. By protecting elastic fibers from enzymatic and oxidative damage, aerosolized HA could alter the natural history of pulmonary emphysema, thereby reducing the risk of respiratory failure.

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The relationship between elastin cross linking and alveolar wall rupture in human pulmonary emphysema

Cited by 4 publications

References 38 publications

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease

Desmosine as a biomarker for the emergent properties of pulmonary emphysema

The Role of the Extracellular Matrix in the Pathogenesis and Treatment of Pulmonary Emphysema

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