Practical Methods for Assessing Emphysema Severity Based on Estimation of Linear Mean Intercept (Lm) in the Context of Animal Models of Alpha-1 Antitrypsin Deficiency

Davis, Airiel M.; Thane, Kristen E.; Hoffman, Andrew M.

doi:10.1007/978-1-4939-7163-3_9

Cited by 2 publications

(1 citation statement)

References 17 publications

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“…Immediately following measurements of lung mechanics (flexiVent), lungs were harvested for morphometric analysis as previously described ( 19 , 38 ).…”

Section: Methodsmentioning

confidence: 99%

Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema

Borel

Sun

Zieger

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceChronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is a genetic disease, α-1 antitrypsin (AAT) deficiency. Humans have only one gene that codes for the AAT protein, but mice have up to six, which made it impossible for decades to create a mouse model of the disease. Here we succeeded in creating this mouse model using CRISPR technology to target all of the mouse genes at once. Importantly, this mouse model spontaneously develops lung disease and recapitulates many aspects of the human disease. We anticipate that this model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research.

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“…Immediately following measurements of lung mechanics (flexiVent), lungs were harvested for morphometric analysis as previously described ( 19 , 38 ).…”

Section: Methodsmentioning

confidence: 99%

Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema

Borel

Sun

Zieger

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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

Fagiola

Reznik

Riaz

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

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Introduction: To better define the role of mechanical forces in pulmonary emphysema, we employed methods recently developed in our laboratory to identify microscopic level relationships between airspace size and elastin-specific desmosine and isodesmosine (DID) crosslinks in normal and emphysematous human lungs. Methods: Free DID in wet tissue (a biomarker for elastin degradation) and total DID in formalin-fixed, paraffin embedded (FFPE) tissue sections were measured using liquid chromatography-tandem mass spectrometry and correlated with alveolar diameter, as determined by the mean linear intercept (MLI) method. Results: There was a positive correlation between free lung DID and MLI (p<0.0001) in formalin-fixed lungs, and elastin breakdown was greatly accelerated when airspace diameter exceeded 400 µm. In FFPE tissue, DID density was markedly increased beyond 300 µm (p<0.0001) and leveled off around 400 µm. Elastic fiber surface area similarly peaked at around 400 µm, but to a much lesser extent than DID density, indicating that elastin crosslinking is markedly increased in response to early increases in airspace size. Conclusions: These findings support the hypothesis that airspace enlargement is an emergent phenomenon in which initial proliferation of DID crosslinks to counteract alveolar wall distention is followed by a phase transition involving rapid acceleration of elastin breakdown, alveolar wall rupture, and progression to an active disease state that is less amenable to therapeutic intervention.

show abstract

Practical Methods for Assessing Emphysema Severity Based on Estimation of Linear Mean Intercept (Lm) in the Context of Animal Models of Alpha-1 Antitrypsin Deficiency

Cited by 2 publications

References 17 publications

Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema

Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema

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

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