The Relationship Between Elastin Crosslinking and Alveolar Wall Rupture in Human Pulmonary Emphysema

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.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.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.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.