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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.