Alveolar fractal box dimension inversely correlates with mean linear intercept in mice with elastase-induced emphysema

Rationale: A widely applicable model of emphysema that allows efficient and sensitive quantification of injury is needed to compare potential therapies. Objectives: To establish such a model, we studied the relationship between elastase dose and the severity of emphysema in female C57BL/6J mice. We compared alveolar fractal box dimension (D-B), a new measure which is an assessment of the complexity of the tissue, with mean linear intercept (L-m), which is commonly used to estimate airspace size, for sensitivity and efficiency of measurement. Methods: Emphysema was induced in female C57BL/6J mice by administering increasing intratracheal doses of porcine pancreatic elastase (PPE). Changes in morphology and static lung compliance (C-L) were examined 21 days later. Correlation of D-B with L-m was determined in histological sections of lungs exposed to PPE. The inverse relationship between D-B and L-m was supported by examining similar morphological sections from another experiment where the development of emphysema was studied 1 to 3 weeks after instillation of human neutrophil elastase (HNE). Results: L-m increased with PPE dose in a sigmoidal curve. C-L increased after 80 or 120 U/kg body weight (P < 0.05), but not after 40 U/kg, compared with the control. D-B progressively declined from 1.66 +/- 0.002 (standard error of the mean) in controls, to 1.47 +/- 0.006 after 120 U PPE/kg (P < 0.0001). After PPE or HNE instillation, D-B was inversely related to L-m (R = -0.95, P < 0.0001 and R = -0.84, P = 0.01, respectively), with a more negative slope of the relationship using HNE (P < 0.0001). Conclusion: Intratracheal instillation of increasing doses of PPE yields a scale of progression from mild to severe emphysema. D-B correlates inversely with L-m after instillation of either PPE or HNE and yields a rapid, sensitive measure of emphysema after elastase instillation.