Alveolar fractal box dimension inversely correlates with mean linear intercept in mice with elastase-induced emphysema
Mary P Andersen1, A Read Parham1, J Clifford Waldrep1,2, Wayland N McKenzie1, Rajiv Dhand1,2
1Division of Pulmonary, Critical Care, and Environmental Medicine, Department of Internal Medicine, University of Missouri, 2Research Services, Harry S Truman Memorial VA Hospital, Columbia, MO, USA
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 (DB), a new measure which is an assessment of the complexity of the tissue, with mean linear intercept (Lm), 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 (CL) were examined 21 days later. Correlation of DB with Lm was determined in histological sections of lungs exposed to PPE. The inverse relationship between DB and Lm 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: Lm increased with PPE dose in a sigmoidal curve. CL increased after 80 or 120 U/kg body weight (P < 0.05), but not after 40 U/kg, compared with the control. DB 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, DB was inversely related to Lm (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. DB correlates inversely with Lm after instillation of either PPE or HNE and yields a rapid, sensitive measure of emphysema after elastase instillation.
Keywords: chronic obstructive pulmonary disease, pulmonary emphysema, lung morphometry, lung compliance
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