Histologic and biochemical alterations predict mechanical dysfunction in aging and chronically inflamed mice (717.4)

Aging produces structural and biochemical alterations to the lung, which impact work of breathing. Mice deficient in surfactant protein D (SP‐D) develop progressive inflammation characterized by increased tissue destruction/remodeling, surfactant composition alterations and retention of foamy macrophages. We have previously reported such alterations in 8, 27 and 80 week old C57BL/6 and congenic SP‐D‐/‐ mice (Groves et al., 2012). In prior studies, alterations to pulmonary function have been inferred from changes in estimated parameters from simple models, however interpretation has been confounded by the simultaneous presence of conflicting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses first‐principles simulation from experimental observations to recapitulate how aging and inflammation alter respiratory impedance (Zrs) at airway opening. An anatomic computational model was developed based on airway morphometry in the literature and Zrs simulated between 0.5 and 20 Hz. Upper airway dimensions were derived from microCT (Thiesse et al., 2010), while lower airways were based on casts (Gomes and Bates, 2002). Airway caliber and patency varied with end expiratory pressure and parenchymal tethering based on elastance changes. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance was estimated in 8 wk WT mice, and varied for each experimental condition based on alteration in parenchymal composition, alveolar geometry and surfactant composition. Reduction in model error is weighed against increasing model complexity to determine essential features underlying mechanical pathology and their contribution to Zrs. Grant Funding Source : NIH HL086621, ES004738, ES007148