Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation

Abstract

Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.

Diaphragm muscle sarcopenia into very old age in mice

“…The changes in respiratory mechanics associated with old age are well established. With very old age, there is an increase in functional reserve capacity and in alveolar size (Huang, Rabold, Schofield, Mitzner, & Tankersley, ; Massa, Groves, Jaggernauth, Laskin, & Gow, ). In addition, respiratory system resistance changes minimally from 6 to 18 mo (~1%–2% decrease per month), and increases more rapidly from 24 to 30 mo, ~5% per month (Elliott, Mantilla, et al, ).…”

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

“…Repeated low-dose ozone exposure (0.8 ppm, 4 h/day, 9 days) generates subchronic multicellular inflammation with extensive airway and goblet cell involvement (94), progressing to fibrosis following 6 weeks of exposure (95). Genetic manipulation of the inflammatory collectin surfactant protein-D further supports the notion that a lifetime of sub-toxic inflammation and oxidative stress reshapes parenchymal function (senescence) and could possibly impact lung responses to exposure later in life (80,96).…”

Back to the Basics: Usefulness of Naturally Aged Mouse Models and Immunohistochemical and Quantitative Morphologic Methods in Studying Mechanisms of Lung Aging and Associated Diseases

“…Novel approaches based on computational models that incorporate age-related changes in lung structure and function might provide more information in this area. Massa et al [52] performed morphometric and mechanical measurements in C57BL6/J and Sftpd-/-mice at 8, 27, and 80 weeks of age. Sftpd-/-mice are deficient in surfactant protein D and develop progressive age-related lung pathology characterized by inflammation.…”