Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence

Abstract

BackgroundRespiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to “low pulmonary reserve”, ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction.Methods/Principal FindingsUsing a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages.Conclusion/SignificanceOur findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology.

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

“…To test whether an induction apoptosis and TGF-b1 expression by Elovl6 deficiency is mediated by ROS generation, we performed immunohistochemical staining for nitrotyrosine, a marker of oxidative stress 22 . Nitrotyrosine immunoreactivity was observed in alveolar epithelial cells in Elovl6 À / À mice but barely detected in WT mice before BLM instillation (Fig.…”

Analysis of Cell Turnover in the Bronchiolar Epithelium Through the Normal Aging Process

“…Using a murine model of aging lung, Calvi et al demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age [7]. Paxson et al found that the regenerative capacity of the murine lung after pneumonectomy is progressively lost with age, with the earliest decline in the rate of lung regeneration measurable by 9 months of age [20].…”

“…Aging is associated with structural changes in the lung that leads to decreased lung function. The best known change that occurs in the lung as it ages is the alveolar enlargement, which causes a reduction in maximum achievable flow in the airways during the breathing cycle [6][7][8]. Significant widening of alveolar air space along with a size increase of interalveolar pores might facilitate the occurrence of edema.…”

Hallmarks of the ageing lung

“…enlargement in the absence of wall destruction [34] and is thus clearly different from pathophysiologically altered lungs of COPD patients. Indeed, lungs of aged rodents show similar "senile" changes when compared with lungs of young animals [35]. However, premature ageing in mouse models does not always recapitulate senile emphysema: senescence-accelerated mice (SAM), Klotho-, and senescence-marker protein-30 deficient mice show air space enlargement without airway wall destruction [36][37][38][39].…”