Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.23). 06/2011; 6(6):e20712. DOI: 10.1371/journal.pone.0020712
Source: PubMed


Respiratory 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.
Using 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.
Our 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.

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Available from: Sharon A McGrath-Morrow, Jun 11, 2014
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    • "As the elderly population is increasing globally, it is necessary to understand the effect of the aging process in the lung in order to provide better care to this population [10] [11]. A stereotyped pattern of structural changes which occur in the lung as it ages is characterized by airspace enlargement [12]. Previous studies have shown that other senescent changes in lung, including the number of alveoli, vary among species and strains [13] [14]. "
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    ABSTRACT: There are several parameters employed to evaluate lung growth or development in biopsies. The simplest method is the radial alveolar count (RAC), which is the number of alveoli transected by a perpendicular line drawn from the center of a respiratory bronchiole to the nearest septal division or pleural margin. The RAC method provides a reliable index of lung growth in intrauterine and early postnatal development, as well as in childhood. The method has been also applied in assessment of lung development in diverse pathological conditions. Up to date there are no data regarding RAC in healthy adulthood and its relation with aging. Lung specimens from CD1 mice at the age of 2, 12 or 24 months were fixed in 10% neutral-buffered formalin and paraffin-embedded. After staining of 5-μm sections with hematoxylin and eosin, RAC was determined. Results showed a statistically significant difference between the RAC means at 2 months (6.2±3.5) and 12 and 24 months (4.3±3.5 and 4.8±2.6, respectively); there was no significant difference between the means at 12 and 24 months (F=8.61, df1=2, df2=259, p=0.000; Student-Newman-Keuls test: M2≠M12=M24). Thus, our findings show that the RAC decreases during aging until it plateau. Aging is associated with morphometric changes in the lung that lead to decreased lung function. The chronicity of this process is poorly understood with respect to time of onset or progression. This work augments our understanding of this phenomenon and demonstrates that the RAC provides a simple and accurate method to analyze aging-related changes in the lung.
    Microscopy: advances in scientific research and education, 6 edited by A. Mendez-Vilas, 09/2014: chapter Radial alveolar count assessment in the aging: pages 344-347; Microscopy Book Series., ISBN: 978-84-942134-3-4
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    • "Infections are frequent in the pulmonary tract of the elderly, leading to a chronic cycle of injury and repair that causes significant changes in the structure, function and gene expression of alveolar epithelial cells contributing to the development of chronic pulmonary diseases (Baarsma et al., 2011; Chilosi et al., 2012). Studies suggest that the senile lung is characterized by airspace enlargement similar to acquired emphysema (Verbeken et al., 1992) even detected in nonsmokers above 50 years of age (Sharma & Goodwin, 2006; Calvi et al., 2011). Similarly to humans, aging of the mouse lung is associated with homogeneous airspace enlargement. "
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    ABSTRACT: In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas-exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferator-activated receptor gamma (PPARγ)-dependent special cell type of the pulmonary tissue. PPARγ levels are directly regulated by Wnt molecules; therefore, changes in the Wnt microenvironment have close control over maintenance of the distal lung. The pulmonary aging process is associated with airspace enlargement, decrease in the distal epithelial cell compartment and infiltration of inflammatory cells. qRT–PCR analysis of purified epithelial and nonepithelial cells revealed that lipofibroblast differentiation marker parathyroid hormone-related protein receptor (PTHrPR) and PPARγ are reduced and that PPARγ reduction is regulated by Wnt4 via a β-catenin-dependent mechanism. Using a human in vitro 3D lung tissue model, a link was established between increased PPARγ and pro-surfactant protein C (pro-SPC) expression in pulmonary epithelial cells. In the senile lung, both Wnt4 and Wnt5a levels increase and both Wnt-s increase myofibroblast-like differentiation. Alteration of the Wnt microenvironment plays a significant role in pulmonary aging. Diminished lipo- and increased myofibroblast-like differentiation are directly regulated by specific Wnt-s, which process also controls surfactant production and pulmonary repair mechanisms.
    Aging cell 06/2014; 13(5). DOI:10.1111/acel.12240 · 6.34 Impact Factor
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    • "Our microarray and immunohistochemical data provide evidence that aging results in low grade chronic inflammation in the trachea, including an increase in activated (immunoglobulin producing) B cells and T cells. Previous investigations have documented age-related changes in the accumulation of immunoglobulins and inflammatory cells in the peripheral tissues of the old lungs of DBA/2 mice but this analysis did not extend to the trachea and main stem bronchi [7]. Other studies on the aging mouse lung also did not include the trachea and extralobar airways [37]. "
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    ABSTRACT: We report here senescent changes in the structure and organization of the mucociliary pseudostratified epithelium of the mouse trachea and main stem bronchi. We confirm previous reports of the gradual appearance of age-related, gland-like structures (ARGLS) in the submucosa, especially in the intercartilage regions and carina. Immunohistochemistry shows these structures contain ciliated and secretory cells and Krt5+ basal cells, but not the myoepithelial cells or ciliated ducts typical of normal submucosal glands. Data suggest they arise de novo by budding from the surface epithelium rather than by delayed growth of rudimentary or cryptic submucosal glands. In old mice the surface epithelium contains fewer cells per unit length than in young mice and the proportion of Krt5+, p63+ basal cells is reduced in both males and females. However, there appears to be no significant difference in the ability of basal stem cells isolated from individual young and old mice to form clonal tracheospheres in culture or in the ability of the epithelium to repair after damage by inhaled sulfur dioxide. Gene expression analysis by Affymetrix microarray and quantitative PCR, as well as immunohistochemistry and flow sorting studies, are consistent with low-grade chronic inflammation in the tracheas of old versus young mice and an increase in the number of immune cells. The significance of these changes for ARGL formation are not clear since several treatments that induce acute inflammation in young mice did not result in budding of the surface epithelium.
    PLoS ONE 03/2014; 9(3):e93496. DOI:10.1371/journal.pone.0093496 · 3.23 Impact Factor
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