Elimination of p19ARF-expressing cells enhances pulmonary function in mice
Michihiro Hashimoto, … , Mitsuo Maruyama, Masataka Sugimoto
Michihiro Hashimoto, … , Mitsuo Maruyama, Masataka Sugimoto
Published August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e87732. https://doi.org/10.1172/jci.insight.87732.
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Research Article Aging Cell biology

Elimination of p19ARF-expressing cells enhances pulmonary function in mice

Abstract

Senescent cells accumulate in many tissues as animals age and are considered to underlie several aging-associated pathologies. The tumor suppressors p19ARF and p16INK4a, both of which are encoded in the CDKN2A locus, play critical roles in inducing and maintaining permanent cell cycle arrest during cellular senescence. Although the elimination of p16INK4a-expressing cells extends the life span of the mouse, it is unclear whether tissue function is restored by the elimination of senescent cells in aged animals and whether and how p19ARF contributes to tissue aging. The aging-associated decline in lung function is characterized by an increase in compliance as well as pathogenic susceptibility to pulmonary diseases. We herein demonstrated that pulmonary function in 12-month-old mice was reversibly restored by the elimination of p19ARF-expressing cells. The ablation of p19ARF-expressing cells using a toxin receptor-mediated cell knockout system ameliorated aging-associated lung hypofunction. Furthermore, the aging-associated gene expression profile was reversed after the elimination of p19ARF. Our results indicate that the aging-associated decline in lung function was, at least partly, attributed to p19ARF and was recovered by eliminating p19ARF-expressing cells.

Authors

Michihiro Hashimoto, Azusa Asai, Hiroyuki Kawagishi, Ryuta Mikawa, Yuji Iwashita, Kazuki Kanayama, Kazushi Sugimoto, Tadashi Sato, Mitsuo Maruyama, Masataka Sugimoto

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Figure 6

Effects of p19ARF-expressing cell elimination on lung morphology.

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Effects of p19ARF-expressing cell elimination on lung morphology. (A) Mi...
(A) Mice were treated with diphtheria toxin (DT) or PBS, as depicted in Figure 4A. Lung tissues were fixed with Bouin solution at 25 cmH2O and subjected to Resorcin-Fuchsin staining, followed by counterstaining with hematoxylin-eosin. Original magnification, ×120 (using digital zoom); scale bar: 20 μm. (B and C) Alveolar mean linear intercepts (B) and septal wall thickness (C) were measured. More than 400 alveoli and 150 septal walls per mouse were counted. (D) Images of the elastin immunostaining of lung sections. Lung sections were immunostained with anti-elastin and visualized using a HRP-conjugated secondary antibody. Immunostaining in each sample was performed under identical conditions. Original magnification, ×40. (E) Captured elastin immunostaining images were analyzed by ImageJ for the quantitation of elastin signals per field. Values represent the mean ± SEM of independent experiments. Data were analyzed 1-way ANOVA followed by post-hoc Tukey-Kramer multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001.