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Elimination of p19^ARF -expressing cells protects against pulmonary emphysema in mice.

ABSTRACT: Senescent cells accumulate in tissues during aging and are considered to underlie several aging-associated phenotypes and diseases. We recently reported that the elimination of p19^ARF -expressing senescent cells from lung tissue restored tissue function and gene expression in middle-aged (12-month-old) mice. The aging of lung tissue increases the risk of pulmonary diseases such as emphysema, and cellular senescence is accelerated in emphysema patients. However, there is currently no direct evidence to show that cellular senescence promotes the pathology of emphysema, and the involvement of senescence in the development of this disease has yet to be clarified. We herein demonstrated that p19^ARF facilitated the development of pulmonary emphysema in mice. The elimination of p19^ARF -expressing cells prevented lung tissue from elastase-induced lung dysfunction. These effects appeared to depend on reduced pulmonary inflammation, which is enhanced after elastase stimulation. Furthermore, the administration of a senolytic drug that selectively kills senescent cells attenuated emphysema-associated pathologies. These results strongly suggest the potential of senescent cells as therapeutic/preventive targets for pulmonary emphysema.

SUBMITTER: Mikawa R

PROVIDER: S-EPMC6156494 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Elimination of p19<sup>ARF</sup> -expressing cells protects against pulmonary emphysema in mice.

Mikawa Ryuta R Suzuki Yohei Y Baskoro Hario H Kanayama Kazuki K Sugimoto Kazushi K Sato Tadashi T Sugimoto Masataka M

Aging cell 20180730 5

Senescent cells accumulate in tissues during aging and are considered to underlie several aging-associated phenotypes and diseases. We recently reported that the elimination of p19<sup>ARF</sup> -expressing senescent cells from lung tissue restored tissue function and gene expression in middle-aged (12-month-old) mice. The aging of lung tissue increases the risk of pulmonary diseases such as emphysema, and cellular senescence is accelerated in emphysema patients. However, there is currently no d ...[more]

PMID: 30058137

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Project description:Pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD-PH) represents a major complication of BPD in extremely preterm infants for which there are currently no safe and effective interventions. The abundance of interleukin-1 (IL-1) is strongly correlated with the severity and long-term outcome of BPD infants and we have previously shown that IL-1 receptor antagonist (IL-1Ra) protects against murine BPD; therefore, we hypothesized that IL-1Ra may also be effective against BPD-PH. We employed daily injections of IL-1Ra in a murine model in which BPD/BPD-PH was induced by antenatal LPS and postnatal hyperoxia of 65% O2. Pups reared in hyperoxia for 28 days exhibited a BPD-PH-like disease accompanied by significant changes in pulmonary vascular morphology: micro-CT revealed an 84% reduction in small vessels (4-5 μm diameter) compared to room air controls; this change was prevented by IL-1Ra. Pulmonary vascular resistance, assessed at day 28 of life by echocardiography using the inversely-related surrogate marker time-to-peak-velocity/right ventricular ejection time (TPV/RVET), increased in hyperoxic mice (0.27 compared to 0.32 in air controls), and fell significantly with daily IL-1Ra treatment (0.31). Importantly, in vivo cine-angiography revealed that this protection afforded by IL-1Ra treatment for 28 days is maintained at day 60 of life. Despite an increased abundance of mediators of pulmonary angiogenesis in day 5 lung lysates, namely vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), no difference was detected in ex vivo pulmonary vascular reactivity between air and hyperoxia mice as measured in precision cut lung slices, or by immunohistochemistry in alpha-smooth muscle actin (α-SMA) and endothelin receptor type-A (ETA) at day 28. Further, on day 28 of life we observed cardiac fibrosis by Sirius Red staining, which was accompanied by an increase in mRNA expression of galectin-3 and CCL2 (chemokine (C-C motif) ligand 2) in whole hearts of hyperoxic pups, which improved with IL-1Ra. In summary, our findings suggest that daily administration of the anti-inflammatory IL-1Ra prevents the increase in pulmonary vascular resistance and the pulmonary dysangiogenesis of murine BPD-PH, thus pointing to IL-1Ra as a promising candidate for the treatment of both BPD and BPD-PH.

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Elimination of p19^ARF -expressing cells protects against pulmonary emphysema in mice.

Publications

Elimination of p19<sup>ARF</sup> -expressing cells protects against pulmonary emphysema in mice.

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Dataset Information

Elimination of p19ARF -expressing cells protects against pulmonary emphysema in mice.

Publications

Elimination of p19<sup>ARF</sup> -expressing cells protects against pulmonary emphysema in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Elimination of p19^ARF -expressing cells protects against pulmonary emphysema in mice.