p19Arf Exacerbates Cigarette Smoke-Induced Pulmonary Dysfunction

Abstract

Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging-and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf -expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf -expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease.Biomolecules 2020, 10, 462 2 of 14 their surrounding non-senescent cells. These are collectively called the senescence-associated secretory phenotype (SASP), and increasing evidence suggests that SASP mediates the deleterious effects of cellular senescence and is involved in a number of pathologies in both humans and mice [11].Senescent cells accumulate in several tissues during aging [12,13], and are considered to contribute to aging-associated pathologies. Recent studies on senolysis (senescent cell elimination) using semi-genetic and pharmacological approaches revealed that the elimination of senescent cells from tissues ameliorates a number of aging-associated tissue dysfunctions and diseases [11,14] and even extends the lifespan of mice [15]. Cellular senescence is also involved in lung disease, and bleomycin-induced idiopathic pulmonary fibrosis (IPF) was shown to be alleviated by the elimination of senescent cells in INK-ATTAC mice or the administration of the senolytic drugs dasatinib and quercetin [16]; however, the efficacy of these drugs in human IPF patients currently remains unclear [17].We also established transgenic mice (ARF-DTR mice) that express luciferase and diphtheria toxin (DT) receptors under the control of the Arf promoter/enhancer, thereby enabling the detection and ablation of Arf -expressing cells by in vivo imaging and DT, respectively [18]. Using ARF-DTR mice, we showed that the elimination of Arf -expressing cells restored pulmonary function in aged animals [19]. Furthermore, the pre-elimination of Arf -expressing cells by DT protected lung tissue against elastase-induced lung injury [20]. This effect may be mediated by reduced pulmonary inflammation exemplified by an increased number of alveolar macrophages. Similar findings were also obtained using the anti-apoptotic Bcl-2 family protein inhibitor ABT-263, which has been shown to exhibit senolytic activity in mice [21]. Collectively, these findings suggest that the elimination of senescent cells exerts protective effe...

Baicalein Delays H2O2-Induced Astrocytic Senescence through Inhibition of Senescence-Associated Secretory Phenotype (SASP), Suppression of JAK2/STAT1/NF-κB Pathway, and Regulation of Leucine Metabolism

“…Cellular senescence refers to cell cycle arrest caused by various stress factors . With aging and pathological processes, senescent cells accumulated in various tissues and organs can accelerate aging and increase the incidence of age-related diseases . Unlike apoptosis, senescent cells still maintain metabolic activity and secrete a variety of extracellular modulators, which are termed as senescence-associated secretory phenotype (SASP), including proinflammatory cytokines, chemokines, tissue-damaging proteases, and growth factors .…”

Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production

“…These results were similar to those of a previous report by Demaria et al., which indicated that ablation of p16 Ink4a -expressing senescent cells suppressed lung tumor metastasis in p16-3MR mice ( Demaria et al., 2017 ). We have previously shown that DT treatment leads to the downregulation of Ink4a and Arf in old ARF-DTR mice, suggesting that the elimination of p19 Arf -expressing cells results in the ablation of p16 Ink4a -expressing senescent cells ( Hashimoto et al., 2016 ; Mikawa et al., 2018 , 2020 ). To confirm that Arf is associated with cellular senescence in mouse tissues, we analyzed the localization of p19 Arf and p16 Ink4a in the ARF-DTR lung.…”

“…Although senescent cells accumulate in tissues during aging, their population is low even in old animals or human tissues ( Dimri et al., 1995 ; Krishnamurthy et al., 2004 ). p19 Arf expression was observed in 1%–2% of mesenchymal cells in old mouse lung tissues, and it was also induced in epithelial cells when mice were challenged by cigarette smoke ( Hashimoto et al., 2016 ; Mikawa et al., 2020 ). Therefore, it is plausible that the promotion of lung metastasis is exerted through the non-cell-autonomous effects of p19 Arf -expressing cells.…”

“…Thus, Adam10 is likely responsible for the senescence-dependent ectodomain shedding of E-cadherin, as its expression was significantly decreased in the DT-treated ARF-DTR lung tissues, although other enzymes, such as Mmp, may also contribute to this process ( Hashimoto et al., 2016 ). Although the p19 Arf -expressing senescent cells are predominantly detected in the lung and ablated by DT in adult ARF-DTR mice ( Hashimoto et al., 2016 ; Mikawa et al., 2018 , 2020 ), the possibility that the systemic senescent cells or senescence in other tissue may also contribute to the seCad production. Tissue-specific senescent cell ablation system needs to be established to address this question.…”

“…We have also established a transgenic mouse line, ARF-DTR, that expresses a diphtheria toxin (DT) receptor and luciferase under the control of the Arf promoter/enhancer. Using ARF-DTR mice, we discovered that the elimination of p19 Arf -expressing cells from lung tissues restored pulmonary function in old animals ( Hashimoto et al., 2016 ) and protected against elastase or cigarette-smoke-induced emphysema ( Mikawa et al., 2018 , 2020 ).…”