Arch. Pharm. Res. (2015) 38:1–10 DOI 10.1007/s12272-014-0494-2

REVIEW

Role of sirtuins in chronic obstructive pulmonary disease Pusoon Chun

Received: 10 August 2014 / Accepted: 5 October 2014 / Published online: 11 October 2014 Ó The Pharmaceutical Society of Korea 2014

Abstract Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is associated with chronic inflammatory response to noxious particles or gases. The airflow limitation may be explained by hypersecretion of mucus, thickening and fibrosis of small airways and alveolar wall destruction in emphysema. Sirtuins, a group of class III deacetylases, have gained considerable attention for their positive effects on aging-related disease, such as cancer, cardiovascular disease, neurodegenerative diseases, osteoporosis and COPD. Among the seven mammalian sirtuins, SIRT1–SIRT7, SIRT1 and SIRT6 are considered to have protective effects against COPD. In the lungs, SIRT1 inhibits autophagy, cellular senescence, fibrosis, and inflammation by deacetylation of target proteins using NAD? as co-substrate and is therefore linked to the redox state. In addition to SIRT1, SIRT6 have also been shown to improve or slow down COPD. SIRT6 is associated with redox state and inhibits cellular senescence and fibrosis. Therefore, activation of SIRT1 and SIRT6 might be an attractive approach for novel therapeutic targets for COPD. The present review describes the protective effects of SIRT1 and SIRT6 against COPD and their target proteins involved in the pathophysiology of COPD. Keywords COPD  Sirtuins  SIRT1  SIRT6  Cigarette smoke  Oxidative stress

P. Chun (&) College of Pharmacy, Inje University, 197 Inje-ro, Gimhae, Gyeongnam 621-749, Korea e-mail: [email protected]

Introduction Chronic obstructive pulmonary disease (COPD) ranked as the third-leading cause of death worldwide, killing over 3 million people. The number of deaths from COPD is projected to increase by more than 30 % in the next 10 years if there is no urgent action to reduce the underlying risk factors, especially tobacco smoke. The most commonly encountered risk factor for COPD is cigarette smoking, while other causes include exposure to occupational hazards and air pollution. A severe hereditary deficiency of alpha-1 antitrypsin is the genetic risk factor that is best documented (WHO 2014). COPD is characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. The airflow limitation may be explained by three pathogenic mechanisms: occlusion of the airway lumen by mucus and inflammatory exudate, thickening and fibrosis of small airways, alveolar wall destruction and airway collapse in emphysema (McDonough et al. 2011; Yao and Rahman 2011). There has been increasing evidence that macrophages play a pivotal role in the pathophysiology of COPD. In the lungs of patients with COPD, the numbers of macrophage are significantly increased (Zheng et al. 2000). These macrophages are derived from circulating monocytes, which migrate to the lungs in response to chemoattractants such as CC-chemokine ligand 2 (CCL2, also known as MCP1) (Deshmane et al. 2009; Qian et al. 2011). Furthermore, there is a correlation between macrophage numbers in the airways and the severity of COPD (Di Stefano et al. 1998). Inhaled cigarette smoke and other irritants activate epithelial cells and macrophages to release several chemokines that attract neutrophils, monocytes and T cells to the lungs (Fig. 1). By secreting proteases, such as

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Fig. 1 Inflammatory and immune cells involved in COPD. Inhaled cigarette smoke activities epithelial cells and macrophages to release chemotactic factors, including CXCL1 and CXCL8, which attract neutrophils and monocytes and CXCL9, CXCL10, and CXCL11, which attract Tc1 cells. Macrophages and neutrophils, which cause elastin degradation and emphysema. Tc1 cells contribute to emphysema. MMP-

2 and MMP-9 also produce lung fibrosis while MMP-12 functions as a direct mediator of inflammation. Neutrophil elastase causes mucus hypersecretion as well. Epithelial cells and macrophages also release TGF-b, which stimulates fibroblast proliferation, resulting in fibrosis in the small airways

matrix metalloproteinases (MMPs) and neutrophil elastase, macrophages and neutrophils contribute to alveolar destruction and emphysema (Barnes 2004; Traves et al. 2004, Churg et al. 2012). There is already a well-established link between elastin degradation and arterial stiffness (Brooke et al. 2003; Zieman et al. 2005; Shifren and Mecham 2006). And both arterial stiffness and elastin degradation have been shown to be associated with emphysema severity in patients with COPD (McAllister et al. 2007; Maclay et al. 2012). MMP-2 and MMP-9 are proposed as a prognosis factor in lung fibrosis (Gueders et al. 2006) while MMP-12 is suggested as a direct mediator of inflammation (Churg et al. 2012). Neutrophil elastase also acts as a potent mucus secretagogue of submucosal gland cells and goblet cells and causes mucus hypersecretion (Sommerhoff et al. 1990; Takeyama et al. 1998). Moreover, the stimulated epithelial cells and macrophage release the chemokines CXC-chemokine ligand 9 (CXCL9, also known as MIG), CXCL10 (also known as IP-10), and CXCL11 (also known as I-TAC), which attract T helper 1 (Th1) cells and type 1 cytotoxic T-cells (Tc1 cells) (Saetta et al. 2002; Costa et al. 2008). Tc1 cells, through the release of perforin and granzyme B, induce apoptosis of type 1 pneumocytes, thereby contributing to the development of emphysema (Majo et al. 2001; Chrysofakis et al. 2004). The increased expression levels of transforming growth factor-b (TGF-b) in small airway epithelial cells and alveolar macrophages of patients with COPD suggest that TGF-b might play a role in pathophysiology of fibrosis in small airways (de Boer et al. 1998; Takizawa et al. 2001; Huynh et al. 2002). Reactive oxygen species (ROS) play an important role in atherosclerosis and vascular dysfunction (Shi et al. 2010). The ROS are produced by cells such as neutrophils, macrophages, eosinophils and epithelial cells, when activated by the inflammation in the respiratory tract (MacNee 2001).

Upon the production of high levels of ROS, the redox balance is disturbed and cells shift into ROS-induced damage, which subsequently result in endothelial dysfunction and senescence (Kurz et al. 2004). ROS may activate redox sensitive transcription factors, such as activator protein-1 (AP-1) and nuclear factor kB (NF-kB), leading to the generation of pro-inflammatory molecules and propagation of a proinflammatory state (Yadav and Ramana 2013). SIRT1 is a potential candidate for redox modulation because its activity is regulated by NAD? and it is, therefore, sensitive to the redox state (Lin et al. 2000; Dioum et al. 2009). SIRT1 is associated with the regulation of a variety of cellular processes, such as apoptosis, mitochondrial biogenesis and autophagy (Guarente and Franklin 2011), and has been shown to protect against lung cellular inflammatory response to oxidative stress imposed by cigarette smoke (Yao et al. 2012). Therefore SIRT1 may improve or slow down COPD. In addition to SIRT1, SIRT6 has also been shown to be associated with redox stress and cellular senescence (Wang et al. 2007; Gozani coworkers 2009). Since activation of these sirtuins might be a potential target for COPD therapy, examining research findings on the protective effects of sirtuins against COPD would provide strategies for management and prevention of COPD. Therefore the aim of the present review was to discuss the role of sirtuins in COPD.

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Mammalian sirtuins: SIRT1–SIRT7 Sirtuins are members of the silent information regulator 2 (Sir2) family, a group of class III deacetylases, which differ from class I and II histone deacetylases (HDACs) by their protein sequences and in that they are NAD?-rather than Zndependent enzymes. In mammals, seven homologues of Sir2

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have been identified, and are designated as SIRT1 through SIRT7 (Table 1). Each sirtuin contains a conserved catalytic core domain of approximately 275 amino acids, which functions as a NAD?-dependent deacetylase and/or ADPribosyltransferase (Landry et al. 2000; Tanner et al. 2000). SIRT1, SIRT2 and SIRT3 are classified as Class I, which show closest homology to yeast SIRT2. The Class I is further divided into Ia (SIRT1) and Ib (SIRT2 and SIRT3). SIRT4 and SIRT5 are sorted into Class II and III, respectively. SIRT6 and SIRT7 belong to Class IV, which is further subdivided into IVa and IVb, respectively (Frye 2000; Michan and Sinclair 2007). These sirtuins also show different intracellular localization. SIRT1 is predominantly in the nucleus, although it has been reported to be present in the cytoplasm and also in mitochondria (Michan and Sinclair 2007; Tanno et al. 2007; Aquilano et al. 2010). Although SIRT2 resides most prominently in the cytoplasm, it is also in the nucleus (North and Verdin 2007; Tanno et al. 2007). SIRT3, SIRT4 and SIRT5 localize to the mitochondria, whereas SIRT3 is also found in the nucleus and cytoplasm (Michishita et al. 2005; Hallows et al. 2008; Verdin et al. 2010). SIRT3 appears to shuttle from the cytosol to mitochondria under cell stress (Scher et al. 2007). SIRT6 is present in the heterochromatin of the nucleus (Tennen et al. 2010) and SIRT7 is present in the nucleolus (Michishita et al. 2005; Tennen et al. 2010). SIRT1, SIRT2, SIRT3, SIRT5, SIRT6 and SIRT7 have NAD-dependent deacetylase activity. They consumed NAD? as a co-substrate for the deacetylation of target proteins. The acetylated lysine residues of the target protein serve as substrates for sirtuin deacetylation, which generates nicotinamide (NAM) and 20 O-acetyl-ADP-ribose (20 -OAADPr) as by-products. SIRT1, SIRT2, and SIRT3 exhibit the most vigorous deacetylase activity (Blander and Guarente 2004; Sauve et al. 2006; Vakhrusheva et al. 2008; Guarente and Franklin 2011; Kim Table 1 Characterisitics of mammalian sirtuins Sirtuin

Classification

Localization

Enzymatic activity

SIRT1

Class Ia

Nucleus, Cytoplasm, Mitochondria

Deacytylase

SIRT2

Class Ib

Cytoplasm, Nucleus

Deacytylase

SIRT3

Class Ib

Mitochondria, Nucleus, Cytoplasm

Deacytylase

SIRT4

Class II

Mitochondria

ADPribosyltransferase

SIRT5

Class III

Mitochondria

Deacytylase Desuccinlylase Demalonylase

SIRT6

Class IVa

Nucleus

Deacytylase ADP-ribosyl transferase

SIRT7

Class IVb

Nucleolus

Deacytylase

and Kim 2013). SIRT5 has been suggested to function as a desuccinylase and/or a demalonylase (Du et al. 2011; Peng et al. 2011). SIRT4 and SIRT6 have ADP-ribosyl transferase activity. ADP-ribosyl transferase also consumes NAD? as a substrate, and ADP-ribose and nicotinamide are generated via the reaction (Liszt et al. 2005; Du et al. 2009; Guarente and Franklin 2011). The biological effects of sirtuin-mediated deacetylation include modulation of transcription, cell growth, aging, stress-tolerance and metabolism (Schwer and Verdin 2008; Bao and Sack 2010). This review focused on the protective effects of sirtuins against COPD (Table 2).

SIRT1 and Inflammation in COPD The inflammatory process is one of the most important mechanisms for the initiation and progression of COPD. Nuclear factor kappaB (NF-jB) is a key redox-sensitive transcription factor responsible for transcription of proinflammatory genes, such as interleukin 8 (IL-8), IL-6, and TNF (tumor necrosis factor)-a (Rahman and MacNee 1998; Kunsch and Medford 1999). Under physiological and pathological conditions, NF-jB undergoes a variety of posttranslational modifications including acetylation (Chen et al. 2005). Upon acetylation of lysine residues in RelA/ p65 subunit of NF-jB, the RelA/p65 subunit remains bound to DNA and can stimulate gene expression (Lanzillotta et al. 2010). Numerous studies have shown that SIRT1 inhibits NFjB activity by deacetylating RelA/p65 at lysine 310 (Yeung et al. 2004). Furthermore, it has been reported that the levels of SIRT1 are reduced by cigarette smoke in lungs of patients with COPD and rat as well as in monocyte-macrophage cell line, implicating an important role of SIRT1 in the pathogenesis of COPD (Yang et al. 2007; Rajendrasozhan et al. 2008). Recently, many studies demonstrate that reduced levels of SIRT1 result in up-regulation of acetylated NF-jB, leading to increased inflammatory response, whereas overexpression of SIRT1 inhibits the inflammation through deacetylation of NF-jB (Schug et al. 2010; Stein et al. 2010; Yoshizaki et al. 2010). Finally, it is suggested that pharmacological activation of SIRT1 may be a potential target for COPD therapy.

SIRT1 and cellular senescence in COPD DNA damage and cellular senescence contribute significantly to vascular dysfunction and the development of atherosclerosis (Gray and Bennett 2011; Wang and Bennett 2012). A number of studies have shown increased DNA damage and cellular senescence in the lung of COPD patients compared to controls, which may contribute to

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Table 2 The proteins regulated by SIRT1/SIRT6 and the effects of the regulations on COPD Sirtuin

Target protein

Subject

Effects

Reference

SIRT1;

:Ace-NF-kB (ReIA/p65)

MonoMac6

:Inflammation

Yang et al. (2007) Rajendrasozhan et al.(2008)

SIRT1;

:Ace-p53

BOEC

:Senescence

Paschalaki et al.(2013)

SIRT1;

:Ace-Fox03a

HBEC

:Autophagy

Shi et al. (2012)

SIRT1;

:Ace-Fox03

SIRT1?/mouse lungs

:Emphysema

Yao et al. (2012)

SIRT1;

:MMP9, :Ace-TIMP

lungs tissues from COPD patients, SIRT1 ± mice

:Emphysema

Yao et al.(2013)

SIRT1;

:Ace-NF-kB (ReIA/p65) :MMP9

Smad3-null mouse lungs

:Emphysema

Xu et al.(2012)

SIRT1;

:MMP9

lung tissues from CPD patients

;Exercise tolerance

Nakamaru et al.(2009)

SIRT6;

:IGF signalling

HBEC

;antisenescence

Takasaka et al.(2014)

SIRT6;

:p21, :IL-1

HBEC

;Senescence

Minagawa et al.(2011)

;Fibrosis Ace acetylated, MonoMac6 monocyte-macrophage cell line, BOEC blood outgrowth endothelial cells, HBEC human brochial epithelial cells, IGF insulin-like growth factor, ; decreased, : increased

accelerated lung aging and pathogenesis of COPD (Tsuji et al. 2010; Amsellem et al. 2011; Aoshiba et al. 2012). There has been increasing evidence that acetylation of p53 leads to enhanced p53 binding to DNA and transcription of genes that cause cell cycle arrest, senescence, or apoptosis (Luo et al. 2001; Kitagawa et al. 2008; Schlereth et al. 2010; Kracikova et al. 2013). SIRT1 prevented cellular senescence by deacetylation and repression of p53 (Langley et al. 2002). Conversely, SIRT1 deficiency caused accumulation of p53 acetylation, thereby enhancing oxidative stress-induced cellular senescence (Furukawa et al. 2007). Ota et al. (2007) also demonstrated that endothelial cells with down-regulated SIRT1 showed increased p53 acetylation and premature senescence-like phenotype. Recently, Paschalaki et al. (2013) reported that SIRT1 protein levels were significantly reduced in blood outgrowth endothelial cells (BOEC) from healthy smokers and COPD patients compared to healthy nonsmokers. Furthermore, they demonstrated that inhibition of SIRT1 expression in BOEC resulted in increased acetylation of p53 at Lys-382. These findings suggest that the protective effect of SIRT1 against senescence may be in part mediated by deacetylation of p53. SIRT1 has been reported to be involved in ataxia-telangiectasia mutated (ATM) activation and downstream signaling pathways promoting cell survival and DNA repair (Gorospe and de Cabo 2008; Yuan et al. 2007). The ATM protein is best known for its role as a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents or by normal processes, such as meiotic recombination (Gorgoulis et al. 2005; Bartkova et al. 2006). Recently, it has been suggested that upregulation of SIRT1 via ATM inhibition could be a therapeutic target in COPD patients. Paschalaki

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et al. (2013) showed that inhibition of ATM expression significantly increased SIRT1 protein levels in BOEC from COPD patients compared to healthy nonsmokers.

SIRT1/SIRT6 and autophagy in COPD Autophagy refers to conserved cellular processes whereby cytoplasmic contents and organelles are sequestered within a double-membrane autophagosome and subsequently degraded at the vacuole or lysosome (Klionsky and Emr 2000). Paradoxically, autophagy can serve to protect cells but may also contribute to cell damage (Ogata et al. 2006; Pulliero et al. 2014). Many studies have identified multifarious roles for SIRT1 in the regulation of autophagy. In lungs of smokers and patients with COPD as well as in epithelial cells exposed to CS, the levels and activity of SIRT1 were decreased, whereas autophagy was increased (Yang et al. 2007; Chen et al. 2008; Kim et al. 2008; Rajendrasozhan et al. 2008; Caito et al. 2010). Hwang et al. (2010) demonstrated that SIRT1 activator attenuated CS-induced autophagy while SIRT1 inhibitor augmented it in lungs of mice. Moreover, they showed that inhibition of poly(ADPribose)-polymerase-1 (PARP-1) attenuated CS-induced autophagy via SIRT1 activation. PARP-1, the most abundant nuclear enzyme of PARP family, catalyzes the formation of the polymer PAR using NAD? as substrate. PARP-1 is activated by reactive oxygen species (ROS)induced DNA strand breaks, upon which it forms extensive PAR polymers from its substrate NAD?. It has been shown that PARP-1 activity is increased in peripheral blood lymphocytes as well as human peripheral blood mononuclear cells (PBMC) in patients with COPD (Hageman et al.

Role of sirtuins in COPD

2003; Oit-Wiscombe et al. 2013). Numerous studies have also shown that CS-induced activation of PARP-1 leads to depletion of NAD? and subsequently reduces SIRT1 activity (Hsu et al. 2009; Huang et al. 2009; Caito et al. 2010). These findings suggest that SIRT1 might play an important role in regulating CS-mediated autophagy which might be mediated by SIRT1-PARP-1 axis in pathogenesis of COPD. Deacetylation of FoxO3a by SIRT1 plays an essential role in CS-induced autophagy. Shi et al. (2012) showed that SIRT1 levels were reduced in CS-induced stress and the reduction was accompanied by increased level of FoxO3a acetylation. They further demonstrated that SIRT1 activator reduced CS condensate-induced autophagy in human bronchial epithelial cells as well as CS-induced autophagy in mouse lungs. These findings imply that deacetylation of FoxO3a by SIRT1 inhibits CS-induced autophagy in lungs of smokers. In addition, the inhibitory effect of SIRT1 activator on CS-induced autophagy correlates with the ability of SIRT1 activator to up-regulate SIRT1 expression and maintain deacetylase activity. In addition to SIRT1-FoxO3a axis, SIRT6 plays an important role in the regulation of autophagy in COPD. Rajendrasozhan et al. (2008) have reported reduced SIRT6 expression in COPD lung, suggesting that SIRT6 antagonizes CS-induced cellular senescence during the development of COPD. Recently, Takasaka et al. (2014) found that SIRT6 expression levels were decreased in lung homogenates from COPD patients. They showed that SIRT6 overexpression inhibited CS extract-induced senescence in human bronchial epithelial cells. They have demonstrated that SIRT6 overexpression induces autophagy via attenuation of insulin-like growth factor-Akt-mammalian target of rapamycin (IGF-Akt-mTOR) signaling. These findings imply that IGF-Akt-mTOR activation leads to the insufficient autophagic elimination of damaged cellular components, which might be involved in the development of COPD, so SIRT6 deficiency might contribute to the development of COPD. SIRT1 and SIRT6 are localized in the nucleus and share considerable functional similarities. Decreased expression levels of both SIRT1 and SIRT6 in response to CS exposure appear to be associated with COPD development, whereas the mechanism for the opposing roles in autophagy regulation between SIRT1 and SIRT6 remains to be determined.

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remodeling. Within the MMP family, MMP-1, MMP-2 (gelatinase A), MMP-8, MMP-9 (gelatinase B), and MMP12 (macrophage elastase) have been shown to be involved in the development of pulmonary fibrosis and COPD including emphysema (Hautamaki et al. 1997; Cataldo et al. 2000; Bonniaud et al. 2004; Mercer et al. 2004; Ilumets et al. 2007). Pulmonary fibrosis is associated with deposition of ECM components in the lung interstitium. Once MMPs are released and activated, their activity is restricted by endogenous inhibitors like tissue inhibitors of metalloproteinases (TIMPs) and a2-macroglobulin. TIMPs bind with high affinity in a 1:1 molar ratio to the catalytic site of active MMPs, resulting in loss of proteolytic activity. This leads to adequate conditions for further extracellular matrix deposition to occur (Murphy and Docherty 1992; Manoury et al. 2007). The imbalance of TIMPs/MMPs is an important element of the pathogenesis of COPD and TIMPs are upregulated in pulmonary fibrosis. Cataldo et al. (2000) showed increased gelatinolytic activity linked to MMP-2 and MMP-9 and higher TIMP-1 levels in the sputum from COPD patients. MMP9 expression is negatively regulated by SIRT1 in human lung tissue and peripheral blood mononuclear cells (Nakamaru et al. 2009). Decreased SIRT1 activity enhanced acetylation of histone H3 at the activator protein (AP)-1, NF-kB, and Pea3 binding sites of the MMP9 promoter, subsequently, amplified MMP9 transcription (Xu et al. 2012). Recently, Yao et al. (2013) reported that MMP-9 protein levels and activity were increased in lungs of SIRT1-deficient mice exposed to cigarette smoking (CS), and the effect was reduced by SIRT1 overexpression. Furthermore, they showed that SIRT1 deficiency increased CS-induced TIMP-1 acetylation, and the effect was reduced by SIRT1 overexpression in mouse lungs with emphysema as well as in lungs of COPD patients. The findings suggest that SIRT1 protects against COPD including emphysema, in part, via redressing the TIMP-1/ MMP-9 imbalance involving TIMP-1 deacetylation. Thus redressing the TIMP-1/MMP-9 imbalance by pharmacological activation of SIRT1 seems to be a novel therapeutic approach in the intervention of COPD. SIRT1 has also been found to protect against emphysema via FoxO3-mediated reduction of premature senescence. Yao et al. (2012) showed the molecular mechanism of CS-induced cellular senescence via a SIRT1-FOXO3 axis, and a crucial role of SIRT1 in protection against airspace enlargement and lung function decline, which are the characteristic features of COPD.

SIRT1 and emphysema/fibrosis in COPD Matrix metalloproteinases (MMPs) are a major group of proteases believed to be involved in extracellular matrix (ECM) cleavage and so they are suggested to be important in the process of lung disease associated with tissue

SIRT6 and fibrosis/cellular senescence in COPD The mechanism responsible for fibrosis and thickening of the airway wall is explained partly by abnormal interaction

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between airway epithelium and mesenchymal cells. Squamous metaplasia (SM) amplifies the interaction by transforming growth factor b (TGF-b) up-regulation. The activated TGF-b facilitates SM via the increased secretion of IL-1b, which induces a fibrotic response in adjacent airway fibroblasts and subsequently contributes to airway wall thickening (Araya et al. 2007). The role of IL-1b and TGF-b in idiopathic pulmonary fibrosis (IPF) pathogenesis has been well established (Sime et al. 1997; Wilson et al. 2010). SIRT6 has been demonstrated to antagonize senescence. SIRT6-deficient mice showed genomic instability caused by a deficiency of base excision repair activity, which is responsible for repair of single-strand DNA breaks (Cheng et al. 2003; Mostoslavsky et al. 2006). Recently, Minagawa et al. (2011) reported that overexpression of SIRT6 efficiently inhibited TGF-b-induced senescence via proteasomal degradation of p21. They also found that TGF-binduced senescent human bronchial epithelial cells (HBEC) secreted increased amounts of IL-1b, which led to myofibroblast differentiation in fibroblasts. In addition, overexpression of SIRT6 efficiently inhibited TGF-binduced cell senescence, whereas knock down of SIRT6 using short interfering RNA (siRNA) increased the senescence. Finally, overexpression of SIRT6 in HBEC suppressed production of profibrotic mediator IL-1b. These findings suggest that SIRT6 may play an important role in inhibiting fibrosis as well as cellular senescence.

Natural SIRT1 activating compounds in COPD Resveratrol (3,5,40 -trihydroxy-trans-stilbene), a polyphenolic phytoalexin, is found in various plants, including grapes, berries and peanuts. It is also present in wines, especially red wines (de la Lastra and Villegas 2007). It was identified as the first natural chemical activator of SIRT1 (Hwang et al. 2013) and achieved an approximately 8-fold activation of SIRT1 (Borra et al. 2005). Resveratrol has anti-inflammatory properties and could be an alternative to corticosteroids in COPD therapy. In the study by Siedlinski et al. (2012), resveratrol or white wine intake was significantly associated with higher lung capacity and lower risk of airway obstruction in the general population. However those effects were not found in SIRT1 SNPs. Recently, Knobloch et al. (2014) suggested resveratrol as an alternative anti-inflammatory therapy in COPD exacerbations, demonstrating that after exposure to lipoteichoic acid, resveratrol attenuated the release of inflammatory cytokines through activation of SIRT1from human bronchial smooth muscle cells in COPD. Moreover, resveratrol reduced the release of steroid-resistant cytokines in COPD (Knobloch et al. 2014). Therefore, resveratrol might be of

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benefit where airway inflammation is insensitive to corticosteroids. In addition to anti-inflammatory effects, resveratrol has anti-senescence effect on vascular endothelial cells through attenuation of oxidative stress by SIRT1/ NADPH oxidase-dependent mechanisms (Tang et al. 2012). SIRT1 activation by resveratrol is also known to modulate MMP9 activity in fibroblasts in COPD (Arunachalam et al. 2010). Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. In the study by Ganesan et al. (2010), quercetin-treated mice showed improved elastic recoil and decreased alveolar chord length compared to controls. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 while increasing expression of SIRT1 (Ganesan et al. 2010).

Synthetic SIRT1 activating compound in COPD The study by Yao et al. (2012) have recently shown that SRT1720, a compound that activates SIRT1, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke in mice. In vivo, SRT1720 promoted the deacetylation of the FOXO3 transcription factor, leading to those effects. Thus, SIRT1 protects against emphysema through FOXO3mediated reduction of cellular senescence, independently of inflammation. Therefore, activation of SIRT1 may be an attractive therapeutic strategy in COPD and emphysema. Further investigation into the targets and functions of other sirtuins will help develop new strategies for protection against COPD.

Conclusion SIRT1, a redox-sensitive deacetylase, plays a crucial role in the initiation and exacerbation of COPD. Under oxidative stress, SIRT1 is reduced by activation of PARP1 and subsequent NAD? depletion. Reduction of SIRT1 promotes acetylation of target proteins including FoxO3, p53, MMP9, and RelA/p65, thereby enhancing autophagy, cellular senescence, emphysema, and fibrosis, as well as inflammation. Conversely, overexpression of SIRT1 inhibits acetylation of the proteins and the subsequent effects. It is noteworthy that SIRT6 inhibits cellular senescence by inducing autophagy. Interestingly, reduction in both SIRT1 and SIRT6 appears to be associated with COPD development, but the mechanisms of autophagy regulation

Role of sirtuins in COPD

between SIRT1 and SIRT6 are opposing. SIRT6 also inhibits TGF-b-induced senescence by degradation of p21 and prevents fibrosis by suppression of IL-1b secretion. With an overall understanding of the involvement of SIRT1 and SIRT6 in COPD, pharmacological activation of SIRT1 or SIRT6 by specific agents is a promising therapeutic strategy against COPD. Since there is currently no cure for advanced COPD and mortality from COPD continues to rise, further studies are necessary to validate the role of SIRT1 and SIRT6 in COPD and to identify novel therapeutic targets for the treatment of COPD. Acknowledgments This work was supported by the 2012 Inje University research grant.

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