Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease

Kim, So Ri; Lee, Kyung Sun; Park, Seoung Ju; Min, Kyung Hoon; Choe, Yeong Hun; Moon, Hee Seok; Yoo, Wan Hee; Chae, Han-Jung; Han, Myung‐Kwan; Lee, Yong Chul

doi:10.1016/j.jaci.2009.08.009

Cited by 66 publications

(72 citation statements)

References 60 publications

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“…Sirtinol (2 mg/kg; Calbiochem) was administered by peritoneal injection, whereas SRT1720 (100 mg/kg, >95% pure by C-13 NMR and LCMS; synthesized from Life Chemicals) was administered through oral gavage 1 hour prior to CS exposure daily for 3 days (81)(82)(83). In a separate experiment, SRT1720 (25,50, and 100 mg/kg) or PHA-408…”

Section: Figurementioning

confidence: 99%

“…indazole-3-carboxamide; 50 mg/kg; Pfizer) was dissolved in 0.5% carboxymethylcellulose containing 0.025% Tween 20 and injected via oral gavage into the conscious mice 24 hours prior to elastase administration, which was repeated daily (5 days per week) until 21 days after elastase administration (81,84). To study the therapeutic effect on emphysema, SRT1720 (100 mg/kg) was orally administered daily for 2 weeks after the development of elastase-induced emphysema.…”

Section: Figurementioning

confidence: 99%

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SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao

Chung²,

Hwang³

et al. 2012

J. Clin. Invest.

311

351

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Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD + -dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao

Chung²,

Hwang³

et al. 2012

J. Clin. Invest.

311

351

View full text Add to dashboard Cite

show abstract

“…Some studies suggest that it has an antiinflammatory role by inhibiting proinflammatory transcription factors, such as NF-kB (23). Other studies show the opposite, with pharmacological inhibition of Sirt1 dampening lung Th2 inflammation by repressing peroxisome proliferator-activated receptor-g (25) or modulating vascular endothelial growth factor expression (26). Our murine studies highlight novel relationships between Chi3l1 and Sirt1 and, in so doing, provide at least a partial explanation for the paradox in the literature.…”

Section: Original Articlementioning

confidence: 54%

“…Sirt1 is believed to be an important regulator of the energy metabolism associated with obesity and allergeninduced airway inflammation and airway hyperresponsiveness (25)(26)(27). However, its roles in these disorders have not been adequately defined, and its relationship to Chi3l1 has not been addressed.…”

mentioning

confidence: 99%

Chitinase 3–like-1 Regulates Both Visceral Fat Accumulation and Asthma-like Th2 Inflammation

Ahangari

Sood²,

Ma³

et al. 2015

Am J Respir Crit Care Med

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Rationale: Obesity, especially truncal obesity, is a risk factor for asthma incidence, prevalence, and severity. Chitinase 3-like-1 (Chi3l1) is an evolutionarily conserved moiety that plays a critical role in antipathogen and Th2 responses. However, the mechanisms that underlie the association between asthma and obesity and the role(s) of Chi3l1 in fat accumulation have not been defined.Objectives: To determine whether Chi3l1 is regulated by a high-fat diet (HFD) and simultaneously plays an important role(s) in the pathogenesis of asthma and obesity.Methods: We evaluated the regulation of Chi3l1 by an HFD and Th2 inflammation. We also used genetically modified mice to define the roles of Chi3l1 in white adipose tissue (WAT) accumulation and Th2 inflammation and blockers of sirtuin 1 (Sirt1) to define its roles in these responses. Finally, the human relevance of these findings was assessed with a case-control study involving obese and lean control subjects and those with asthma. Measurements and MainResults: These studies demonstrate that an HFD and aeroallergen challenge augment the expression of WAT and pulmonary Chi3l1. Chi3l1 also played a critical role in WAT accumulation and lung Th2 inflammation. In addition, Chi3l1 inhibited Sirt1 expression, and the deficient visceral fat and Th2 responses in Chi3l1 null mice were reversed by Sirt1 inhibition. Finally, serum and sputum Chi3l1 were positively associated with truncal adiposity, and serum Chi3l1 was associated with persistent asthma and low lung function in obese subjects with asthma.Conclusions: Chi3l1 is induced by an HFD and Th2 inflammation, and simultaneously contributes to the genesis of obesity and asthma.

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“…Using a similar mouse model of allergic airways disease, findings from our laboratory, indicate that systemic administration of resveratrol, inhibits airway hyperresponsiveness, reduces subepithelial collagen deposition and has antiinflammatory effects as assessed by TGFβ1 expression [77]. In paradoxical findings, the SIRT1 inhibitor, sirtinol has been recently shown to attenuate airway inflammation and hyperresponsiveness in an analogous ovalbumin-induced mouse model of asthma [78]. This indicates that the mechanisms accounting for the beneficial effects of resveratrol in models of asthma may be separate from modulation of SIRT1.…”

Section: Sirtuins and Resveratrol For The Treatment Of Asthmamentioning

confidence: 97%

Controversies Surrounding the Potential Use of Histone Deacetylase Inhibitors for the Treatment of Asthma

2012

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Management of asthma with long-acting β 2 -adrenergic receptor agonists and corticosteroids is exceptionally effective for the majority of asthma patients. However, corticosteroid insensitivity or resistance remains a significant clinical problem for a significant proportion of patients, requiring the investigation of new potential therapeutics for asthma. Histone deacetylase inhibitors represent a different class of compounds that have been evaluated for their potential antiasthmatic effects. Although accumulating evidence is indicating beneficial effects in rodent models of allergic airways disease, the potential use of histone deacetylase inhibitors in asthma remains controversial given their mechanisms of action. The aim of this paper is to provide an overview of histone deacetylases and pharmacological modifiers of these enzymes. The discussion represents a balanced account of the emerging evidence indicating the beneficial effects of histone deacetylase inhibitors in inflammatory lung diseases. The potential problems associated with the use of this class of compounds in asthma are also carefully considered.

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Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease

Cited by 66 publications

References 60 publications

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Chitinase 3–like-1 Regulates Both Visceral Fat Accumulation and Asthma-like Th2 Inflammation

Controversies Surrounding the Potential Use of Histone Deacetylase Inhibitors for the Treatment of Asthma

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