Peroxisome Proliferator-Activated Receptor γ Regulates Eosinophil Functions: A New Therapeutic Target for Allergic Airway Inflammation

Ueki, Shigeharu; Matsuwaki, Yoshinori; Kayaba, Hiroyuki; Oyamada, Hirokazu; Kanda, Akira; Usami, Atsuko; Saito, Norihiro; Chihara, Junichi

doi:10.1159/000077790

Cited by 53 publications

(43 citation statements)

References 42 publications

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“…PPARg also transrepresses inflammatory mediators, such as tumor necrosis factor-a; inducible nitric oxide synthase; IL-1b; chemokine receptors (e.g., chemokine receptors-7); adhesion molecules; and matrix metalloproteinase-9 (63, 64). Moreover, PPARg can potentiate inflammatory cell apoptosis (65,70,71) and transactivate antiinflammatory mediators including IL-10 (68). Enhanced pulmonary p65 NF-kB and IL-6 and reduced inflammatory cell apoptosis in mice with suppressed pulmonary PPARg determined in the current study supports the antiinflammatory mechanisms through PPARg in ALI.…”

Section: Discussionmentioning

confidence: 99%

“…Asthma and allergy models are under intense investigation, and thiazolidinediones (e.g., rosiglitazone, ciglitazone, and pioglitazone) reduced eosinophilic inflammation and allergic symptoms by various allergens in mice (26,58,(71)(72)(73). Studies using the agonists or adenovirus carrying Pparg cDNA in mice also determined that enhanced PTEN and suppressed phosphorylated Akt/phosphoinositol 3 kinase and NF-kB was involved in the antiasthmatic effect of PPARg on eosinophilia and airway hyperresponsiveness (66).…”

Section: Discussionmentioning

confidence: 99%

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Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Cho

Gladwell

Wang

et al. 2010

Am J Respir Crit Care Med

199

176

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Rationale: The NF-E2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is essential for protection against oxidative injury and inflammation including hyperoxia-induced acute lung injury. Microarray expression profiling revealed that lung peroxisome proliferator activated receptor g (PPARg) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2 2/2 ) mice compared with wild-type (Nrf2 1/1 ) mice. PPARg has pleiotropic beneficial effects including antiinflammation in multiple tissues. Objectives: We tested the hypothesis that PPARg is an important determinant of pulmonary responsivity to hyperoxia regulated by Nrf2. Methods: A computational bioinformatic method was applied to screen potential AREs in the Pparg promoter for Nrf2 binding. The functional role of a potential ARE was investigated by in vitro promoter analysis. A role for PPARg in hyperoxia-induced acute lung injury was determined by temporal silencing of PPARg via intranasal delivery of PPARg-specific interference RNA and by administration of a PPARg ligand 15-deoxy-D 12,14 -prostaglandin J 2 in mice. Measurements and Main Results: Deletion or site-directed mutagenesis of a potential ARE spanning -784/-764 sequence significantly attenuated hyperoxia-increased Pparg promoter activity in airway epithelial cells overexpressing Nrf2, indicating that the -784/-764 ARE is critical for Nrf2-regulated PPARg expression. Mice with decreased lung PPARg by specific interference RNA treatment had significantly augmented hyperoxia-induced pulmonary inflammation and injury. 15 Deoxy-D 12,14 -prostaglandin J 2 administration significantly reduced hyperoxia-induced lung inflammation and edema in Nrf2 1/1 , but not in Nrf2 2/2 mice. Conclusions: Results indicate for the first time that Nrf2-driven PPARg induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPARg in airway oxidative inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Cho

Gladwell

Wang

et al. 2010

Am J Respir Crit Care Med

199

176

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“…Specifically, PPAR-␥ ligands were previously shown to inhibit eosinophil 27 and monocyte 28 chemotaxis in a dose-dependent manner. In addition, in vivo animal studies suggest that PMN migration to sites of inflammation is impaired after PPAR-␥ ligand administration.…”

Section: Discussionmentioning

confidence: 99%

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Reddy

Narala

Keshamouni

et al. 2008

Blood

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IntroductionHuman peripheral polymorphonucleocytes (PMNs) represent the predominant cellular component at sites of acute inflammation. These cells serve a critical role in host defense with transendothelial migration of PMNs being a crucial component of the immune/ inflammatory response. 1 In addition to their phagocytic activity, PMNs produce mediators such as reactive oxygen intermediates, cytokines/chemokines, and enzymes. 1,2 The directed migration, or chemotaxis, of PMNs occurs in response to a variety of molecules, including formylmethionyl-leucyl-phenylalanine (fMLP), a bacterial peptide, and chemokines such as IL-8, which are released from sites of inflammation or injury. fMLP and IL-8 bind to receptors on PMNs, resulting in both G-protein-dependent and -independent responses. 3 Emerging evidence indicates that sepsis, most commonly caused by bacteria, results in impaired host defenses, including a reduced ability of PMNs to migrate appropriately. [4][5][6] Moreover, higher mortality rates have been observed in patients with sepsis-induced immune deactivation. 7 Mechanistic pathways resulting in altered leukocyte function during sepsis, however, remain incompletely understood.Peroxisome proliferator-activated receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear hormone receptor family. Three PPAR subtypes (␣, ␤, and ␥), each with a specific pattern of expression, have been identified. PPAR-␥ also exists in 2 isoforms, PPAR-␥1 and PPAR-␥2, with the human PPAR-␥2 protein consisting of 28 additional amino acids compared with PPAR-␥1. Ligands for PPAR-␥ include a variety of compounds, both natural and synthetic. Most of the natural ligands are fatty acids or fatty acid derivatives. Synthetic ligands for PPAR-␥ include the antidiabetic thiazolidinediones such as troglitazone.PPAR-␥ is highly expressed in adipose tissue and plays a crucial role in adipocyte differentiation, 8 but it is also expressed in a variety of tissue and cell types, including a majority of those in the hematopoietic system. In cells of the immune system, treatment with PPAR-␥ ligands typically results in the down-regulation of inflammatory responses. 9 For example, activation of PPAR-␥ in macrophages results in inhibition of cytokine, nitric oxide, and hydrogen peroxide production. 10 Freshly isolated human peripheral PMNs were previously shown to express PPAR-␥ mRNA. 11 Treatment of human PMNs with PPAR-␥ ligands results in decreased adhesion-dependent H 2 O 2 production 12 and blocks up-regulation of the CD11b/CD18 adhesion complex. 13 However, no previous study has examined regulation of PPAR-␥ expression in human PMNs or the specific role this transcription factor may play in the migration of these cells. In this study, we assessed the expression and regulation of PPAR-␥ in PMNs and investigated the effect of PPAR-␥ activation on the ability of PMNs to migrate in response to chemoattractants. Furthermore, we investigated the expression of PPAR-␥ in PMNs during the septic response and the effects on che...

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“…Specifically, PPARγ can modulate eosinophil survival and activation [47], as well as epithelial mucin production [48]. It is possible that the relatively rapid effects of γT against allergen-induced inflammation could be mediated by an acute activation of PPARγ to inhibit signaling cascades that lead to airway inflammatory cell recruitment and activation.…”

Section: Discussionmentioning

confidence: 99%

Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

Wagner

Jiang

Harkema

et al. 2007

Free Radical Biology and Medicine

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Ozone is a commonly encountered environmental oxidant which has been linked to asthma exacerbation in epidemiological studies. Ozone induces airway inflammation and enhances response to inhaled allergen. It has been suggested that antioxidant therapy may minimize the adverse effects of ozone in asthma. We have previously shown that the antioxidant gammatocopherol (γT), an isoform of vitamin E, also has anti-inflammatory effects. We employed a Brown Norway rat model of ozone-enhanced allergic responses to test the therapeutic effects of γT on O 3 -induced airway inflammation. Ovalbumin (OVA) -sensitized rats were intranasally challenged with 0 or 0.5% OVA on Days 1 and 2, and exposed to 0 or 1 ppm ozone (8h/day) on Days 4 and 5. Rats were also given 0 or 100 mg/kg γT on Days 2 through 5. Pulmonary tissue and bronchoalveolar lavage fluid (BALF) were collected on Day 6. OVA challenge caused increased total cells (267% increase) and eosinophils (4000%) in BALF that was unaffected by ozone exposure. Morphometric evaluation of lung tissue revealed increases in intraepithelial mucosubstances (IM) (300%) and subepithelial eosinophils (400%) in main axial airways. Ozone exposure of allergic rats enhanced IM increases in proximal axial airways (200%), induced cysleukotrienes, MCP-1 and IL-6 production in BALF, and upregulated expression of IL-5 and IL-13 mRNA. γT treatment had no effect on IM increases by allergen, but blocked enhancement by ozone. γT attenuated both OVA-or ozone -stimulated eosinophilic infiltration, and increases of BALF cys-leukotrienes, MCP-1 and IL-6, as well as IL-5 and IL-13 mRNA. These data Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript demonstrate broad anti-inflammatory effects of a γT and suggest it may be an effective therapy of allergic airway inflammation.

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Peroxisome Proliferator-Activated Receptor γ Regulates Eosinophil Functions: A New Therapeutic Target for Allergic Airway Inflammation

Cited by 53 publications

References 42 publications

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

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