Seoung Ju Park

PPAR-gamma modulates allergic inflammation through up-regulation of PTEN

The ligand‐activated nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) has been shown to regulate cell activation, differentiation, proliferation, and/or apoptosis. PPARγ is also associated with anti‐inflammatory responses. However, the signaling mechanism remains elusive. We have used a mouse model for asthma to determine the effect of PPARγ agonists, rosiglitazone or pioglitazone, and PPARγ on allergen‐induced bronchial inflammation and airway hyperresponsiveness. Administration of PPARγ agonists or adenovirus carrying PPARγ cDNA (AdPPARγ) reduced bronchial inflammation and airway hyperresponsiveness. Expression of PPARγ was increased by ovalbumin (OVA) inhalation, and the increase was further enhanced by the administration of the PPARγ agonists or AdPPARγ. Levels of IL‐4, IL‐5, IL‐13, and eosinophil cationic protein were increased after OVA inhalation, and the increased levels were significantly reduced by the administration of PPARγ agonists or AdPPARγ. The results also showed that the administration of PPARγ agonists or AdPPARγ up‐regulated phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression in allergen‐induced asthmatic lungs. This up‐regulation correlated with decreased phosphatidylinositol 3‐kinase activity as measured by reduced phosphorylation of Akt. These findings demonstrate a protective role of PPARγ in the pathogenesis of the asthma phenotype through regulation of PTEN expression.

Prevalence of chronic obstructive pulmonary disease in Korea: The fourth Korean National Health and Nutrition Examination Survey, 2008

Background and objective:  Because the mortality and social burden associated with COPD is increasing, repeated surveys of the prevalence of COPD have been used to assess risk factors, detect potential patients, and establish early diagnoses and management protocols. We report the prevalence of spirometrically detected COPD in Korea in 2008, using data from the fourth Korean National Health and Nutrition Survey.

Peroxisome Proliferator-Activated Receptor γ Agonist Down-Regulates IL-17 Expression in a Murine Model of Allergic Airway Inflammation

Peroxisome proliferator-activated receptor γ (PPARγ) plays a critical role in the control of airway inflammation. Recently, IL-17 has been found to be implicated in many immune and inflammatory responses, including airway inflammation. However, no data are available concerning the effect of PPARγ on IL-17 production in airway inflammatory diseases. In this study, we used a mouse model of asthma to evaluate the effect of two PPARγ agonists, rosiglitazone or pioglitazone, on IL-17 expression in allergic airway disease. After OVA inhalation, mice developed the typical pathophysiological features of asthma, and the expression of IL-17 protein and mRNA in the lungs was increased. Administration of rosiglitazone or pioglitazone reduced the pathophysiological features of asthma and decreased the increased IL-17 protein and mRNA expression after OVA inhalation. In addition, the attenuating effect of PPARγ agonist on allergic airway inflammation and bronchial hyperresponsiveness is abrogated by coadministration of rIL-17. This study also showed that the inhibition of IL-17 activity with anti-IL-17 Ab remarkably reduced the increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, and the increased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and OVA-specific IgE in serum. In addition, we found that administration of rosiglitazone or pioglitazone decreased the increased NF-κB activity and that a NF-κB inhibitor, BAY 11-7085, substantially reduced the increased IL-17 protein levels in the lung tissues after OVA inhalation. These findings suggest that the therapeutic effect of PPARγ in asthma is partly mediated by regulation of IL-17 expression via NF-κB pathway.

Interleukin-17 regulation: an attractive therapeutic approach for asthma

Interleukin (IL)-17 is recognized to play a critical role in numerous immune and inflammatory responses by regulating the expression of various inflammatory mediators, which include cytokines, chemokines, and adhesion molecules. There is growing evidence that IL-17 is involved in the pathogenesis of asthma. IL-17 orchestrates the neutrophilic influx into the airways and also enhances T-helper 2 (Th2) cell-mediated eosinophilic airway inflammation in asthma. Recent studies have demonstrated that not only inhibitor of IL-17 per se but also diverse regulators of IL-17 expression reduce antigen-induced airway inflammation, bronchial hyperresponsiveness, and Th2 cytokine levels in animal models of asthma. This review will summarize the role of IL-17 in the context of allergic airway inflammation and discuss the therapeutic potential of various strategies targeting IL-17 for asthma.

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimers disease, Parkinsons disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-κB and hypoxia-inducible factor-1α (HIF-1α) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-κB and HIF-1α as well as reducing ROS generation in allergic airway disease.

Blockade of airway hyperresponsiveness and inflammation in a murine model of asthma by a prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid

Oxidative stress plays an important role in the pathogenesis of bronchial asthma. An excess production of reactive oxygen species (ROS) and defective endogenous antioxidant defense mechanisms may be present in asthma. Reduced glutathione (GSH) is one of the most important reducing agents against oxidant free radicals. A reducing agent, L‐2‐oxothiazolidine‐4‐ carboxylic acid (OTC), a prodrug of cysteine, increases intracellular GSH. We have used a mouse model for asthma to determine effects of OTC on allergen‐induced bronchial inflammation and airway hyper‐responsiveness. The administration of OTC reduced bronchial inflammation and airway hyper‐responsiveness. ROS generation in bronchoalveolar lavage fluids was increased by ovalbumin (OVA) inhalation, but this increase was diminished by administration of OTC. The increased IL‐4, IL‐5, IL‐13, and eosinophil cationic protein levels in lungs after OVA inhalation were significantly reduced by the administration of OTC. In addition, the increased expression of ICAM‐1, VCAM‐1, RANTES, and eotaxin in lungs after OVA inhalation was significantly reduced by the administration of OTC. We also showed that the increased NF‐κB levels in nuclear protein extracts of lung tissues at 72 h after OVA inhalation were decreased by the administration of OTC. These findings suggest that OTC may reduce airway inflammation and hyper‐responsiveness through regulation of NF‐κB activity.

Modulation of Airway Remodeling and Airway Inflammation by Peroxisome Proliferator-Activated Receptor γ in a Murine Model of Toluene Diisocyanate-Induced Asthma

Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARγ in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARγ agonist, rosiglitazone, or pioglitazone, and PPARγ on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-β1, and NF-κB in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPARγ agonists or adenovirus carrying PPARγ2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-β1, and NF-κB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-κB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-β1 after TDI inhalation. These findings demonstrate a protective role of PPARγ in the pathogenesis of the TDI-induced asthma phenotype.

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

BACKGROUND Bronchial asthma is a chronic inflammatory disorder of the airways characterized by increased expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases is associated with increased gene transcription, whereas hypoacetylation induced by histone deacetylases is associated with suppression of gene expression. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family that belongs to class III histone deacetylase. OBJECTIVE This study aimed to investigate the role of SIRT1 and the related molecular mechanisms in the pathogenesis of allergic airway disease. METHODS By using a murine model of ovalbumin (OVA)-induced allergic airway disease and murine tracheal epithelial cells, this study investigated the involvement of SIRT1 and its signaling networks in allergic airway inflammation and hyperresponsiveness. RESULTS In this study with mice after inhalation of OVA, the increased levels of SIRT1, hypoxia-inducible factor 1alpha (HIF-1alpha), and vascular endothelial growth factor protein in the lungs after OVA inhalation were decreased substantially by the administration of a SIRT1 inhibitor, sirtinol. We also showed that the administration of sirtinol reduced significantly the increased numbers of inflammatory cells of the airways; airway hyperresponsiveness; increased levels of IL-4, IL-5, and IL-13; and increased vascular permeability in the lungs after OVA inhalation. In addition, we have found that inhibition of SIRT1 reduced OVA-induced upregulation of HIF-1alpha in airway epithelial cells. CONCLUSIONS These results indicate that inhibition of SIRT1 might attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular endothelial growth factor expression mediated by HIF-1alpha in mice.

HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium.

Hypoxia‐inducible factor‐1α (HIF‐1α) plays a critical role in immune and inflammatory responses. One of the HIF‐1α target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA‐treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF‐1α activation and the role of HIF‐1α in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF‐1α siRNA suppressed VEGF expression. In addition, the increased levels of HIF‐1α and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF‐1α inhibitor, 2‐methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL‐4, IL‐5, IL‐13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2‐methoxyestradiol or a VEGF inhibitor, CBO‐P11. Moreover, we found that inhibition of the PI3K p110δ isoform (PI3K‐δ) or HIF‐1α reduced OVA‐induced HIF‐1α activation in airway epithelial cells. These findings indicate that HIF‐1α inhibition may attenuate antigen‐induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K‐δ signaling may be involved in the allergen‐induced HIF‐1α activation.

Autophagy induction and CHOP under-expression promotes survival of fibroblasts from rheumatoid arthritis patients under endoplasmic reticulum stress

IntroductionSynovial fibroblasts from rheumatoid arthritis show resistance to apoptotic stimuli, indicating they may be difficult to treat. To clearly understand these mechanisms of resistance, rheumatoid and osteoarthritis synovial fibroblasts (RASF and OASF) were exposed to endoplasmic reticulum (ER) stress such as thapsigargin, Ca2+-ATPase inhibitor.MethodsFibroblasts were assessed microscopically for cell viability by trypan blue exclusion and for autophagic cells by LC-3II formation. Caspase-3 activity was measured as aminomethyl-coumarin (AMC) liberated from AC-DEVD-AMC. Immunoblotting was performed to compare protein expression in OASF and RASF.ResultsER stress caused cell death in OASF but not in RASF. Thapsigargin, a Ca2+-ATPase inhibitor, did not change the expression of GRP78, an ER chaperone in OASF and RASF, but induced another ER stress protein, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) differently, showing high levels in OASF and low levels in RASF. Thapsigargin increased the autophagy response in RASF, with autophagosome formation, beclin expression, and LC3-II conversion. Transfection with beclin siRNA inhibited autophagy and increased the susceptibility to ER stress-induced cell death. On the other hand, CHOP siRNA increased autophagy and improved cell survival, especially in RASF, indicating that CHOP is involved in regulation of autophagy and cell death, but that low expression of CHOP protects RASF from apoptosis.ConclusionsAutophagy induction and CHOP under-expression increases cell resistance against ER stress-induced cell death in fibroblasts from rheumatoid arthritis patients.