Peroxisome proliferator activated receptor-γ modulates reactive oxygen species generation and activation of nuclear factor-κB and hypoxia-inducible factor 1α in allergic airway disease of mice

Lee, Kyung Sun,Kim, So Ri,Park, Seoung Ju,Park, Hee Sun,Min, Kyung Hoon,Jin, Sun Mi,Lee, Moon Kyu,Kim, Uh Hyun,Lee, Yong Chul Elsevier 2006 The journal of allergy and clinical immunology Vol.118 No.1

<P><B>Background</B></P><P>Reactive oxygen species (ROSs) play a crucial role in the pathogenesis of airway inflammation. Peroxisome proliferator activated receptor (PPAR)-γ is also involved in airway inflammation. We have demonstrated that the administration of PPARγ agonists or adenovirus carrying PPARγ cDNA (AdPPARγ) reduced bronchial inflammation and airway hyperresponsiveness. However, the effects of PPARγ on ROS generation in conditions associated with airway inflammation have not been clarified.</P><P><B>Objective</B></P><P>This study aimed to investigate the effects of the PPARγ on ROS generation in allergic airway disease of mice.</P><P><B>Methods</B></P><P>We have used a female C57BL/6 mouse model for allergic airway disease to determine the role of PPARγ.</P><P><B>Results</B></P><P>In this study with an ovalbumin-induced murine model of allergic airway disease, the increased ROS generation and the increased expression of T<SUB>H</SUB>2 cell cytokines, adhesion molecules, chemokines, and vascular endothelial growth factor in lungs after ovalbumin inhalation were significantly reduced by the administration of PPARγ agonists or AdPPARγ. We also showed that the increased nuclear factor-κB and hypoxia-inducible factor 1α levels in nuclear protein extracts of lung tissues after ovalbumin inhalation were decreased by the administration of PPARγ agonists or AdPPARγ.</P><P><B>Conclusion</B></P><P>These results indicate that the effects of PPARγ are mediated by the modulation of ROS generation and activation of redox-sensitive transcription factor nuclear factor-κB and HIF-1α in allergic airway disease of mice.</P><P><B>Clinical implications</B></P><P>Thus, these findings provide a pivotal molecular mechanism for the use of PPARγ agonists to prevent and/or treat asthma and other airway inflammatory disorders.</P>

Antioxidant Down-Regulates Interleukin-18 Expression in Asthma

Lee, Kyung Sun,Kim, So Ri,Park, Seoung Ju,Min, Kyung Hoon,Lee, Ka Young,Jin, Sun Mi,Yoo, Wan Hee,Lee, Yong Chul American Society for PharmacologyExperimental Ther 2006 Molecular pharmacology Vol.70 No.4

<P>An alteration in the balance between a T-helper type 2 cell (Th2) response and a Th1 response may predispose to the development of bronchial asthma. Interleukin-18 (IL-18) has an ability to promote both Th1 and Th2 responses, depending on the surrounding cytokine environment. Reactive oxygen species (ROS) play a crucial 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 asthma. In this study, we used a C57BL/6 mouse model of allergic asthma to examine the effects of antioxidants on the regulation of IL-18 expression. Our present study with ovalbumin-induced murine model of asthma revealed that ROS production in cells from bronchoalveolar lavage fluids was increased and that administration of L-2-oxothiazolidine-4-carboxylic acid or alpha-lipoic acid reduced the increased levels of ROS, the increased expression of IL-18 protein and mRNA, airway inflammation, and bronchial hyperresponsiveness. Our results also showed that antioxidants down-regulated a transcription factor, nuclear factor-kappaB (NF-kappaB), activity. These results indicate that antioxidants may reduce IL-18 expression in asthma by inhibiting the activity of NF-kappaB and suggest that ROS regulate the IL-18 expression.</P>

Vascular Endothelial Growth Factor Modulates Matrix Metalloproteinase-9 Expression in Asthma

Lee, Kyung Sun,Min, Kyung Hoon,Kim, So Ri,Park, Seoung Ju,Park, Hee Sun,Jin, Gong Yong,Lee, Yong Chul American Thoracic Society 2006 American journal of respiratory and critical care Vol.174 No.2

<P>RATIONALE: Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) are mediators of airway inflammation and remodeling in asthma. OBJECTIVES: This study investigates a potential relationship between VEGF and MMP-9, and the mechanisms by which VEGF signaling regulates MMP-9 expression in asthma. METHODS: We evaluated whether levels of VEGF correlated with levels of MMP-9 in the sputum of asthma patients, and the effect of VEGF receptor inhibitors on MMP-9 expression in murine model of asthma. Measurements and MAIN RESULTS: We have found that levels of VEGF and MMP-9 are significantly higher in the sputum of patients with asthma than in healthy control subjects, and a significant correlation is found between the levels of VEGF and MMP-9. This study with the ovalbumin-induced model of asthma revealed the following typical pathophysiologic features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of MMP-9 and VEGF. Administration of VEGF receptor inhibitors reduced the pathophysiologic signs of asthma and decreased the increased expression of MMP-9 after ovalbumin inhalation. CONCLUSIONS: These results indicate that there is a close relationship between VEGF and MMP-9 expression and that inhibition of VEGF receptor down-regulates the expression of MMP-9. These findings suggest that VEGF signaling regulates MMP-9 expression and plays a critical role in initiation and maintenance of asthma.</P>

Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma

Lee, Kyung Sun,Park, Seoung Ju,Kim, So Ri,Min, Kyung Hoon,Jin, Sun Mi,Puri, Kamal D.,Lee, Yong Chul Elsevier 2006 The Journal of allergy and clinical immunology Vol.118 No.2

<P><B>Background</B></P><P>Bronchial asthma is characterized by inflammation of the airways, which is usually accompanied by increased vascular permeability, resulting in plasma exudation. Vascular endothelial growth factor (VEGF) has been implicated in contributing to asthmatic tissue edema through its effect on vascular permeability. Many cellular responses of VEGF are regulated by the lipid products of phosphoinositide 3-kinase (PI3K). However, the effect of PI3K catalytic subunit p110δ on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110δ catalytic activity, has been identified.</P><P><B>Objective</B></P><P>We have sought to investigate the role of PI3K-δ, more specifically in the increase of vascular permeability.</P><P><B>Methods</B></P><P>Female BALB/c mice were sensitized and challenged with ovalbumin. We have investigated the effect of IC87114 on airway inflammation, T<SUB>H</SUB>2 cytokines expression, airway hyperresponsiveness, plasma extravasation, hypoxia-inducible factor 1α expression, and VEGF expression in a murine model of asthma.</P><P><B>Results</B></P><P>Our current study has revealed that IC87114 reduces antigen-induced airway infiltration of inflammatory cells, secretion of T<SUB>H</SUB>2 cytokines in lungs, airway hyperresponsiveness, and vascular permeability. Moreover, we have found that inhibition of p110δ reduces ovalbumin-induced upregulation of VEGF level.</P><P><B>Conclusion</B></P><P>These results suggest that PI3K-δ inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice.</P><P><B>Clinical implications</B></P><P>These findings provide a crucial molecular mechanism for the potential role of PI3K-δ in asthma and other airway inflammatory disorders.</P>

A novel thiol compound, N-acetylcysteine amide, attenuatesallergic airway disease by regulating activation of NF-κB andhypoxia-inducible factor-1α

Kyung Sun Lee, So Ri Kim,Young Rae Lee,Jong Suk Kim,Daphne Atlas,Yong Chul Lee,박희선,Seoung Ju Park,Kyung Hoon Min,Ka Young Lee,Yeong Hun Choe,Sang Hyun Hong,Hyo Jin Han 생화학분자생물학회 2007 Experimental and molecular medicine Vol.39 No.6

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 Alzheimer's disease, Parkinson's 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.

Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma.

Lee, Kyung Sun,Park, Seoung Ju,Kim, So Ri,Min, Kyung Hoon,Jin, Sun Mi,Lee, Hern Ku,Lee, Yong Chul American Association of Immunologists 2006 Journal of Immunology Vol.177 No.8

<P>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 gamma (PPARgamma) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARgamma in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARgamma agonist, rosiglitazone, or pioglitazone, and PPARgamma 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-beta1, and NF-kappaB 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 PPARgamma agonists or adenovirus carrying PPARgamma2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-beta1, and NF-kappaB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-kappaB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-beta1 after TDI inhalation. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the TDI-induced asthma phenotype.</P>

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Reduces Vascular Endothelial Growth Factor Expression in Allergen-Induced Airway Inflammation

Lee, Kyung Sun,Kim, So Ri,Park, Seoung Ju,Lee, Ho Kyung,Park, Hee Sun,Min, Kyung Hoon,Jin, Sun Mi,Lee, Yong Chul American Society for PharmacologyExperimental Ther 2006 Molecular pharmacology Vol.69 No.6

<P>Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of bronchial asthma. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the phosphoinositide 3-kinase (PI3K)/Akt pathway. The key role of PI3K in VEGF-mediated signal transduction is established. However, the effects of PTEN on VEGF-mediated signaling in asthma are unknown. This study aimed to determine the effect of PI3K inhibitors and PTEN on VEGF expression in allergen-induced airway inflammation. We have used a female C57BL/6 mouse model for asthma to determine the role of PTEN in allergen-induced airway inflammation, specifically in the expression of VEGF. Allergen-induced airway inflammation leads to increased activity of PI3K in lung tissue. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways; airway hyper-responsiveness; increased expression of interleukin (IL)-4, IL-5, IL-13, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, regulated on activation normal T cell expressed and secreted (RANTES), and eotaxin; increased vascular permeability; and increased levels of VEGF. Administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA reduced the symptoms of asthma and decreased the increased levels of plasma extravasation and VEGF in allergen-induced asthmatic lungs. These results indicate that PTEN reduces VEGF expression in allergen-induced airway inflammation.</P>

Hydrogen Peroxide Induces Vascular Permeability via Regulation of Vascular Endothelial Growth Factor

Lee, Kyung Sun,Kim, So Ri,Park, Seoung Ju,Park, Hee Sun,Min, Kyung Hoon,Lee, Min Hee,Jin, Sun Mi,Jin, Gong Yong,Yoo, Wan Hee,Lee, Yong Chul American Thoracic Society 2006 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR Vol.35 No.2

<P>Oxidative stress plays critical roles in initiation and/or worsening of respiratory disease process. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce an increase in vascular permeability are not clearly understood. In this study, we have used a murine model to evaluate the effect of hydrogen peroxide (H(2)O(2)) to examine roles of ROS and the molecular mechanism in vascular permeability. The results have revealed that ROS levels, vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor-1alpha protein level, airway hyperresponsiveness, and vascular permeability are increased after inhalation of H(2)O(2). Administration of antioxidants markedly reduced plasma extravasation and VEGF levels in lungs treated with H(2)O(2). These results indicate that ROS may modulate vascular permeability via upregulation of VEGF expression.</P>

Change of connexin 37 in allergen-induced airwayinflammation

Seoung Ju Park/Kyung Sun Lee,김소리,Kyung Hoon Min,Ka Young Lee,Yeong Hun Choe,Seung Yong Park,Sang Hyun Hong,이용철 생화학분자생물학회 2007 Experimental and molecular medicine Vol.39 No.5

Gap junction channels formed with connexins directly link to the cytoplasm of adjacent cells and have been implicated in intercellular signaling. Connexin 37 (Cx37) is expressed in the gas-exchange region of the lung. Recently, Cx37 has been reported to be involved in the pathogenesis of inflammatory disease. However, no data are available on the role of Cx37 in allergic airway inflammatory disease. In the present study, we used a murine model of ovalbumin (OVA)- induced allergic airway disease and primary murine epithelial cells to examine the change of Cx37 in allergic airway disease. These mice develop the following typical pathophysiological features of asthma: airway hyperresponsiveness, airway inflammation, and increased IL-4, IL-5, IL-13, intercellular adhesion molecule- 1, vascular cell adhesion molecule-1, eotaxin, and RANTES levels in lungs. Cx37 protein and mRNA expression were decreased in OVA-induced allergic airway disease. Immunoreactive Cx37 localized in epithelial layers around the bronchioles in control mice, which dramatically disappeared in allergen-induced asthmatic lungs. Moreover, the levels of Cx37 protein in lung tissues showed significantly negative correlations with airway inflammation, airway responsiveness, and levels of Th2 cytokines in lungs. These findings indicate that change of Cx37 may be associated with the asthma phenotype.

A Prodrug of Cysteine, l-2-Oxothiazolidine-4-carboxylic Acid, Regulates Vascular Permeability by Reducing Vascular Endothelial Growth Factor Expression in Asthma

Lee, Kyung Sun,Park, Hee Sun,Park, Seoung Ju,Kim, So Ri,Min, Kyung Hoon,Jin, Sun Mi,Park, Kwang-Hyun,Kim, Uh-Hyun,Kim, Chan Young,Lee, Yong Chul American Society for PharmacologyExperimental Ther 2005 Molecular pharmacology Vol.68 No.5

<P>Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Oxidative stress plays critical roles in airway inflammation. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce increased vascular permeability are not clearly understood. We have used a murine model of asthma to evaluate the effect of l-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine that acts as an antioxidant, more specifically in the increase of vascular permeability. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of vascular endothelial growth factor (VEGF). Administration of OTC markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that at 72 h after ovalbumin inhalation, increased levels of hypoxia-inducible factor-1alpha (a transcriptional activator of VEGF) in nuclear protein extracts of lung tissues were decreased by the administration of OTC. These results indicate that OTC modulates vascular permeability by lowering VEGF expression.</P>