gw9662 and Asthma

Efferocytosis can resolve airway inflammation and enhance airway tolerance in allergic asthma. While previous work has reported that progranulin (PGRN) regulated macrophage efferocytosis, but it is unclear whether PGRN-mediated efferocytosis is associated with asthma. Here, we found that in an ovalbumin (OVA)-induced allergic asthma model, the airway inflammation was suppressed and the apoptosis in lung tissues was ameliorated in PGRN-deficient mice. In contrast, PGRN knockdown in human bronchial epithelial cells increased apoptosis in vitro. Furthermore, PGRN-deficient macrophages had significantly stronger efferocytosis ability than wild type (WT) macrophages both in vitro and in vivo. PGRN-deficient peritoneal macrophages (PMs) exhibited increased expression of genes associated with efferocytosis including milk fat globule-epidermal growth factor 8 (MFG-E8), peroxisome proliferator-activated receptor gamma (PPAR-γ) and sirtuin1 (SIRT1) and increased capacity to produce the anti-inflammatory mediator interleukin (IL)-10 during efferocytosis. GW9662, the inhibitor of PPAR-γ, abolished increased efferocytosis and MFG-E8 expression in PGRN-deficient PMs suggesting that PGRN deficiency enhanced MFG-E8-mediated efferocytosis through PPAR-γ. Correspondingly, efferocytosis genes were increased in the lungs of OVA-induced PGRN-deficient mice. GW9662 treatment reduced MFG-E8 expression but did not significantly affect airway inflammation. Our results demonstrated that PGRN deficiency enhanced efferocytosis via the PPAR-γ/MFG-E8 pathway and this may be one of the reasons PGRN deficiency results in inhibition of airway inflammation in allergic asthma.

Topics: Animals; Asthma; Factor VIII; Humans; Inflammation; Macrophages; Mice; PPAR gamma; Progranulins

Peroxisome proliferator-activated receptor gamma (PPARγ) is a multifaceted ligand-activated transcription factor that regulates inflammatory responses in asthma pathophysiology. The present study corroborates PPARγ-mediated anti-asthmatic action of the flavonoid, galangin (norizalpinin). In silico molecular interactions reveal that galangin formed three H-bonds (Glu291, Leu340 and Ser342) and a π-sigma bond (Arg288) with PPARγ, contributing to the binding affinity and stability of the complex. In vivo studies explore the role of galangin as a propitious PPARγ agonist in mitigating airway inflammation, thereby excluding ligand-independent action of PPARγ. Accordingly, oral administration of galangin significantly ameliorated airway hyperresponsiveness, inflammation and goblet cell hyperplasia by the suppression of IL-4, 5, 13, 17, TNF-α, NO, ROS, EPO, IgE and increase of IFN-γ in ovalbumin-induced allergic asthma model. PPARγ expression (mRNA and protein) studies were performed to elucidate a possible mechanism by which galangin modulates. Furthermore, to eliminate PPARγ-independent effects of galangin, a specific PPARγ antagonist (GW9662) was administered, which dramatically reversed the effects of galangin on PPARγ up-regulation, confirming the pleiotropic role of galangin as a PPARγ agonist in asthma therapeutics. Taken together, our findings communicate that PPARγ plays as a master regulator in the anti-asthmatic action of galangin.

Topics: Amino Acid Sequence; Anilides; Animals; Anti-Asthmatic Agents; Asthma; Binding Sites; Biomechanical Phenomena; Female; Flavonoids; Gene Expression Regulation; Humans; Hydrogen Bonding; Interleukins; Lung; Mice, Inbred BALB C; Molecular Docking Simulation; Ovalbumin; PPAR gamma; Protein Binding; Protein Conformation; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dose-dependently reduced the IL-1β-induced release of IL-6 and vascular endothelial growth factor, the TNF-α-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-α-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-γ (PPARγ), these anti-inflammatory effects were not affected by a specific PPARγ inhibitor (GW 9662) or by the knockdown of PPARγ using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the anti-inflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARγ or AMPK.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Anilides; Anti-Inflammatory Agents; Antimetabolites; Asthma; Cells, Cultured; Chromans; Cytokines; Enzyme Activators; Enzyme Inhibitors; Gene Knockdown Techniques; Humans; Hypoglycemic Agents; Inflammation Mediators; Metformin; Myocytes, Smooth Muscle; PPAR gamma; Pyrazoles; Pyrimidines; Respiratory System; Ribonucleotides; Rosiglitazone; Thiazolidinediones; Troglitazone; Vidarabine

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

Topics: Anilides; Animals; Asthma; Chemokine CCL5; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; NF-kappa B; Pioglitazone; PPAR gamma; Reactive Oxygen Species; Rosiglitazone; Thiazolidinediones; Vascular Cell Adhesion Molecule-1

Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.

Topics: Anilides; Animals; Asthma; Cell Movement; Cytokines; Dendritic Cells; Disease Models, Animal; Eosinophils; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; T-Lymphocytes; Thiazolidinediones; Transcription Factors; Vasodilator Agents

Allergic asthma is characterized by airway hyperresponsiveness, eosinophilia, and mucus accumulation and is associated with increased IgE concentrations. We demonstrate here that peroxisome proliferator-activated receptors (PPARs), PPAR-alpha and PPAR-gamma, which have been shown recently to be involved in the regulation of various cell types within the immune system, decrease antigen-induced airway hyperresponsiveness, lung inflammation, eosinophilia, cytokine production, and GATA-3 expression as well as serum levels of antigen-specific IgE in a murine model of human asthma. In addition, we demonstrate that PPAR-alpha and -gamma are expressed in eosinophils and their activation inhibits in vitro chemotaxis and antibody-dependent cellular cytotoxicity. Thus, PPAR-alpha and -gamma (co)agonists might be of therapeutic interest for the regulation of allergic or inflammatory reactions by targeting both regulatory and effector cells involved in the immune response.

Topics: Anilides; Animals; Asthma; Chemotaxis; Disease Models, Animal; DNA-Binding Proteins; Down-Regulation; Eosinophils; GATA3 Transcription Factor; Humans; Inflammation; Lung; Mice; Mice, Inbred BALB C; Mice, Knockout; Rats; Receptors, Cytoplasmic and Nuclear; Respiratory Hypersensitivity; Rosiglitazone; Thiazoles; Thiazolidinediones; Trans-Activators; Transcription Factors