Abstract

Clinical and experimental studies have established eosinophilia as a sign of allergic disorders. Activation of eosinophils in the airways is believed to cause epithelial tissue injury, contraction of airway smooth muscle and increased bronchial responsiveness. As part of the search for new anti-asthmatic agents produced by medicinal plants, the effects of 270 standardized medicinal plant extracts on cytokine-activated A549 human lung epithelial cells were evaluated. After several rounds of activity-guided screening, the new natural compound, 1H,8H-Pyrano[3,4-c]pyran-1,8-dione (PPY), was isolated from Vitex rotundifolia L. To elucidate the mechanism by which the anti-asthmatic responses of PPY occurred in vitro, lung epithelial cells (A549 cell) were stimulated with TNF-α, IL-4 and IL-1β to induce the expression of chemokines and adhesion molecules involved in eosinophil chemotaxis. PPY treatments reduced the expression of eotaxin, IL-8, IL-16 and VCAM-1 mRNA significantly. Additionally, PPY reduced eotaxin secretion in a dose-dependent manner and significantly inhibited eosinophil migration toward A549 medium. In addition, PPY treatment suppressed the phosphorylation of p65 and ERK1/2, suggesting that it can inhibit the MAPK/NF-κB pathway. To clarify the anti-inflammatory and anti-asthmatic effects of PPY in vivo, we examined the influence of PPY on the development of pulmonary eosinophilic inflammation in a murine model of asthma. To accomplish this, mice were sensitized and challenged with ovalbumin (OVA) and then examined for the following typical asthmatic reactions: an increase in the number of eosinophils in BALF; the presence of Th2 cytokines such as IL-4 and IL-5 in the BALF; the presence of allergen-specific IgE in the serum; and a marked influx of inflammatory cells into the lung. Taken together, our results revealed that PPY exerts profound inhibitory effects on the accumulation of eosinophils into the airways while reducing the levels of IL-4, IL-5, and IL-13 in the BALF. Therefore, these results suggest that PPY may be useful as a new therapeutic drug for the treatment of allergic asthma. Copyright © by BIOLIFE, s.a.s.

Author keywords

1H,8H-Pyrano[3,4-c]pyran-1,8-dione; Asthma; Eosinophils; Infiltration

Indexed keywords

EMTREE drug terms: 1h 8h pyrano[3,4]pyran 1,8 dione; antiasthmatic agent; eotaxin; gamma interferon; immunoglobulin E; immunoglobulin enhancer binding protein; interleukin 13; interleukin 1beta; interleukin 4; interleukin 5; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; ovalbumin; synaptotagmin I; tumor necrosis factor alpha; unclassified drug; vascular cell adhesion molecule 1

EMTREE medical terms: allergic asthma; animal cell; animal experiment; animal model; animal tissue; antiinflammatory activity; article; CD4+ T lymphocyte; cell migration; controlled study; disease course; drug isolation; drug structure; eosinophil; human; in vitro study; in vivo study; lung alveolus epithelium; male; nonhuman; pneumonia; priority journal; protein phosphorylation; real time polymerase chain reaction; Th1 cell

MeSH: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cell Line, Tumor; Cell Movement; Chemokine CCL5; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Epithelial Cells; Fruit; Humans; Immunoglobulin E; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukins; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Ovalbumin; Phosphorylation; Pulmonary Eosinophilia; Pyrones; Respiratory Mucosa; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vitex
Medline is the source for the MeSH terms of this document.

Chemicals and CAS Registry Numbers: gamma interferon, 82115-62-6; immunoglobulin E, 37341-29-0; interleukin 13, 148157-34-0; mitogen activated protein kinase, 142243-02-5; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; ovalbumin, 77466-29-6;1H,8H-pyrano(3,4-c)pyran-1,8-dione; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Ccl5 protein, mouse; Chemokine CCL5; Immunoglobulin E, 37341-29-0; Intercellular Adhesion Molecule-1, 126547-89-5; Interferon-gamma, 82115-62-6; Interleukins; Mitogen-Activated Protein Kinase 1, 2.7.11.24; Mitogen-Activated Protein Kinase 3, 2.7.11.24; Ovalbumin, 9006-59-1; Pyrones; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1