A new compound, 1H,8H-pyrano[3,4-c]pyran-1,8-dione, suppresses airway epithelial cell inflammatory responses in a murine model of asthma.
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 antiasthmatic 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-alpha, IL-4 and IL-1beta 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-KB pathway. To clarify the anti-inflammatory and antiasthmatic 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.
Lee
H
H
Department of Physiology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
Han
A R
AR
Kim
Y
Y
Choi
S H
SH
Ko
E
E
Lee
N Y
NY
Jeong
J H
JH
Kim
S H
SH
Bae
H
H
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology; D005638:Fruit; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010047:Ovalbumin; D010766:Phosphorylation; D011657:Pulmonary Eosinophilia / Q000188:drug therapy* / Q000276:immunology; D011753:Pyrones / Q000302:isolation & purification / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D020950:Vitex / Q000737:chemistry
C545170:1H,8H-pyrano(3,4-c)pyran-1,8-dione; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D007378:Interleukins; D011753:Pyrones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3