Signaling networks involved in allergic airway disease
저자
Lee, Yong Chul (Department of Internal Medicine, Chonbuk National University Medical School)
발행기관
학술지명
권호사항
발행연도
2009
작성언어
English
주제어
KDC
470
자료형태
학술저널
수록면
10-11(2쪽)
제공처
Phosphatase and tens in homologue deleted on chromosome ten(PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN blocks the action of PI3K by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. We have used a mouse model for asthma to determine the effect of PI3K inhibitors and PTEN on allergen-induced bronchial inflammation and airway hyperresponsiveness. PI3K activity increased significantly after allergen challenge. PTEN protein expression and PTEN activity were decreased in OVA-induced asthma. Immunoreactive PTEN localized in epithelial layers around the bronchioles in control mice. However, this immunoreactive PTEN dramatically disappeared in allergen-induced asthmatic lungs. The increased IL-4, IL-5, and eosinophil cationic protein levels in bronchoalveolar lavage fluids after OVA inhalation were significantly reduced by the intratracheal administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA(AdPTEN). Intratracheal administration of PI3K inhibitors or AdPTEN remarkably reduced bronchial inflammation and airway hyperresponsiveness. These findings indicate that PTEN may play a pivotal role in the pathogenesis of the asthma phenotype.
The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma(PPARgamma) has been shown to regulate cell activation, differentiation, proliferation, and/or apoptosis. PPARgamma 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 PPARgamma agonists, rosiglitazone or pioglitazone, and PPARgamma on allergen-induced bronchial inflammation and airway hyperresponsiveness. Administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA(AdPPARgamma) reduced bronchial inflammation and airway hyperresponsiveness. The results also showed that the administration of PPARgamma agonists or AdPPARgamma up-regulated PTEN expression in allergen-induced asthmatic lungs. This upregulation correlated with decreased PI3K activity as measured by reduced phosphorylation of Akt. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the asthma phenotype through regulation of PTEN expression.
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 PI3K. However, the effect of PI3K catalytic subunit p110delta on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110delta catalytic activity, has been identified. We have sough1t to investigate the role of PI3K-delta, more specifically in the increase of vascular permeability. This study has revealed that IC87114 reduces antigen-induced airway infiltration of inflammatory cells, secretion of Th2 cytokines in lungs, airway hyperresponsiveness, and vascular permeability. Moreover, we have found that inhibition of p110delta reduces OVA-induced upregulation of VEGF level. These results suggest that PI3K-delta inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice. These findings provide a crucial molecular mechanism for the potential role of PI3K-delta in asthma and other airway inflammatory disorders.
Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood. We used genetically mast cell-deficient WBB6F1-Kit^(W)/Kit^(W-υ)(W/W^(υ)) mice and the congenic normal WBB6F1(+/+) mouse model for allergic airway disease to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease, more specifically in vascular permeability. Our present study, with OVA-sensitized without adjuvant and OVA-challenged mice, revealed the following typical pathophysiologic features of allergic airway diseases: increased inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. However, levels of VEGF and plasma exudation in W/W^(υ) mice after OVA inhalation were significantly lower than levels in WBB6F1(+/+) mice. Moreover, mast cell-reconstituted W/W^(υ) mice restored vascular permeability and VEGF levels similar to those of the WBB6F1(+/+) mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1alpha(HIF-1alpha) activation through the PI3K-HIF-1alpha pathway in allergic airway disease. These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K-HIF-1alpha-VEGF axis(PHV axis).
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