Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1alpha-VEGF axis.
BACKGROUND
Bronchial inflammation is usually accompanied by increased vascular permeability. Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. Vascular endothelial growth factor (VEGF) has been implicated to contribute to asthmatic tissue edema through its effect on vascular permeability. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood.


OBJECTIVE
An aim of the present study was to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease.


METHODS
We used genetically mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-v) (W/W(v)) mice and the congenic normal WBB6F(1)(+/+) 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.


RESULTS
Our present study, with ovalbumin (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(v) mice after OVA inhalation were significantly lower than levels in WBB6F(1)(+/+) mice. Moreover, mast cell-reconstituted W/W(v) mice restored vascular permeability and VEGF levels similar to those of the WBB6F(1)(+/+) mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) activation through the phosphatidylinositol 3-kinase (PI3K)-HIF-1alpha pathway in allergic airway disease.


CONCLUSIONS
These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K-HIF-1alpha-VEGF axis.
Lee
Kyung Sun
KS
Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea.
Kim
So Ri
SR
Park
Seoung Ju
SJ
Min
Kyung Hoon
KH
Lee
Ka Young
KY
Choe
Yeong Hun
YH
Park
Seung Yong
SY
Chai
Ok Hee
OH
Zhang
Xin
X
Song
Chang Ho
CH
Lee
Yong Chul
YC
D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000502:physiology*; D003720:Densitometry; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D015415:Biomarkers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases