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01.10.2012 | Original Research Paper

AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma

verfasst von: Seoung Ju Park, Kyung Sun Lee, So Ri Kim, Han Jung Chae, Wan Hee Yoo, Dong Im Kim, Myoung Shin Jeon, Yong Chul Lee

Erschienen in: Inflammation Research | Ausgabe 10/2012

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Abstract

Background

Occupational asthma is characterized by airway inflammation and hyperresponsiveness associated with increased vascular permeability. AMP-activated protein kinase (AMPK) has been suggested to be a novel signaling molecule modulating inflammatory responses.

Objective

We sought to evaluate the involvement of AMPK in pathogenesis of occupational asthma and more specifically investigate the effect and molecular mechanisms of AMPK activation in regulating vascular permeability.

Methods

The mechanisms of action and therapeutic potential of an AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) were tested in a murine model of toluene diisocyanate (TDI)-induced asthma.

Results

AICAR attenuated airway inflammation and hyperresponsiveness increased by TDI inhalation. Moreover, TDI-induced increases in levels of hypoxia-inducible factor (HIF)-1α, HIF-2α, vascular endothelial growth factor A (VEGFA), and plasma exudation were substantially decreased by treatment with AICAR. Our results also showed that VEGFA expression was remarkably reduced by inhibition of HIF-1α and HIF-2α with 2-methoxyestradiol (2ME2) and that an inhibitor of VEGFA activity, CBO-P11 as well as 2ME2 significantly suppressed vascular permeability, airway infiltration of inflammatory cells, and airway hyperresponsiveness induced by TDI. In addition, AICAR reduced reactive oxygen species (ROS) generation and levels of malondialdehyde and T-helper type 2 cytokines (IL-4, IL-5, and IL-13), while this agent enhanced expression of an anti-inflammatory cytokine, IL-10.

Conclusions

These results suggest that AMPK activation ameliorates airway inflammatory responses by reducing vascular permeability via HIF/VEGFA pathway as well as by inhibiting ROS production and thus may be a possible therapeutic strategy for TDI-induced asthma and other airway inflammatory diseases.

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Titel: AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma
verfasst von: Seoung Ju Park
Kyung Sun Lee
So Ri Kim
Han Jung Chae
Wan Hee Yoo
Dong Im Kim
Myoung Shin Jeon
Yong Chul Lee
Publikationsdatum: 01.10.2012
Verlag: SP Birkhäuser Verlag Basel
Erschienen in: Inflammation Research / Ausgabe 10/2012
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-012-0499-6

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