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

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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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Abbreviations

Ab:

Antibody

AHR:

Airway hyperresponsiveness

AICAR:

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside

AMPK:

AMP-activated protein kinase

BAL:

Bronchoalveolar lavage

CMC:

Carboxymethylcellulose

DCF:

Dichlorofluorescein

DMSO:

Dimethylsulfoxide

EBD:

Evans blue dye

HIF:

Hypoxia-inducible factor

MDA:

Malondialdehyde

2ME2:

2-Methoxyestradiol

p-AMPK:

Phosphorylated AMPK

PBS:

Phosphate buffered saline

ROS:

Reactive oxygen species

Rrs:

Respiratory system resistance

TDI:

Toluene diisocyanate

Th2:

T-helper type 2

Treg:

Regulatory T

VEGFA:

Vascular endothelial growth factor A

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Acknowledgments

We thank Professor Mie-Jae Im for critical reading of the manuscript. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A084144) and by the Korea Research Foundation Grant funded by the Korean Government (KRF-2008-313-E00249).

Conflict of interest

The authors declared that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Chonbuk National University Medical School, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, Jeonbuk, 561-180, South Korea

    Seoung Ju Park, Kyung Sun Lee, So Ri Kim, Wan Hee Yoo, Dong Im Kim, Myoung Shin Jeon & Yong Chul Lee

  2. Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea

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

  3. Department of Pharmacology, Chonbuk National University Medical School, Jeonju, South Korea

    Han Jung Chae

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  1. Seoung Ju Park
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Correspondence to Yong Chul Lee.

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Responsible Editor: Andras Falus.

S. J. Park and K. S. Lee contributed equally to this work.

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Park, S.J., Lee, K.S., Kim, S.R. et al. AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma. Inflamm. Res. 61, 1069–1083 (2012). https://doi.org/10.1007/s00011-012-0499-6

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  • DOI: https://doi.org/10.1007/s00011-012-0499-6

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