AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma.
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.
Department of Internal Medicine, Chonbuk National University Medical School, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, Jeonbuk 561-180, South Korea. sjp@jbnu.ac.kr
Seoung Ju
SJ
Park
Kyung Sun
KS
Lee
So Ri
SR
Kim
Han Jung
HJ
Chae
Wan Hee
WH
Yoo
Dong Im
DI
Kim
Myoung Shin
MS
Jeon
Yong Chul
YC
Lee
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D014051:Toluene 2,4-Diisocyanate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D014051:Toluene 2,4-Diisocyanate; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse; C031143:AICA ribonucleotide