Department of Internal Medicine, Chonbuk National University Medical School, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, Jeonbuk 561-180, South Korea.
Inflamm Res. 2012 Oct;61(10):1069-83. doi: 10.1007/s00011-012-0499-6. Epub 2012 Jun 13.
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.
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.
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.
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.
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.
职业性哮喘的特征是气道炎症和气道高反应性，同时伴有血管通透性增加。AMP 激活的蛋白激酶（AMPK）已被认为是一种调节炎症反应的新型信号分子。
我们旨在评估 AMPK 在职业性哮喘发病机制中的作用，并特别研究 AMPK 激活在调节血管通透性中的作用和分子机制。
我们在甲苯二异氰酸酯（TDI）诱导的哮喘小鼠模型中测试了 AMPK 激活剂 5-氨基咪唑-4-甲酰胺-1-β-D-核糖呋喃糖苷（AICAR）的作用机制和治疗潜力。
AICAR 可减轻 TDI 吸入引起的气道炎症和气道高反应性。此外，AICAR 治疗可显著降低 TDI 诱导的缺氧诱导因子（HIF）-1α、HIF-2α、血管内皮生长因子 A（VEGFA）和血浆渗出物水平的增加。我们的研究结果还表明，用 2-甲氧基雌二醇（2ME2）抑制 HIF-1α 和 HIF-2α 可显著降低 VEGFA 表达，而 VEGFA 活性抑制剂 CBO-P11 和 2ME2 可显著抑制 TDI 诱导的血管通透性、气道炎症细胞浸润和气道高反应性。此外，AICAR 可减少活性氧（ROS）的生成和丙二醛的水平，以及辅助性 T 细胞 2 型细胞因子（IL-4、IL-5 和 IL-13），同时该药物增强抗炎细胞因子 IL-10 的表达。
这些结果表明，AMPK 激活通过减少 HIF/VEGFA 通路介导的血管通透性，以及通过抑制 ROS 产生，从而改善气道炎症反应，可能是 TDI 诱导的哮喘和其他气道炎症性疾病的一种潜在治疗策略。
