A prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, regulates vascular permeability by reducing vascular endothelial growth factor expression in asthma.
Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Oxidative stress plays critical roles in airway inflammation. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce increased vascular permeability are not clearly understood. We have used a murine model of asthma to evaluate the effect of l-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine that acts as an antioxidant, more specifically in the increase of vascular permeability. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of vascular endothelial growth factor (VEGF). Administration of OTC markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that at 72 h after ovalbumin inhalation, increased levels of hypoxia-inducible factor-1alpha (a transcriptional activator of VEGF) in nuclear protein extracts of lung tissues were decreased by the administration of OTC. These results indicate that OTC modulates vascular permeability by lowering VEGF expression.
Lee
Kyung Sun
KS
Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keumamdong, Jeonju, 561-712, South Korea.
Park
Hee Sun
HS
Park
Seoung Ju
SJ
Kim
So Ri
SR
Min
Kyung Hoon
KH
Jin
Sun Mi
SM
Park
Kwang-Hyun
KH
Kim
Uh-Hyun
UH
Kim
Chan Young
CY
Lee
Yong Chul
YC
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011355:Prodrugs / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid; D017382:Reactive Oxygen Species; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D008063:Thioctic Acid / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D011355:Prodrugs; D017382:Reactive Oxygen Species; D013844:Thiazoles; D053778:Thiazolidines; D042461:Vascular Endothelial Growth Factor A; D008063:Thioctic Acid; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid