Blockade of airway hyperresponsiveness and inflammation in a murine model of asthma by a prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid.
Oxidative stress plays an important role in the pathogenesis of bronchial asthma. An excess production of reactive oxygen species (ROS) and defective endogenous antioxidant defense mechanisms may be present in asthma. Reduced glutathione (GSH) is one of the most important reducing agents against oxidant free radicals. A reducing agent, L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, increases intracellular GSH. We have used a mouse model for asthma to determine effects of OTC on allergen-induced bronchial inflammation and airway hyper-responsiveness. The administration of OTC reduced bronchial inflammation and airway hyper-responsiveness. ROS generation in bronchoalveolar lavage fluids was increased by ovalbumin (OVA) inhalation, but this increase was diminished by administration of OTC. The increased IL-4, IL-5, IL-13, and eosinophil cationic protein levels in lungs after OVA inhalation were significantly reduced by the administration of OTC. In addition, the increased expression of ICAM-1, VCAM-1, RANTES, and eotaxin in lungs after OVA inhalation was significantly reduced by the administration of OTC. We also showed that the increased NF-kappaB levels in nuclear protein extracts of lung tissues at 72 h after OVA inhalation were decreased by the administration of OTC. These findings suggest that OTC may reduce airway inflammation and hyper-responsiveness through regulation of NF-kappaB activity.
Lee
Yong Chul
YC
Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, South Korea. leeyc@chonbuk.ac.kr
Lee
Kyung Sun
KS
Park
Seoung Ju
SJ
Park
Hee Sun
HS
Lim
Jae Sung
JS
Park
Kwang-Hyun
KH
Im
Mie-Jae
MJ
Choi
Il-Whan
IW
Lee
Hern-Ku
HK
Kim
Uh-Hyun
UH
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001991:Bronchitis / Q000188:drug therapy / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D047150:Eosinophil Cationic Protein / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011355:Prodrugs / Q000627:therapeutic use*; D011761:Pyrrolidonecarboxylic Acid; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines
D015815:Cell Adhesion Molecules; D018925:Chemokines; D007378:Interleukins; D016328:NF-kappa B; D011355:Prodrugs; D017382:Reactive Oxygen Species; D013844:Thiazoles; D053778:Thiazolidines; D010047:Ovalbumin; D047150:Eosinophil Cationic Protein; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid