Blockade of airway inflammation and hyperresponsiveness by inhibition of BLT2, a low-affinity leukotriene B4 receptor.
BLT2 is a low-affinity receptor for leukotriene B(4) (LTB(4)), a potent lipid mediator of inflammation generated from arachidonic acid via the 5-lipoxygenase pathway. Unlike BLT1, a high-affinity receptor for LTB(4), no clear physiological function has yet been identified for BLT2, especially with regard to the pathogenesis of asthma. The aim of this study was to investigate whether BLT2 plays a role in the pathogenesis of asthma. A murine model of allergic asthma was used to evaluate the role of BLT2 in ovalbumin-induced airway inflammation and airway hyperresponsiveness. The levels of BLT2 mRNA and its ligand, LTB(4), in the lung airway were highly elevated after ovalbumin challenge, and down-regulation of BLT2 with antisense BLT2 oligonucleotides markedly attenuated airway inflammation and airway hyperresponsiveness. Further analysis, aimed at identifying mediators downstream of BLT2, revealed that BLT2 activation led to elevation of reactive oxygen species and subsequent activation of NF-kappaB, thus inducing the expression of vascular cell adhesion molecule-1, which is known to be involved in eosinophil infiltration into the lung airway. Together, our results suggest that BLT2 plays a pivotal, mediatory role in the pathogenesis of asthma, acting through a "reactive oxygen species-NF-kappaB"-linked inflammatory signaling pathway.
Cho
Kyung-Jin
KJ
School of Life Sciences and Biotechnology, Korea University, 5-1 Anam dong, Sungbuk-gu, Seoul, 136-701, Korea.
Seo
Ji-Min
JM
Shin
YoungHyun
Y
Yoo
Min-Hyuk
MH
Park
Choon-Sik
CS
Lee
Shin-Hwa
SH
Chang
Yoon-Seok
YS
Cho
Sang-Heon
SH
Kim
Jae-Hong
JH
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000503:physiopathology; D001706:Biopsy; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin; D011014:Pneumonia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C513240:LTB4R protein, human; C412867:Ltb4r2 protein, mouse; D016328:NF-kappa B; D016372:RNA, Antisense; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D019010:Vascular Cell Adhesion Molecule-1; D010047:Ovalbumin; C063823:LY 255283