Intracerebroventricular injection of leukotriene B4 attenuates antigen-induced asthmatic response via BLT1 receptor stimulating HPA-axis in sensitized rats.
BACKGROUND
Basic and clinical studies suggest that hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine-immune pathway that functionally regulates the chronic inflammatory disease including asthma. Our previous studies showed corresponding changes of cytokines and leukotriene B4 (LTB4) between brain and lung tissues in antigen-challenged asthmatic rats. Here, we investigated how the increased LTB4 level in brain interacts with HPA axis in regulating antigen-induced asthmatic response in sensitized rats.


METHODS
Ovalbumin-sensitized rats were challenged by inhalation of antigen. Rats received vehicle, LTB4 or U75302 (a selective LTB4 BLT1 receptor inhibitor) was given via intracerebroventricular injection (i.c.v) 30 min before challenge. Lung resistance (RL) and dynamic lung compliance (Cdyn) were measured before and after antigen challenge. Inflammatory response in lung tissue was assessed 24 h after challenge. Expression of CRH mRNA and protein in hypothalamus were evaluated by RT-PCR and Western Blot, and plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using the ELISA kits.


RESULTS
Antigen challenge decreased pulmonary function and induced airway inflammation, evoked HPA axis response in sensitized rats. Administration of LTB4 via i.c.v markedly attenuated airway contraction and inflammation. Meanwhile, LTB4 via i.c.v markedly increased CORT and ACTH level in plasma before antigen challenge, and followed by further increases in CORT and ACTH levels in plasma after antigen challenge in sensitized rats. Expression of CRH mRNA and protein in hypothalamus were also significantly increased by LTB4 via i.c.v in sensitized rats after antigen challenge. These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng), but not by BLT2 antagonist LY255283.


CONCLUSIONS
LTB4 administered via i.c.v down-regulates the airway contraction response and inflammation through activation of the HPA axis via its BLT1 receptor. This study expands our concept of the regulatory role of intracranial inflammatory mediators in inflammatory diseases including asthma. The favourable effects of LTB4 on the HPA axis may help to explain the phenomenon of self-relief after an asthmatic attack.
Zhang
Shui-Juan
SJ
Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical Science College of Zhejiang University, Hangzhou, China. zsjdxw@163.com
Deng
Yang-Mei
YM
Zhu
Yi-Liang
YL
Dong
Xin-Wei
XW
Jiang
Jun-Xia
JX
Xie
Qiang-Min
QM
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000403:Airway Resistance; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005233:Fatty Alcohols / Q000008:administration & dosage; D005260:Female; D006018:Glycols / Q000008:administration & dosage; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007031:Hypothalamus / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007276:Injections, Intraventricular; D007975:Leukotriene B4 / Q000008:administration & dosage / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008170:Lung Compliance; D008297:Male; D010047:Ovalbumin; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018102:Receptors, Leukotriene B4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005233:Fatty Alcohols; D006018:Glycols; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018102:Receptors, Leukotriene B4; C062137:U 75302; D007975:Leukotriene B4; D000324:Adrenocorticotropic Hormone; D010047:Ovalbumin; D003346:Corticotropin-Releasing Hormone
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