Leukotriene B4, administered via intracerebroventricular injection, attenuates the antigen-induced asthmatic response in sensitized guinea pigs.
BACKGROUND
Despite intensive studies focused on the pathophysiology of asthmatic inflammation, little is known about how cross-talk between neuroendocrine and immune systems regulates the inflammatory response during an asthmatic attack. We recently showed corresponding changes of cytokines and leukotriene B4 (LTB4) in brain and lung tissues of antigen-challenged asthmatic rats. Here, we investigated how LTB4 interacts with the neuroendocrine-immune system in regulating antigen-induced asthmatic responses in sensitized guinea pigs.


METHODS
Ovalbumin-sensitized guinea pigs were challenged by inhalation of antigen. Vehicle, LTB4 or U75302 (a selective LTB4 BLT1 receptor inhibitor) was given via intracerebroventricular injection (i.c.v.) 30 min before challenge. Airway contraction response was evaluated using Penh values before and after antigen challenge. The inflammatory response in lung tissue was evaluated 24 h after challenge. The LTB4 content of lung and brain homogenate preparations was detected by reversed phase high-performance liquid chromatography (RP-HPLC). Plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using ELISA kits.


RESULTS
Antigen challenge impaired pulmonary function and increased inflammatory cell infiltration in lung tissue. These responses could be significantly suppressed by LTB4, 30 ng i.c.v., in ovalbumin-sensitized guinea pigs. LTB4 content of lung and brain homogenates from antigen-challenged guinea pigs was significantly increased. In addition, administration of LTB4 via i.c.v. markedly increased CORT and ACTH level in plasma before antigen challenge, and there were further increases in CORT and ACTH levels in plasma after antigen challenge. U75302, 100 ng i.c.v., completely blocked the effects of LTB4. In addition, U75302, 100 ng via i.c.v. injection, markedly decreased LTB4 content in lung homogenates, but not in brain homogenates.


CONCLUSIONS
Increased LTB4 levels in brain during asthmatic attacks down-regulates airway contraction response and inflammation through the BLT1 receptor. Stimulation of the hypothalamic-pituitary-adrenal axis by LTB4 may result in an increase in systemic glucocorticoids which, in turn, would feed back to suppress the asthmatic response.
Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical Science College of Zhejiang University, Hangzhou, China.
Yi-Liang
YL
Zhu
Shui-Jun
SJ
Zhang
Yang-Mei
YM
Deng
Xin-Wei
XW
Dong
Jun-Xia
JX
Jiang
Qiang-Min
QM
Xie
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid; D056148:Chromatography, Reverse-Phase / Q000379:methods; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005233:Fatty Alcohols / Q000494:pharmacology; D006018:Glycols / Q000494:pharmacology; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000097:blood; D007276:Injections, Intraventricular / Q000379:methods; D020300:Intracranial Hemorrhages / Q000139:chemically induced; D007975:Leukotriene B4 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D010047:Ovalbumin; D013997:Time Factors
D005233:Fatty Alcohols; D006018:Glycols; C062137:U 75302; D007975:Leukotriene B4; D000324:Adrenocorticotropic Hormone; D010047:Ovalbumin; D006854:Hydrocortisone