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Intracerebroventricular injection of leukotriene B4 attenuates antigen-induced asthmatic response via BLT1 receptor stimulating HPA-axis in sensitized rats.

Zhang SJ, Deng YM, Zhu YL, Dong XW, Jiang JX, Xie QM - Respir. Res. (2010)

Bottom Line: Administration of LTB4 via i.c.v markedly attenuated airway contraction and inflammation.These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng), but not by BLT2 antagonist LY255283.The favourable effects of LTB4 on the HPA axis may help to explain the phenomenon of self-relief after an asthmatic attack.

View Article: PubMed Central - HTML - PubMed

Affiliation: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical Science College of Zhejiang University, Hangzhou, China. zsjdxw@163.com

ABSTRACT

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.

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LTB4 via i.c.v attenuates the antigen-induced increases of inflammatory cell in the BALF, and U75302 blocks the inhibitory effect of LTB4. Total inflammatory cells in BALF were counted, and cell classification was performed on a minimum of 200 cells to classify monocytes (lymphocytes and macrophages) and polymorphonuclear cells (eosinophils and neutrophils) 24 hr after the final antigen challenge. Data are expressed as the mean ± S.D. of vehicle-sham (n = 8), vehicle-OVA (n = 10), LTB4-OVA (n = 9), U75302-OVA (n = 9) and U75302-LTB4-OVA (n = 10). ##P < 0.01 vs the vehicle-sham group;**P < 0.01 vs the vehicle-OVA group; ††P < 0.01 vs the LTB4-OVA group.
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Figure 2: LTB4 via i.c.v attenuates the antigen-induced increases of inflammatory cell in the BALF, and U75302 blocks the inhibitory effect of LTB4. Total inflammatory cells in BALF were counted, and cell classification was performed on a minimum of 200 cells to classify monocytes (lymphocytes and macrophages) and polymorphonuclear cells (eosinophils and neutrophils) 24 hr after the final antigen challenge. Data are expressed as the mean ± S.D. of vehicle-sham (n = 8), vehicle-OVA (n = 10), LTB4-OVA (n = 9), U75302-OVA (n = 9) and U75302-LTB4-OVA (n = 10). ##P < 0.01 vs the vehicle-sham group;**P < 0.01 vs the vehicle-OVA group; ††P < 0.01 vs the LTB4-OVA group.

Mentions: To further study the effect of LTB4 i.c.v on antigen-induced airway inflammation, we evaluated the inflammatory cell infiltration in OVA sensitized rats. 24 h after the final OVA challenge, inflammatory cells including polymorphonuclear (PMN) cells (eosinophils and neutrophils) and monocytes (lymphocytes and macrophages) in BALF were counted. The total inflammatory cells in BALF of vehicle-OVA rats was 6-fold greater than that in vehicle-sham rats. LTB4 10 ng (i.c.v) significantly decreased the total inflammatory cells in BALF. Classification of these inflammatory cells showed that in vehicle-OVA rats, numbers of PMN and monocytes in the BALF increased 11.6 and 4.2 fold, respectively, as compared with those observed in vehicle-sham rats (Fig. 2). LTB4 10 ng (i.c.v) significantly decreased PMN in BALF. U75302 10 ng itself (i.c.v) did not alter the infiltration of inflammatory cells in airways, but almost fully blocked inhibitory effects of LTB4 on the inflammatory cell numbers in BALF (P < 0.01).


Intracerebroventricular injection of leukotriene B4 attenuates antigen-induced asthmatic response via BLT1 receptor stimulating HPA-axis in sensitized rats.

Zhang SJ, Deng YM, Zhu YL, Dong XW, Jiang JX, Xie QM - Respir. Res. (2010)

LTB4 via i.c.v attenuates the antigen-induced increases of inflammatory cell in the BALF, and U75302 blocks the inhibitory effect of LTB4. Total inflammatory cells in BALF were counted, and cell classification was performed on a minimum of 200 cells to classify monocytes (lymphocytes and macrophages) and polymorphonuclear cells (eosinophils and neutrophils) 24 hr after the final antigen challenge. Data are expressed as the mean ± S.D. of vehicle-sham (n = 8), vehicle-OVA (n = 10), LTB4-OVA (n = 9), U75302-OVA (n = 9) and U75302-LTB4-OVA (n = 10). ##P < 0.01 vs the vehicle-sham group;**P < 0.01 vs the vehicle-OVA group; ††P < 0.01 vs the LTB4-OVA group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865448&req=5

Figure 2: LTB4 via i.c.v attenuates the antigen-induced increases of inflammatory cell in the BALF, and U75302 blocks the inhibitory effect of LTB4. Total inflammatory cells in BALF were counted, and cell classification was performed on a minimum of 200 cells to classify monocytes (lymphocytes and macrophages) and polymorphonuclear cells (eosinophils and neutrophils) 24 hr after the final antigen challenge. Data are expressed as the mean ± S.D. of vehicle-sham (n = 8), vehicle-OVA (n = 10), LTB4-OVA (n = 9), U75302-OVA (n = 9) and U75302-LTB4-OVA (n = 10). ##P < 0.01 vs the vehicle-sham group;**P < 0.01 vs the vehicle-OVA group; ††P < 0.01 vs the LTB4-OVA group.
Mentions: To further study the effect of LTB4 i.c.v on antigen-induced airway inflammation, we evaluated the inflammatory cell infiltration in OVA sensitized rats. 24 h after the final OVA challenge, inflammatory cells including polymorphonuclear (PMN) cells (eosinophils and neutrophils) and monocytes (lymphocytes and macrophages) in BALF were counted. The total inflammatory cells in BALF of vehicle-OVA rats was 6-fold greater than that in vehicle-sham rats. LTB4 10 ng (i.c.v) significantly decreased the total inflammatory cells in BALF. Classification of these inflammatory cells showed that in vehicle-OVA rats, numbers of PMN and monocytes in the BALF increased 11.6 and 4.2 fold, respectively, as compared with those observed in vehicle-sham rats (Fig. 2). LTB4 10 ng (i.c.v) significantly decreased PMN in BALF. U75302 10 ng itself (i.c.v) did not alter the infiltration of inflammatory cells in airways, but almost fully blocked inhibitory effects of LTB4 on the inflammatory cell numbers in BALF (P < 0.01).

Bottom Line: Administration of LTB4 via i.c.v markedly attenuated airway contraction and inflammation.These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng), but not by BLT2 antagonist LY255283.The favourable effects of LTB4 on the HPA axis may help to explain the phenomenon of self-relief after an asthmatic attack.

View Article: PubMed Central - HTML - PubMed

Affiliation: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical Science College of Zhejiang University, Hangzhou, China. zsjdxw@163.com

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus