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Effects of 7,8-dihydro-8-oxo-deoxyguanosine on antigen challenge in ovalbumin-sensitized mice may be mediated by suppression of Rac.
- Source :
- British Journal of Pharmacology; Dec2009, Vol. 158 Issue 7, p1743-1752, 10p
- Publication Year :
- 2009
-
Abstract
- <bold>Background and Purpose: </bold>Earlier we reported that 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG), an oxidatively modified guanine nucleoside, exerted anti-inflammatory activity through inactivation of the GTP binding protein, Rac. In the present study, the effects of 8-oxo-dG were investigated on responses to antigen challenge in sensitized mice, as Rac is also involved at several steps of the immune process including antigen-induced release of mediators from mast cells.<bold>Experimental Approach: </bold>Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG during the challenge. Effects of 8-oxo-dG were assessed by measuring lung function, cells and cytokines in broncho-alveolar lavage fluid (BALF) and serum levels of antigen-specific IgE. Rac activity in BALF cells was also measured.<bold>Key Results: </bold>8-oxo-dG inhibited the increased airway resistance and decreased lung compliance of sensitized and challenged mice to the levels of non-sensitized control mice and lowered the increased leukocytes particularly, eosinophils, in BALF. Furthermore, 8-oxo-dG suppressed allergy-associated immune responses, such as raised anti- ovalbumin IgE antibody in serum, increased expression of CD40 and CD40 ligand in lung, increased interleukin-4, -5, -13, interferon-gamma and tumour necrosis factor-alpha in BALF and mRNA levels of these cytokines in BALF cells, dose-dependently. The corresponding purine, 8-oxo-guanine, showed no effects in the same experiments. Finally, 8-oxo-dG, but not 8-oxo-guanine, inhibited the increased Rac activity in sensitized and challenged mice.<bold>Conclusion and Implications: </bold>8-Oxo-dG had anti-allergic actions that might be mediated by Rac inactivation. This compound merits further evaluation of its therapeutic potential in allergic asthma. [ABSTRACT FROM AUTHOR]
- Subjects :
- ANTIGENS
ALBUMINS
LABORATORY mice
G proteins
ANTI-inflammatory agents
ASTHMA treatment
PROTEIN metabolism
DRUG therapy for asthma
ANIMAL experimentation
ANTIHISTAMINES
ASTHMA
BODY fluids
COMPARATIVE studies
CYTOKINES
DOSE-effect relationship in pharmacology
IMMUNOGLOBULINS
MAST cells
RESEARCH methodology
MEDICAL cooperation
MICE
ORAL drug administration
PURINES
RESEARCH
PULMONARY function tests
EVALUATION research
DEOXYRIBONUCLEOSIDES
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 158
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 64862833
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00436.x