Abstract | BACKGROUND: RESULTS:
Disulfide HMGB1 elicited abdominal mechanical hypersensitivity 24 hours after intravesical (5, 10, 20 μg/150 μl) instillation. In contrast, all- thiol HMGB1 did not produce abdominal mechanical hypersensitivity in any of the doses tested (1, 2, 5, 10, 20 μg/150 μl). Both HMGB1 redox forms caused micturition changes only at the highest dose tested (20 μg/150 μl) while eliciting mild bladder edema and reactive changes at all doses. We subsequently tested whether the effects of intravesical disulfide HMGB1 (10 μg/150 μl; a dose that did not produce inflammation) were prevented by systemic (i.p.) or local ( intravesical) administration of either a TLR4 antagonist (TAK-242) or a RAGE antagonist (FPS-ZM1). Systemic administration of either TAK-242 (3 mg/kg) or FPS-ZM1 (10 mg/kg) prevented HMGB1 induced abdominal mechanical hypersensitivity while only intravesical TLR4 antagonist pretreatment (1.5 mg/ml; not RAGE) had this effect. CONCLUSIONS: The disulfide form of HMGB1 mediates bladder pain directly (not secondary to inflammation or injury) through activation of TLR4 receptors in the bladder. Thus, TLR4 receptors are a specific local target for bladder pain.
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Authors | Fei Ma, Dimitrios E Kouzoukas, Katherine L Meyer-Siegler, Karin N Westlund, David E Hunt, Pedro L Vera |
Journal | BMC physiology
(BMC Physiol)
Vol. 17
Issue 1
Pg. 6
(May 25 2017)
ISSN: 1472-6793 [Electronic] England |
PMID | 28545586
(Publication Type: Journal Article)
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Chemical References |
- Disulfides
- HMGB1 Protein
- Receptor for Advanced Glycation End Products
- Toll-Like Receptor 4
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Topics |
- Abdominal Pain
(chemically induced, etiology, metabolism)
- Animals
- Disulfides
(administration & dosage, metabolism)
- Female
- HMGB1 Protein
(administration & dosage, metabolism)
- Mice, Inbred C57BL
- Receptor for Advanced Glycation End Products
(metabolism)
- Toll-Like Receptor 4
(metabolism)
- Urinary Bladder
(metabolism, pathology)
- Urination
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