Specialized proresolution mediators in the bladder: annexin-A1 normalizes inflammation and bladder dysfunction during...

Area of Science:

• Urology
• Inflammation Research
• Pharmacology

Background:

• Bladder outlet obstruction (BOO), often due to benign prostatic hyperplasia, affects most men and involves significant bladder inflammation.
• While inflammation initiation via NLRP3 inflammasome is understood, the resolution of bladder inflammation remains unstudied.
• Specialized proresolving mediators (SPMs) are key to inflammation resolution, acting through specific receptors.

Purpose of the Study:

• To investigate the presence and role of SPM receptors and the annexin-A1 resolution system in the bladder during BOO.
• To evaluate the therapeutic potential of targeting the annexin-A1 pathway for BOO-related bladder dysfunction and inflammation.
• To establish a foundation for 'resolution pharmacology' in treating bladder inflammation.

Main Methods:

• Immunocytochemistry was used to detect SPM receptors in control and BOO rat bladders.
• The peptide mimetic Ac2-26, targeting the annexin-A1 system, was administered to BOO rats.
• NLR family pyrin domain containing 3 (NLRP3) activation, inflammation (Evans blue dye extravasation), and bladder function (urodynamics) were assessed.

Main Results:

• Six of seven known SPM receptors were identified in rat bladders, primarily in urothelia and smooth muscle.
• Ac2-26 treatment blocked NLRP3 activation, reduced BOO-induced inflammation, and normalized bladder function.
• Ac2-26 significantly accelerated functional recovery following surgical deobstruction.

Conclusions:

• The rat bladder possesses functional proresolving pathways, including the annexin-A1 system.
• Modulating the annexin-A1 pathway with Ac2-26 effectively alleviates BOO-induced inflammation and dysfunction.
• This study introduces 'resolution pharmacology' as a novel approach for managing bladder inflammation and improving recovery.