Sub-noxious Intravesical Lipopolysaccharide Triggers Bladder Inflammation and Symptom Onset in A Transgenic Autoimmune Cystitis Model: A MAPP Network Animal Study

Abstract

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) can potentially develop symptom flares after exposure to minor bladder irritants such as subclinical bacterial infection. To reproduce this symptom onset, we intravesically instilled a sub-noxious dose of uropathogenic E. coli component lipopolysaccharide (LPS) in young URO-OVA/OT-I mice, a transgenic autoimmune cystitis model that spontaneously develops bladder inflammation at ≥10 weeks of age. Female URO-OVA/OT-I mice (6-weeks old) were treated intravesically with phosphate-buffered saline (PBS) or PBS containing a sub-noxious dose (1 μg) of LPS. Mice were evaluated for bladder inflammation, pelvic pain, and voiding dysfunction at days 1, 7, and 14 post-treatment. Mice treated with LPS but not PBS developed early bladder inflammation with increased macrophage infiltration. Accordingly, the inflamed bladders expressed increased levels of mRNA for proinflammatory cytokines (IL-1β and IL-6) and pain mediator (substance P precursor). In addition, LPS-treated mice exhibited pelvic pain and voiding dysfunction such as increased urinary frequency and reduced bladder capacity. These functional changes sustained up to day 14 tested. Our results indicate that a single sub-noxious dose of intravesical LPS triggers early bladder inflammation and symptom onset in URO-OVA/OT-I mice, providing a useful model for IC/BPS symptom flare study.