Abstract
Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 μg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.
Highlights
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic condition that is usually associated with pain, increased urinary frequency, nocturia, and urgency without evidence of urinary tract infection and other identifiable causes[1]
We examined the levels of p-Smad[2] protein, a surrogate marker of activated transforming growth factor-β (TGF-β) signaling that plays a key role in tissue fibrosis[23]
We developed a cystitis rat model with chronic inflammation and prominent fibrosis by increasing the frequency of intravesical LPS instillation
Summary
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic condition that is usually associated with pain, increased urinary frequency, nocturia, and urgency without evidence of urinary tract infection and other identifiable causes[1]. In bladder tissue from patients with IC/BPS, non-Hunner-type IC has been shown to cause fibrosis and mast cell infiltration, whereas Hunner-type IC caused urothelium denudation and inflammation[12]. Lipopolysaccharide (LPS) once weekly for 5 weeks in our previous study[17] This previous model showed prominent urothelial denudation and inflammation like Hunner-type IC; meaningful fibrotic changes were not induced. N-acetylcysteine (NAC), a precursor of glutathione, is an antioxidant that directly scavenges oxygen free radicals and alters the structure of transforming growth factor-β (TGF-β) to attenuate pro-fibrotic activities[18] It is clinically used as a mucolytic drug, an agent for preventing lung fibrosis in idiopathic pulmonary fibrosis, and a hepatoprotective agent[19]. NAC has been found to be effective against neutrophilic airway inflammation in patients with cystic fibrosis[20] and as a neuroprotective agent in a brain injury animal model[21]
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