Molecular imaging of nuclear factor-κB in bladder as a primary regulator of inflammatory response.

Abstract

Nuclear factor-κB activation is implicated in chronic inflammatory disorders and it is a key regulator of genes involved in the response to infection, inflammation and stress. Interstitial cystitis and painful bladder syndrome are common inflammatory disorders of the bladder characterized by frequent urination and bladder pain. The role of nuclear factor-κB activation in bladder inflammation is not well defined. Female transgenic nuclear factor-κB-luciferase Tag mice (The Jackson Laboratory, Bar Harbor, Maine) were used to perform serial, noninvasive in vivo and ex vivo molecular imaging of nuclear factor-κB activation in the whole body after administering arsenic trioxide (5 mg/kg), lipopolysaccharide (2 mg/kg) or cyclophosphamide (Sigma®) (200 mg/kg) to initiate acute transient bladder inflammation. Pretreatment with dexamethasone (Sigma) (10 mg/kg) was used to modulate cyclophosphamide induced nuclear factor-κB dependent luminescence in vivo. Treatment of nuclear factor-κB-luciferase Tag mice with chemicals increased luminescence in a time and organ specific manner in vivo and ex vivo. The highest levels of bladder nuclear factor-κB dependent luminescence were observed 4 hours after cyclophosphamide administration. Pretreatment with dexamethasone 1 hour before cyclophosphamide injection significantly down-regulated cyclophosphamide induced bladder nuclear factor-κB dependent luminescence, ameliorated the grossly evident pathological features of acute inflammation and decreased cellular immunostaining for nuclear factor-κB in the bladder. Nuclear factor-κB activity may have an important role in the pathophysiology of bladder inflammation. Nuclear factor-κB-luciferase mice can serve as a useful model in which to screen potential candidate drugs for cystitis associated with aberrant nuclear factor-κB activity. Such screening may significantly aid the development of therapeutic strategies to manage inflammatory bladder disorders.