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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 \u03bcg) after protamine sulfate (10\u2009mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200\u2009mg\/kg NAC (n\u2009=\u200910, IC\u2009+\u2009NAC group) or phosphate-buffered saline (n\u2009=\u200910, 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 <jats:italic>Tgfb2<\/jats:italic>, <jats:italic>Tgfb3<\/jats:italic>, <jats:italic>Smad2<\/jats:italic>, <jats:italic>Smad3<\/jats:italic>, <jats:italic>Cxcl10<\/jats:italic>, and <jats:italic>Card10<\/jats:italic>. 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