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TGF-\u03b21 is produced in latent form and requires dissociation from the latency-associated peptide (LAP) to act as primary anti-inflammatory and pro-healing modulator following tissue injury in the upper urinary tract. Since the role of TGF-\u03b21 in lower urinary tract inflammation is currently unknown, and since gender-based differences exist in the setting of interstitial cystitis (IC), the present study examined the relationship between TGF-\u03b21 and iNOS\/NO in the pathogenesis of CYP-induced cystitis in both male and female rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sprague-Dawley rats, 4 months of age, of either gender were given 150 mg\/kg CYP intraperitoneally. Urinary and bladder tissue TGF-\u03b21 and NO reaction products (NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>) were quantified as a function of time following CYP. Expression of active and latent TGF-\u03b21 as well as iNOS in harvested bladder tissue was assessed by immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Female rats had significantly higher levels of NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>in urine even at baseline as compared to male rats (p &lt; 0.001), whereas there was no gender based significant difference in urine levels of active or latent TGF-\u03b21 prior to CYP injection. Inflammatory and cytotoxic changes were induced by CYP in the bladder of both sexes that were accompanied by differences in the urine levels of NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>and TGF-\u03b21. Male rats responded to CYP with significantly lower levels of NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>and significantly higher levels of TGF-\u03b21 in urine (p &lt; 0.05) as compared to females at all time points after CYP. The urine levels of NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>after CYP were inversely correlated to latent and active TGF-\u03b21 (Pearson coefficient of -0.72 and -0.69 in females and -0.89 and -0.76 in males, respectively; p &lt; 0.01). Bladder tissue of male rats exhibited significantly higher levels of both latent and active TGF-\u03b21 (p &lt; 0.01) compared to female rats after CYP. TGF-\u03b21 and iNOS protein was mostly localized in the urothelium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results of this study suggest that there exists an inverse relationship between the expression of TGF-\u03b21 and iNOS\/NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>in CYP-inflamed bladder. The gender of the animal appears to magnify the differences in urine levels of TGF-\u03b21 and NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>in this inflammatory setting. These results support the hypothesis that TGF-\u03b21 can suppress iNOS expression associated with bladder inflammation and reduce systemic levels of NO<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>\/NO<jats:sub>3<\/jats:sub><jats:sup>-<\/jats:sup>, and further suggest that this feature of TGF-\u03b21 can be harnessed for therapy and diagnosis of interstitial cystitis.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1476-9255-6-23","type":"journal-article","created":{"date-parts":[[2009,8,19]],"date-time":"2009-08-19T18:14:15Z","timestamp":1250705655000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Gender-based reciprocal expression of transforming growth factor-\u03b21 and the inducible nitric oxide synthase in a rat model of cyclophosphamide-induced cystitis"],"prefix":"10.1186","volume":"6","author":[{"given":"Pradeep","family":"Tyagi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich","family":"Witteemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Barclay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A","family":"Loughran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoram","family":"Vodovotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2009,8,19]]},"reference":[{"issue":"11","key":"107_CR1","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1007\/s00296-008-0581-0","volume":"28","author":"RQ Hu","year":"2008","unstructured":"Hu RQ, Mehter H, Nadasdy T, Satoskar A, Spetie DN, Rovin BH, Hebert L: Severe hemorrhagic cystitis associated with prolonged oral cyclophosphamide therapy: case report and literature review. 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