Estudo dos mediadores inflamatórios envolvidos na patogênese da cistite hemorrágica induzida por ciclofosfamida

Abstract

Cystitis were produced in Wistar male rats by ip administration of cyclophosphamide ( CP ) at doses of 50, 100 or 200 mg/kg. They were sacrificed 48 h later , their bladders were extirpated and evaluated for the differences in their wet and dry weights ( A weight ). Thereafter. depending on the experimental protocol, it was decided to treat the animais with a 100 mg/kg dose of CP and to kill them after 6, 12, 24, 48 or 72 hours. In these experiments, comparison of results was accomplished from the wet weights, vascular leakage as determined by Evans blue dye and light microscopy with Hematoxylin and Eosin stain. It was observed that the CP, at doses of 100 and 200 mg/kg significantly increased the A weight, but show no differentiation at these doses. Although the increase in vascular permeability attained to the maximum after 12 hours, the increase in vesical weight and the histopathological alterations such as edema, mucosal ulcerations and inflammatory cell infiltration were more intense after 48 hours of CP administration. The pretreatment of animais with dexamethasone ( phospholipase A2 inhibitor ), indomethacin ( cycloxygenase inhibitor ) and NDGA ( dual cyclo- lipoxygenase inhibitor ) blocked the CP-induced pathologic increase in vascular permeability and the wet weight of bladder; the permeability being more intense and occurred at smaller doses. From the kinetic study of CIC, it was observed that pretreatment of rats with compounds BN-52021 ( PAF antagonist ) and HOE-140 (bradykinin antagonist ) produced much early blockade of vascular permeability and subsequently the increase in vesical weight, the former being more significant than the latter. The mastocyte degranulation by chronic treatment of rats with compound 48/80, was efficient to reduce significantly the pathologic vascular permeability but produced no considerable alterations in the vesical weight. However, detectable reductions of edema and inflammatory cell exsudate was observed when specimens were examined under light microscopy. The utilization of L-NAME, a inhibitor of NO synthetase revealed the involvement of NO in the pathogenesis of CIC as indicated by its ability to decrease significantly the CP-induced increase in vascular permeability and vesical wet weight( after 48 h ). In addition, the inhibitory effect of L-NAME on vascular permeability was found to be reversed by L- arginine. the precursor of NO synthesis in a dose dependent manner but not by D-arginine at similar dosage.