Participation of TNF-alpha and IL-1 in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis.
The involvement of cytokines TNF-alpha and IL-1 has been investigated in a mouse model of cyclophosphamide (CYP)-induced hemorrhagic cystitis. Male Swiss mice (25-30 g) received CYP in a single i.p. dose of 100, 200 or 400 mg/kg and were sacrificed 6, 12, 24, 48 and 72 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BW) and plasma protein extravasation (PPE, measured by the Evans blue leakage technique). CYP treatment induced a marked increase in BW and in PPE, which was significant within 6 h and reached maximal values within 12 h (BW, 118%, P < 0.05; N = 11; and PPE, 824%, P < 0.05; N = 11), continuing to be significant until 48 h. Pretreatment of animals with whole anti-TNF-alpha serum (25 or 50 microliters diluted in 500 microliters 0.9% saline, i.p., 30 min earlier) caused a significant reduction in the CYP-induced BW increase in 6-h and 12-h cystitis (82% and 91%, respectively, P < 0.05; N = 6) and in the CYP-induced PPE increase (60% and 52%, respectively, P < 0.05; N = 6). In addition, the administration of whole anti-IL- 1 beta serum at the same dose promoted a significant blockage of the CYP-induced increase in BW (47%, P < 0.05; N = 6) and PPE increase (41%, P < 0.05; N = 6) only in 12-h cystitis. The control serum did not modify the effect of CYP. Histopathologic analysis of the bladders from anti-TNF-alpha- and anti-IL-1 beta-pretreated groups revealed a significant reduction of the following parameters compared to the control groups: mucosal erosion, hemorrhage, edema, leukocyte migration, fibrin deposition and ulcerations. These results suggests that TNF-alpha and IL-1 are crucial mediators involved in inflammatory events occurring in CYP-induced hemorrhagic cystitis.
Gomes
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TN
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil.
Santos
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CC
Souza-Filho
M V
MV
Cunha
F Q
FQ
Ribeiro
R A
RA
D000477:Alkylating Agents / Q000008:administration & dosage*; D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003556:Cystitis / Q000139:chemically induced*; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000477:Alkylating Agents; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide