Deletion or pharmacological blockade of TLR4 confers protection against cyclophosphamide-induced mouse cystitis

Author(s)

de Oliveira, Mariana G. ^[1] ; Monica, Fabiola Z. ^[1] ; Calmasini, Fabiano B. ^[1] ; Alexandre, Eduardo C. ^[1] ; Tavares, Edith B. G. ^[1] ; Soares, Antonio G. ^[2] ; Costa, Soraia K. P. ^[2] ; Antunes, Edson ^[1]

Affiliation

^[1] Univ Estadual Campinas, Fac Med Sci, Dept Pharmacol, BR-13084971 Campinas, SP - Brazil

^[2] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 315, n. 3, p. F460-F468, SEP 2018.
• Web of Science Citations: 4

Abstract

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. We investigate the role of toll-like receptor 4 (TLR4) on voiding dysfunction and inflammation in the cyclophosphamide (CYP)-induced mouse cystitis. Male C57BL/6 {[}wild-type,(WT)] and/or TLR4 knockout (TLR4(-/-)) mice were treated with an injection of CYP (300 mg/kg, 24 h) or saline (10 ml/kg). The pharmacological blockade of the TLR4 by resatorvid (10 mg/kg) was also performed 1 h prior CYP-injection in WT mice. Urodynamic profiles were assessed by voiding stain on filter paper and filling cystometry. Contractile responses to carbachol were measured in isolated bladders. In CYP-exposed WT mice, mRNA for TLR4, myeloid differentiation primary response 88, and TIR-domain-containing adapter-inducing interferon-beta increased by 45%, 72%. and 38%, respectively (P < 0.05). In free-moving mice, CYP-exposed mice exhibited a higher number of urinary spots and smaller urinary volumes. Increases of micturition frequency and nonvoiding contractions. concomitant with decreases of intercontraction intervals and capacity, were observed in the filling cystometry of WT mice (P < 0.05). Carbachol-induced bladder contractions were significantly reduced in the CYP group, which was paralleled by reduced mRNA for M2 and M3 muscarinic receptors. These functional and molecular alterations induced by CYP were prevented in TLR4(-/-) and resatorvid-treated mice. Additionally, the increased levels of inflammatory markers induced by CYP exposure, myeloperoxidase activity, interleukin-6, and tumor necrosis factor-alpha were significantly reduced by resatorvid treatment. Our findings reveal a central role for the TLR4 signaling pathway in initiating CYP-induced bladder dysfunction and inflammation and thus emphasize that TLR4 receptor blockade may have clinical value for IC/BPS treatment. (AU)

• FAPESP's process: 17/15175-1 - Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate
• Grantee: Edson Antunes
• Support Opportunities: Research Projects - Thematic Grants