Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced by ifosfamide

Dornelas-Filho, Amílcar Figueiredo; Pereira, Venúcia Bruna Magalhães; Wong, Deysi Viviana Tenazoa; Nobre, Lívia Maria Soares; Melo, Anielle Torres de; Silva, Camila Meirelles Souza; Wanderley, Carlos W.; Nour, Mariana Lima; Araújo, Lis Caetano Nóbrega Costa; Silva, Renan Oliveira; Pinto, Francisco Maxwell Martins; Bingana, Rudy D.; Souza, Marcellus H.; Alencar, Nylane Maria Nunes de; Silva, Paulo Goberlânio de Barros; Alves, Ana Paula Negreiros Nunes; Almeida, Paulo Roberto Carvalho de; Cunha, Fernando; Lima-Júnior, Roberto César Pereira

doi:10.1016/j.intimp.2018.06.031

Cited by 13 publications

(11 citation statements)

References 44 publications

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“…In hemorrhagic cystitis, neutrophils play major roles in exacerbating bladder inflammation. It has been reported that hemorrhagic cystitis was suppressed when neutrophils were depleted with anti‐Ly6G antibody 59 . In our findings, MPO activity, an indicator of neutrophils, and gene expression of chemokines such as Cxcl1 were suppressed in Ptgis −/− mice compared to Ptgis +/+ mice.…”

Section: Discussionsupporting

confidence: 63%

“…It has been reported that hemorrhagic cystitis was suppressed when neutrophils were depleted with anti-Ly6G antibody. 59 In our findings, MPO activity, an indicator of neutrophils, and gene expression of chemokines such as Cxcl1 were suppressed in Ptgis −/− mice compared to Ptgis +/+ mice. On the other hand, we could not detect LTB 4 , which plays an important role in the activation and migration of neutrophils, 60 in the bladder tissues.…”

Section: Discussionsupporting

confidence: 58%

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Absence of prostacyclin greatly relieves cyclophosphamide‐induced cystitis and bladder pain in mice

et al. 2021

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Cyclophosphamide (CP) has been widely used in the treatment of various malignancies and autoimmune diseases, but acrolein, a byproduct of CP, causes severe hemorrhagic cystitis as the major side effect of CP. On the other hand, a large amount of prostacyclin (PGI 2 ) is produced in bladder tissues, and PGI 2 has been shown to play a critical role in bladder homeostasis. PGI 2 is biosynthesized from prostaglandin (PG) H 2 , the common precursor of PGs, by PGI 2 synthase (PTGIS) and is known to also be involved in inflammatory responses. However, little is known about the roles of PTGIS-derived PGI 2 in bladder inflammation including CP-induced hemorrhagic cystitis. Using both genetic and pharmacological approaches, we here revealed that PTGIS-derived PGI 2 -IP (PGI 2 receptor) signaling exacerbated CP-induced bladder inflammatory reactions. Ptgis deficiency attenuated CP-induced vascular permeability and chemokine-mediated neutrophil migration into bladder tissues and then suppressed hemorrhagic cystitis. Treatment with RO1138452, an IP selective antagonist, also suppressed CP-induced cystitis. We further found that cystitis-related nociceptive behavior was also relieved in both Ptgis −/− mice and RO1138452-treated mice. Our findings may provide new drug targets for bladder inflammation and inflammatory pain in CP-induced hemorrhagic cystitis.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionsupporting

confidence: 58%

Absence of prostacyclin greatly relieves cyclophosphamide‐induced cystitis and bladder pain in mice

et al. 2021

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“…A 2 M H 2 SO 4 solution was added to stop the reaction and the absorbance was determined at 450 nm using a spectrophotometer. The readings were plotted in a standard curve of neutrophils, as previously described (Dornelas‐Filho et al, 2018). The data are expressed as neutrophils/mg of tissue.…”

Section: Methodsmentioning

confidence: 99%

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

Wong

Holanda

Cajado

et al. 2021

British J Pharmacology

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Background and purpose Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll‐like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4−/−) mice were given irinotecan to investigate the severity of the induced diarrhoea. Experimental approach Forty‐six patients treated with irinotecan‐based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild‐type (WT) or Tlr4−/− mice were given irinotecan (45 or 75 mg·kg−1, i.p.) or saline (3 ml·kg−1). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. Key results All patients with TLR4 SNPs chemotherapy‐treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan‐related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il‐18 expression along with IL‐10 decreased production in Tlr4−/− mice also indicated an intensified intestinal damage and inflammatory response. Conclusion and implications TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late‐onset diarrhoea during irinotecan‐based treatment. Identifying patients genetically predisposed to chemotherapy‐associated diarrhoea is a strategy toward precision medicine.

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“…One explanation is that patients with cervical cancer are frequently treated with the chemotherapeutic drug ifosfamide, which produces microscopic alterations in bladder mucosa, such as edema, exocytosis, and hemorrhage. [ 24 ] These changes may result in lower bladder capacity. Radiation-induced bladder injury may result from direct cell killing through DNA double-strand breaks and the activation of cytokines and growth factors causing fibrosis and reduced elasticity.…”

Section: Discussionmentioning

confidence: 99%

Urodynamic assessment of bladder storage function after radical hysterectomy for cervical cancer

Cao

Wen

Gao

et al. 2020

Chinese Medical Journal

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Background After radical hysterectomy for cervical cancer, the most common complication is lower urinary tract symptoms. Post-operatively, bladder capacity can alter bladder function for a prolonged period. This study aimed to identify factors affecting bladder storage function. Methods A multicenter, retrospective cohort study was conducted. Information of patients with stages IA2 to IIB cervical cancer with urodynamic study results were retrospectively collected from nine hospitals between June 2013 and June 2018 according to the inclusion criteria. Demographic, surgical, and oncological data were collected. The univariate and multivariate logistic regression was used to identify clinical factors associated with bladder storage function. Results Two hundred and three patients with cervical cancer had urodynamic testing post-operatively. Ninety-five (46.8%) patients were diagnosed with stress urinary incontinence (SUI). The incidence of low bladder compliance (LBC) was 23.2%. Twenty-seven (13.3%) patients showed detrusor overactivity (DO). Fifty-seven patients (28.1%) presented with a decreased maximum cystometric capacity (DMCC). The probability of composite bladder storage dysfunction was 68.0%. Multivariate analysis confirmed that laparoscopy represents a protective factor for SUI with an odds ratio of 0.498 ( P = 0.034). Patients who underwent a nerve-sparing procedure were less odds to experience SUI ( P = 0.014). A significant positive correlation between LBC and DO was observed ( P < 0.001). A greater length of the resected vagina and chemoradiotherapy were common risk factors for LBC and DO, while radiotherapy exerted a stronger effect than chemotherapy. Additionally, patients who received chemoradiotherapy frequently developed a DMCC. The follow-up time was not correlated with bladder storage function. Conclusion A nerve-sparing procedure without longer resected vagina is recommended for protecting the bladder storage function.

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Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced by ifosfamide

Cited by 13 publications

References 44 publications

Absence of prostacyclin greatly relieves cyclophosphamide‐induced cystitis and bladder pain in mice

Absence of prostacyclin greatly relieves cyclophosphamide‐induced cystitis and bladder pain in mice

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

Urodynamic assessment of bladder storage function after radical hysterectomy for cervical cancer

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