Models of inflammation of the lower urinary tract

Bjorling, Dale E.; Wang, Zunyi; Bushman, Wade

doi:10.1002/nau.21078

Cited by 77 publications

(79 citation statements)

References 139 publications

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“…Furthermore, the neutrophil populations increased approximately 5-fold in the presence of E. faecalis in implanted animals compared to implanted animals without bacterial challenge. All the above immune characteristics, from edema to neutrophilia, are associated with activation of the neurogenic inflammatory pathway in various experimental models of cystitis, including cyclophosphamide-induced hemorrhagic cystitis (39). This is an inflammatory response triggered by the release of proinflammatory neuropeptides and activation of surface receptors, including NK1R, on the surface of sensory neurons (40).…”

Section: Discussionmentioning

confidence: 99%

Enterococcus faecalis Overcomes Foreign Body-Mediated Inflammation To Establish Urinary Tract Infections

et al. 2013

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Urinary catheterization elicits major histological and immunological changes that render the bladder susceptible to microbial invasion, colonization, and dissemination. However, it is not understood how catheters induce these changes, how these changes act to promote infection, or whether they may have any protective benefit. In the present study, we examined how catheter-associated inflammation impacts infection by Enterococcus faecalis, a leading cause of catheter-associated urinary tract infection (CAUTI), a source of significant societal and clinical challenges. Using a recently optimized murine model of foreign body-associated UTI, we found that the implanted catheter itself was the primary inducer of inflammation. In the absence of the silicone tubing implant, E. faecalis induced only minimal inflammation and was rapidly cleared from the bladder. The catheter-induced inflammation was only minimally altered by subsequent enterococcal infection and was not suppressed by inhibitors of the neurogenic pathway and only partially by dexamethasone. Despite the robust inflammatory response induced by urinary implantation, E. faecalis produced biofilm and high bladder titers in these animals. Induction of inflammation in the absence of an implanted catheter failed to promote infection, suggesting that the presence of the catheter itself is essential for E. faecalis persistence in the bladder. Immunosuppression prior to urinary catheterization enhanced E. faecalis colonization, suggesting that implant-mediated inflammation contributes to the control of enterococcal infection. Thus, this study underscores the need for novel strategies against CAUTIs that seek to reduce the deleterious effects of implant-mediated inflammation on bladder homeostasis while maintaining an active immune response that effectively limits bacterial invaders. U rinary catheterization is directly associated with 80% of hospital-acquired urinary tract infections (UTIs) (1). The insertion and presence of indwelling urinary catheters disrupt the normal mechanical and host defenses of the urinary tract, allow extracellular microbes access to the sterile environment of the bladder by ascending through the catheter lumen or from the urethral meatus along the catheter, and provide an additional surface for biofilm formation and the establishment of antibioticrecalcitrant chronic or recurrent infections (2-9). Even in the absence of microbial colonization, urinary catheterization was shown to be associated with histological and immunological alterations in the bladder, including urothelial damage and exfoliation, bladder wall edema, inflammatory cytokine production, immune cell infiltration, and mucosal lesions of the bladders and kidneys (7, 10-13) which can lead to bladder cancers (14, 15). However, there remains a need to uncover molecular details and the functional role of the catheter-induced host responses during bacterial colonization and catheter-associated UTIs (CAUTIs).We recently optimized a murine model of foreign body-associated UTI to inv...

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Section: Discussionmentioning

confidence: 99%

Enterococcus faecalis Overcomes Foreign Body-Mediated Inflammation To Establish Urinary Tract Infections

et al. 2013

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“…The importance of translational models for uncovering the elusive pathophysiology of IC/PBS is well recognized (8).…”

Section: Discussionmentioning

confidence: 99%

Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model

Bicer

Altuntas

İzgi

et al. 2015

American Journal of Physiology-Renal Physiology

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The cause of chronic pelvic pain in interstitial cystitis/painful bladder syndrome (IC/PBS) remains unclear; autoimmunity is a possible etiology. We have recently shown that injection of a single immunogenic peptide of uroplakin 3A (UPK3A 65-84) induces experimental autoimmune cystitis (EAC) in female BALB/cJ mice that is unique among experimental models in accurately reflecting both the urinary symptoms and pelvic pain of IC/PBS. The aim of this project was to identify the roles of mast cells and mast cell chemoattractant/activator monocyte chemoattractant protein-1 [chemokine (C-C motif) ligand 2 (CCL2)] in the allodynia in this model. We immunized 6- to 8-wk-old female BALB/cJ mice with UPK3A 65-84 peptide and, 5–40 days later, observed increased responses to stimulation of the suprapubic abdominal and hindpaw surfaces with von Frey monofilaments compared with mice injected with adjuvant alone. Suprapubic and hindpaw tactile allodynia responses by EAC mice were blocked by instillation of lidocaine into the bladder but not by lidocaine in the uterus, confirming the bladder as the source of the hypersensitivity. Markedly increased numbers of activated mast cells and expression of CCL2 were found in the bladder after immunization with UPK3A 65-84. Hypersensitive responses were inhibited by mast cell stabilizer cromolyn sodium and antagonists of histamine receptors 1 and 2. Furthermore, BALB/cJ mice with deletion of the Ccl2 or chemokine (C-C motif) receptor 2 gene exhibited markedly reduced allodynia and accumulation of mast cells after UPK3A 65-84 immunization. These results show that UPK3A 65-84 immunization causes chronic visceral allodynia and suggest that it is mediated by CCL2-driven mast cell accumulation in the bladder.

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“…Over the years, a number of animal models have been proposed to be used for IC and include chemical damage, autoimmune cystitis, intravesical inflammatory agents such as lipopolysaccharide, and others (1). With the possible exception of feline IC, all are highly artificial and probably poorly represent the processes that occur in humans.…”

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confidence: 99%

In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats

Hurst

Gordon

Tyler

et al. 2016

American Journal of Physiology-Renal Physiology

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In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats. Am J Physiol Renal Physiol 310: F1074 -F1080, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00566.2015.-Loss of integrity of the protective impermeability barrier in the urothelium has been identified as significant in bladder dysfunction. In this study, we tested the theory that the luminal layer of glycosaminoglycans (GAG) serves as an important component of barrier function. The peptide polycation protamine sulfate (PS), 1 mg/ml, was instilled intravesically for 10 min into rat bladders. Chondroitinase ABC (ChABC), 63 IU/ml, was instilled into an additional six rats for 30 min to digest the GAG layer. Unmanipulated controls and sham-injected controls were also performed. After 24 h, the rats were euthanized, the bladders were removed, and permeability was assessed in the Ussing chamber and by diffusion of FITC-labeled dextran (4 kDa) to measure macromolecular permeability. The status of tight junctions was assessed by immunofluorescence and electron microscopy. In control and sham treated rat bladders, the transepithelial electrical resistance were means of 2.5 Ϯ 1.1 vs. 2.6 Ϯ 1.1 vs 1.2 Ϯ 0.5 and 1.01 Ϯ 0.7 k⍀·cm 2 in the PS-treated and ChABC-treated rat bladders (P ϭ 0.0016 and P ϭ 0.0039, respectively). Similar differences were seen in dextran permeability. Histopathology showed a mild inflammation following PS treatment, but the ChABC-treated bladders were indistinguishable from controls. Tight junctions generally remained intact. ChABC digestion alone induced bladder permeability, confirming the importance of the GAG layer to bladder barrier function and supports that loss of the GAG layer seen in bladder biopsies of interstitial cystitis patients could be a significant factor producing symptoms for at least some interstitial cystitis/painful bladder syndrome patients. urinary bladder; administration; intravesical; cystitis; interstitial; permeability; models; animal INTERSTITIAL CYSTITIS (IC) is a disease of the bladder diagnosed by exclusion on the basis of urgency, frequency, and pain (6). Although the etiology of this disease remains unknown, the evidence suggests that there is disruption of the urothelium that could result in enhanced bladder permeability (9,17,22,31). For the IC patient, the presence of urine is responsible for inflammation and pain in addition to promoting thinning and sloughing of the urothelium and distinct changes in the muscle (21,27,30). A high proportion of IC patients show loss of chondroitin sulfate from the luminal surface of the urothelium as well as abnormalities in uroplakin, the cell adherence protein E-cadherin, and ZO-1, the molecule in the zona occludens that links cells together (9). The identification of comorbitities that appear frequently with IC has suggested that the bladder symptoms are part of a wider spectrum of symptoms denoted by chronic pelvic pain (CPP) or IC/painful bladder syndrome (IC/...

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Models of inflammation of the lower urinary tract

Cited by 77 publications

References 139 publications

Enterococcus faecalis Overcomes Foreign Body-Mediated Inflammation To Establish Urinary Tract Infections

Enterococcus faecalis Overcomes Foreign Body-Mediated Inflammation To Establish Urinary Tract Infections

Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model

In the absence of overt urothelial damage, chondroitinase ABC digestion of the GAG layer increases bladder permeability in ovariectomized female rats

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