Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis

Chen, Michael C.; Mudge, Christopher S.; Klumpp, David J.

doi:10.1152/ajprenal.00081.2006

Cited by 28 publications

(40 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies in this same mouse model also suggest that antiTNF and anti CCL5 therapies stabilize barrier dysfunction that may otherwise contribute to heightened Cfiber activity. 15,16,39 Alternatively, temporary pain relief in IC is achieved by intravesical 2% lidocaine, and is consistent with our observa tions of lidocaineinduced pelvic pain relief in the murine IC model. 6 Figure 2 Multimodal therapy for chronic pelvic pain.…”

Section: Cortical Changes From Chronic Painsupporting

confidence: 89%

“…14 Lamina propria mastcell accumula tion was mediated by urothelial expression of the chemokine CCL5 (previously known as RANTES) and resulted in urothelial lesions and diminished bladder-barrier function. 15,16 Because human IC symptoms are associated with lamina propria mastcell accumulation and urothelial lesions, 17,18 PRVinduced neurogenic cystitis recapitulates key aspects of the human disease, 15 suggesting the possibility of pelvic pain in PRVinduced cystitis. Indeed, PRV infected mice showed tactile hypersensitivity, or allodynia, that was specific to the pelvic region.…”

Section: Pelvic Organ Crosstalkmentioning

confidence: 99%

See 1 more Smart Citation

Summation model of pelvic pain in interstitial cystitis

Klumpp

Rudick

2008

Nat Rev Urol

View full text Add to dashboard Cite

Many patients with interstitial cystitis (IC) find that particular foods exacerbate disease symptoms. These patients may modify their diet to manage symptoms, but the mechanism by which dietary modification benefits patients with IC is unclear. We hypothesize that integration of neural signals from pelvic organs mediates the effects of diet on symptoms of IC. In animal models, pelvic inflammation is subject to crosstalk, so an inflammatory stimulus in one pelvic organ evokes a response in an independent organ. Recent data show that the colon can modulate bladder-associated pelvic pain in mice. As pelvic organs are innervated through shared circuitry, perceived pelvic pain might occur when spatial summation of individual pelvic inputs exceeds a threshold. Through this mechanism, a noxious dietary stimulus, which otherwise does not exceed the pain threshold in a normal individual, may substantially exacerbate pain in a patient with bladder symptoms. Repeated painful stimuli over time further contribute to symptoms by a process of temporal summation, resulting in enhanced responsiveness through central sensitization. Thus, pelvic organ crosstalk might modulate symptoms of pelvic pain by spatial and temporal summation, suggesting a mechanism for the benefits of dietary modification in patients with IC, as well as therapeutic opportunities.

show abstract

Section: Cortical Changes From Chronic Painsupporting

confidence: 89%

Section: Pelvic Organ Crosstalkmentioning

confidence: 99%

Summation model of pelvic pain in interstitial cystitis

Klumpp

Rudick

2008

Nat Rev Urol

View full text Add to dashboard Cite

show abstract

“…TNF-␣ and iNOS have been shown to be crucial in experimental models of other bacterial infections (20,36). In UTI, both mediators were produced in large amounts (5,30). However, a functional role in this infection has not been proven, although some studies reported partial dependence on iNOS in mice deficient for this enzyme or upon chemical inhibition of NO (26,29).…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Alpha- and Inducible Nitric Oxide Synthase-Producing Dendritic Cells Are Rapidly Recruited to the Bladder in Urinary Tract Infection but Are Dispensable for Bacterial Clearance

Engel¹,

Dobrindt²,

Tittel³

et al. 2006

Infect Immun

View full text Add to dashboard Cite

The role of dendritic cells (DC) in urinary tract infections (UTI) is unknown. These cells contribute directly to the innate defense against various viral and bacterial infections. Here, we studied their role in UTI using an experimental model induced by transurethral instillation of the uropathogenic Escherichia coli (UPEC) strain 536 into C57BL/6 mice. While few DC were found in the uninfected bladder, many had been recruited after 24 h, mostly to the submucosa and uroepithelium. They expressed markers of activation and maturation and exhibited the CD11b tumor necrosis factor alpha (TNF-␣)-and inducible nitric oxide synthase (iNOS)-producing CD11bINT DC (Tip-DC) were detected, which recently were proposed to be critical in the defense against bacterial infections. However, Tip-DC-deficient CCR2 ؊/؊ mice did not show reduced clearance of UPEC from the infected bladder. Moreover, clearance was also unimpaired in CD11c-DTR mice depleted of all DC by injection of diphtheria toxin. This may be explained by the abundance of granulocytes and of iNOS-and TNF-␣-producing non-DC that were able to replace Tip-DC functionality. These findings demonstrate that some of the abundant DC recruited in UTI contributed innate immune effector functions, which were, however, dispensable in the microenvironment of the bladder.

show abstract

“…PD07I normal bladder urothelium cells were from Dr. Klumpp (Northwestern University, Chicago, IL) and cultured in EpiLife Medium (Cascade Biologics) supplemented with HKGS (Cascade Biologics) and PSA (Cascade Biologics) [24].…”

Section: Methodsmentioning

confidence: 99%

The Differential Expression of EphB2 and EphB4 Receptor Kinases in Normal Bladder and in Transitional Cell Carcinoma of the Bladder

Choi

Yan

et al. 2014

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Effective treatment of transitional cell carcinoma (TCC) of the bladder requires early diagnosis. Identifying novel molecular markers in TCC would guide the development of diagnostic and therapeutic targets. Ephrins mediate signals via tyrosine kinase activity that modulates diverse physiologic and developmental processes, and ephrins are increasingly implicated in carcinogenesis. The aim of our study was to examine the differential regulation of EphB4 and EphB2 in normal bladder and in TCC of the bladder in 40 patients undergoing radical cystectomy for curative intent. Immunostaining and Western blotting revealed that normal urothelium expresses EphB2 (20 of 24 cases, 83% of the time) not EphB4 (0 of 24 cases, 0%). In sharp contrast, TCC specimens show loss of EphB2 expression (0 of 34 cases, 0%) and gain of EphB4 expression (32 of 34, 94%). Furthermore, EphB4 signal strength statistically correlated with higher tumor stage, and trended toward the presence of carcinoma in situ (CIS). These results are confirmed by analysis of normal urothelial and tumor cell lines. EphB2 is not a survival factor in normal urothelium, while EphB4 is a survival factor in TCC. Treatment of bladder tumor xenograft with an EphB4 inhibitor sEphB4-HSA leads to 62% tumor regression and complete remission when combined with Bevacizumab. Furthermore, tissue analysis revealed that sEphB4-HSA led to increased apoptosis, decreased proliferation, and reduced vessel density, implicating direct tumor cell targeting as well as anti-angiogenesis effect. In summary loss of EphB2 and gain of EphB4 expression represents an inflection point in the development, growth and possibly progression of TCC. Therapeutic compounds targeting EphB4 have potential for diagnosing and treating TCC.

show abstract

Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis

Cited by 28 publications

References 54 publications

Summation model of pelvic pain in interstitial cystitis

Summation model of pelvic pain in interstitial cystitis

Tumor Necrosis Factor Alpha- and Inducible Nitric Oxide Synthase-Producing Dendritic Cells Are Rapidly Recruited to the Bladder in Urinary Tract Infection but Are Dispensable for Bacterial Clearance

The Differential Expression of EphB2 and EphB4 Receptor Kinases in Normal Bladder and in Transitional Cell Carcinoma of the Bladder

Contact Info

Product

Resources

About