Increased concentration of neutrophil elastase in urine from patients with interstitial cystitis

Kuromitsu, Sadao; Yokota, Hiroyuki; Hiramoto, Masashi; Morita, Shigeaki; Mita, Haruhisa; Yamada, Tetsuo

doi:10.1080/00365590802025881

Cited by 25 publications

(31 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is possible that urine proteases, already elevated in PBS/IC patients, activate urothelial PAR4 receptors to release MIF into the urine [35, 36]. MIF, in turn, activates urothelial MIF receptors to elicit HMGB1 release.…”

Section: Discussionmentioning

confidence: 99%

Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

Kouzoukas

Meyer-Siegler

et al. 2017

BMC Physiol

View full text Add to dashboard Cite

BackgroundBladder pain is a prominent symptom in several urological conditions (e.g. infection, painful bladder syndrome/interstitial cystitis, cancer). Understanding the mechanism of bladder pain is important, particularly when the pain is not accompanied by bladder pathology. Stimulation of protease activated receptor 4 (PAR4) in the urothelium results in bladder pain through release of urothelial high mobility group box-1 (HMGB1). HGMB1 has two functionally active redox states (disulfide and all-thiol) and it is not known which form elicits bladder pain. Therefore, we investigated whether intravesical administration of specific HMGB1 redox forms caused abdominal mechanical hypersensitivity, micturition changes, and bladder inflammation in female C57BL/6 mice 24 hours post-administration. Moreover, we determined which of the specific HMGB1 receptors, Toll-like receptor 4 (TLR4) or receptor for advanced glycation end products (RAGE), mediate HMGB1-induced changes.ResultsDisulfide HMGB1 elicited abdominal mechanical hypersensitivity 24 hours after intravesical (5, 10, 20 μg/150 μl) instillation. In contrast, all-thiol HMGB1 did not produce abdominal mechanical hypersensitivity in any of the doses tested (1, 2, 5, 10, 20 μg/150 μl). Both HMGB1 redox forms caused micturition changes only at the highest dose tested (20 μg/150 μl) while eliciting mild bladder edema and reactive changes at all doses. We subsequently tested whether the effects of intravesical disulfide HMGB1 (10 μg/150 μl; a dose that did not produce inflammation) were prevented by systemic (i.p.) or local (intravesical) administration of either a TLR4 antagonist (TAK-242) or a RAGE antagonist (FPS-ZM1). Systemic administration of either TAK-242 (3 mg/kg) or FPS-ZM1 (10 mg/kg) prevented HMGB1 induced abdominal mechanical hypersensitivity while only intravesical TLR4 antagonist pretreatment (1.5 mg/ml; not RAGE) had this effect.ConclusionsThe disulfide form of HMGB1 mediates bladder pain directly (not secondary to inflammation or injury) through activation of TLR4 receptors in the bladder. Thus, TLR4 receptors are a specific local target for bladder pain.

show abstract

Section: Discussionmentioning

confidence: 99%

Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

Kouzoukas

Meyer-Siegler

et al. 2017

BMC Physiol

View full text Add to dashboard Cite

show abstract

“…Although local thrombin formation during inflammation is likely to occur in the suburothelial compartment and thus stimulate basal and intermediate cells to elicit MIF release, our findings suggest that proteases present in the urine may also be able to activate PAR1 receptors in the urothelium, elicit MIF release and thus contribute to the initiation or maintenance of cystitis. In fact, both mast cell tryptase and neutrophil elastase were documented to be increased in the urine of patients with interstitial cystitis [34], [35], thus raising the possibility that PAR1 receptors could be activated in interstitial cystitis. Activation of PAR1 receptors by neutrophil elastase was reported to induce apoptosis in lung epithelial cells [36] while activation of PAR1 and PAR2 receptors were shown to increase epithelial permeability in intestinal epithelia [37].…”

Section: Discussionmentioning

confidence: 99%

Thrombin Induces Macrophage Migration Inhibitory Factor Release and Upregulation in Urothelium: A Possible Contribution to Bladder Inflammation

et al. 2010

View full text Add to dashboard Cite

PurposeMacrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine expressed by urothelial cells that mediates bladder inflammation. We investigated the effect of stimulation with thrombin, a Protease Activated Receptor-1 (PAR1) agonist, on MIF release and MIF mRNA upregulation in urothelial cells.Materials and MethodsMIF and PAR1 expression was examined in normal human immortalized urothelial cells (UROtsa) using real-time RT-PCR, Western blotting and dual immunostaining. MIF and PAR1 immunostaining was also examined in rat urothelium. The effect of thrombin stimulation (100 nM) on urothelial MIF release was examined in UROtsa cells (in vitro) and in rats (in vivo). UROtsa cells were stimulated with thrombin, culture media were collected at different time points and MIF amounts were determined by ELISA. Pentobarbital anesthetized rats received intravesical saline (control), thrombin, or thrombin +2% lidocaine (to block nerve activity) for 1 hr, intraluminal fluid was collected and MIF amounts determined by ELISA. Bladder or UROtsa MIF mRNA was measured using real time RT-PCR.ResultsUROtsa cells constitutively express MIF and PAR1 and immunostaining for both was observed in these cells and in the basal and intermediate layers of rat urothelium. Thrombin stimulation of urothelial cells resulted in a concentration- and time-dependent increase in MIF release both in vitro (UROtsa; 2.8-fold increase at 1 hr) and in vivo (rat; 4.5-fold) while heat-inactivated thrombin had no effect. In rats, thrombin-induced MIF release was reduced but not abolished by intravesical lidocaine treatment. Thrombin also upregulated MIF mRNA in UROtsa cells (3.3-fold increase) and in the rat bladder (2-fold increase) where the effect was reduced (1.4-fold) by lidocaine treatment.ConclusionsUrothelial cells express both MIF and PAR1. Activation of urothelial PAR1 receptors, either by locally generated thrombin or proteases present in the urine, may mediate bladder inflammation by inducing urothelial MIF release and upregulating urothelial MIF expression.

show abstract

“…Subsequent MALDI-TOF analysis identified the protein spots significantly down-regulated in the IC group as a uromodulin and two kininogens (precursors of kinin) and the protein spot significantly upregulated in the IC group as inter-α-trypsin inhibitory heavy chain H4. Kuromitsu et al [46] applied the 2D-DIGE method to compare proteins in urine samples from three IC patients and three healthy subjects. Several protein spots around 40 kDa were significantly increased in the IC group.…”

Section: Proteomics Studiesmentioning

confidence: 99%

“…Kuromitsu et al [46] reported on an active substance in urine from IC patients that drives the expression of the serum response element-dependent luciferase reporter gene in GPR18-expressing HEK293 cells. This material was identified by nanoLC-MS/MS as epidermal growth factor.…”

Section: Proteomics Studiesmentioning

confidence: 99%

'Omics' Approaches to Understanding Interstitial Cystitis/Painful Bladder Syndrome/Bladder Pain Syndrome

et al. 2012

View full text Add to dashboard Cite

Recent efforts in the generation of large genomics, transcriptomics, proteomics, metabolomics and other types of 'omics' data sets have provided an unprecedentedly detailed view of certain diseases, however to date most of this literature has been focused on malignancy and other lethal pathological conditions. Very little intensive work on global profiles has been performed to understand the molecular mechanism of interstitial cystitis/painful bladder syndrome/bladder pain syndrome (IC/PBS/BPS), a chronic lower urinary tract disorder characterized by pelvic pain, urinary urgency and frequency, which can lead to long lasting adverse effects on quality of life. A lack of understanding of molecular mechanism has been a challenge and dilemma for diagnosis and treatment, and has also led to a delay in basic and translational research focused on biomarker and drug discovery, clinical therapy, and preventive strategies against IC/PBS/BPS. This review describes the current state of 'omics' studies and available data sets relevant to IC/PBS/BPS, and presents opportunities for new research directed at understanding the pathogenesis of this complex condition.

show abstract

Increased concentration of neutrophil elastase in urine from patients with interstitial cystitis

Abstract: The concentration of neutrophil elastase increased in the urine of the IC patient subset with bladder pain and small bladder capacity.

Cited by 25 publications

References 26 publications

Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4

Thrombin Induces Macrophage Migration Inhibitory Factor Release and Upregulation in Urothelium: A Possible Contribution to Bladder Inflammation

'Omics' Approaches to Understanding Interstitial Cystitis/Painful Bladder Syndrome/Bladder Pain Syndrome

Contact Info

Product

Resources

About