Histamine and mucosal mast cells in interstitial cystitis

Interstitial cystitis (IC) is a chronic inflammatory disorder of the urinary bladder of unknown aetiology and pathogenesis. The classic form (Hunner's ulcer) is characterized by high mast cell numbers in the detrusor muscle and an expansion of mucosal mast cells in the lamina propria and also in the epithelium. Such cells can be recovered in bladder washings and in the urine in single cell suspensions. We have counted the mast cells and measured the histamine in bladder washings from 16 patients with classic IC and from a control group of 15 patients with so-called early, non-ulcerative IC. The bladder washings from all patients with classic IC contained well preserved mast cells (median 2.16, range 0.5–8.6×10³ cells/I) and histamine (median 14.3, range 6–66 ng/l), while only occasional mast cells and traces of histamine were found in washings from patients with non-ulcerative IC. The histamine content was strongly correlated to the number of mast cells (r=0.87). The mean histamine content per mast cell was estimated at 7.6±0.65 (SEM) pg/cell. The high histamine content per mast cell in relation to previously published data (2.8–4.6 pg/cell) can be attributed to the mild and rapid handling of the specimens.     

Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis

Interstitial cystitis (IC) is a debilitating disease that has been adversely affecting the quality of women's lives for many years. The trigger in IC is not entirely known, and a role for the sensory nerves in its pathogenesis has been suggested. In addition to inflammation, increased mast cell numbers in the detrusor muscle have been reported in a subset of IC patients. Experimentally, several lines of evidence support a central role for substance P and neurokinin-1 (NK-1) receptors in cystitis. The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R(-/-)) allows us to directly evaluate the importance of substance P in cystitis. An unexpected finding of this investigation is that NK-1R(-/-) mice present increased numbers of mast cells in the bladder when compared with wild-type control mice. Despite the increase in mast cell numbers, no concomitant inflammation was observed. In addition, bladder instillation of wild-type mice with a sensitizing antigen induces activation of mast cells and an acute inflammatory response characterized by plasma extravasation, edema, and migration of neutrophils. Antigen-sensitized NK-1R(-/-) mice also exhibit bladder mast cell degranulation in response to antigen challenge. However, NK-1R(-/-) mice are protected from inflammation, failing to present bladder inflammatory cell infiltrate or edema in response to antigen challenge. This work presents the first evidence of participation of NK-1 receptors in cystitis and a mandatory participation of these receptors on the chain of events linking mast cell degranulation and inflammation.     

MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

Bladder pain syndrome (BPS) is a clinical syndrome of pelvic pain and urinary urgency-frequency in the absence of a specific cause. Investigating the expression levels of genes involved in the regulation of epithelial permeability, bladder contractility, and inflammation, we show that neurokinin (NK)1 and NK2 tachykinin receptors were significantly down-regulated in BPS patients. Tight junction proteins zona occludens-1, junctional adherins molecule -1, and occludin were similarly down-regulated, implicating increased urothelial permeability, whereas bradykinin B₁ receptor, cannabinoid receptor CB1 and muscarinic receptors M3-M5 were up-regulated. Using cell-based models, we show that prolonged exposure of NK1R to substance P caused a decrease of NK1R mRNA levels and a concomitant increase of regulatory micro(mi)RNAs miR-449b and miR-500. In the biopsies of BPS patients, the same miRNAs were significantly increased, suggesting that BPS promotes an attenuation of NK1R synthesis via activation of specific miRNAs. We confirm this hypothesis by identifying 31 differentially expressed miRNAs in BPS patients and demonstrate a direct correlation between miR-449b, miR-500, miR-328, and miR-320 and a down-regulation of NK1R mRNA and/or protein levels. Our findings further the knowledge of the molecular mechanisms of BPS, and have relevance for other clinical conditions involving the NK1 receptor.Bladder pain syndrome (BPS) should be diagnosed on the basis of symptoms of pain associated with the urinary bladder, accompanied by at least one other symptom, such as day-time and/or night-time urinary frequency after exclusion of confounding symptoms, according to the European Society for the Study of Interstitial Cystitis proposal and European Association of Urology guidelines.¹ The term “interstitial cystitis” (IC) was not omitted to avoid problems of reimbursement, disability benefits and so forth. The European Society for the Study of Interstitial Cystitis proposal coined the term BPS, however considered the use of painful bladder syndrome and IC in parallel acceptable. Overall, this disease, which has a significant impact on social and psychological well-being, affects approximately 1 million patients in the United States alone,² with at least 230 confirmed cases per 100,000 females.³ The etiology of BPS is unknown, and its treatment is largely empirical. A multitude of pathogenetic mechanisms have been postulated ranging from neuroinflammatory to autoimmune or possibly infectious or toxic agents, but an inflammatory component is commonly thought to be involved.⁴ Epithelial damage has often been invoked: the mucinous layer of the healthy bladder is often compromised in patients with BPS/IC, as well as in some animal models.^5,6 An initiating event (toxin) may lead to increased urothelial permeability, which in turn leads to nerve sensitization and possibly up-regulation of neurotransmitter release (tachykinins, glutamate, calcitonin gene-related peptide).⁷ Sensory nerves secrete inflammatory mediators such as substance P (SP), a nociceptive neurotransmitter in the central and peripheral nervous system. It is not clear whether there are differences in urinary SP between IC patients and controls, although several studies demonstrated increased amounts of the released SP in the urine of BPS/IC patients, and there is a suggestion that increased SP-positive nerve fibers may be present in IC patients.^8–10Activated G protein-coupled receptors are implicated in inflammatory conditions, including BPS/IC and prostatitis.¹¹ Recent results suggest that neurogenic inflammation may be involved in the pathogenesis of BPS/IC in the animal model.¹² However to date this has not been clearly shown in human tissue. Tachykinins (TK), including SP, mediate neurogenic inflammation and smooth muscle contraction in the genitourinary tract through stimulation of neurokinin (NK)1 and NK2 receptors (NK1R and NK2R).¹³ NK1 receptor-expressing sensory neurons are found in the muscle layer of bladder (detrusor), within and just below the urothelium, and around blood vessels, being more abundant in the bladder base than in the dome.¹⁴ In the urinary system, TKs are thought to be responsible for overactivity, hypersensitivity, inflammation, and changes in urothelial permeability.¹⁵ Experiments with NK1R knockout mice demonstrated an obligatory requirement of NK1R in cystitis and participation of these receptors in mast cell degranulation and inflammation.¹² It has previously been shown, using semiquantitative methods, that the NK1R mRNA is increased in bladder biopsies from patients with BPS/IC.¹⁶ In addition, NK2 receptors, which play a pivotal role in the modulation of motor and sensory functions, have been localized in human bladder detrusor muscle.¹⁷ In human urothelium, NK2R expression has not been detected, which is in contrast to animal studies, where NK2 receptors are present in rat urothelium and have a role initiating micturition.^18,19 The apparent species-specific differences in expression patterns of TK receptors warrant caution in interpreting the data obtained from animal models of BPS/IC, and prompted us to investigate the expression and localization of these receptors in healthy and diseased human bladders.Changes in bladder function are often concomitant with structural alterations in smooth muscle and urothelial cells, which manifest themselves in changes of gene expression.²⁰ Such changes are indicative of the pathophysiological processes taking place during the progression of a disease; therefore some of the causative factors of BPS/IC might be elucidated by uncovering a link between the expression of proteins, mediating neurogenic inflammation, bladder contractility and epithelial permeability. Although there are several studies examining gene expression changes during experimentally induced cystitis in animals,^21–25 human data are scarce. In human BPS patients, the molecular markers for bladder permeability and proteoglycan core proteins have been shown to be down-regulated,^26,27 and there was an increased permeability and decreased tight junction formation of bladder epithelial cell monolayers grown from biopsies in patients with BPS/IC, as compared with cells from normal controls.²⁸Recently, microRNAs (miRNAs) have been defined as an important class of gene expression regulators, involved in the processes of inflammation and cancer.^29,30 MiRNAs are noncoding single-stranded RNAs of about 22 nucleotides that regulate the expression of mRNAs, inhibiting the protein production by base-pairing with complementary sequences.³¹ Studies in psoriasis, atopic eczema, and inflammatory bowel disease have shown an involvement of miRNAs in the pathogenesis of these inflammatory diseases.^32,33We collected biopsy material from 28 BPS patients with a high degree of continuous pain and 8 controls and quantified the disease-related changes in the expression levels of the genes involved in the regulation of epithelial permeability, bladder contractility, and neurogenic inflammation. We identified and validated several miRNA species, significantly up-regulated in BPS patients. Our findings suggest a causative role of miRNAs in the regulation of gene expression in BPS, and possible mechanisms of their induction and targeting.     

Activation of bladder mast cells in interstitial cystitis.

Interstitial cystitis (IC) is a sterile, inflammatory bladder condition characterized by urinary frequency and urgency, as well as burning and suprapubic pain, which occurs more frequently in women who may suffer for years before diagnosis. An increased number of mast cells have been associated with IC, but the published reports are inconclusive and often conflicting. Human bladder biopsies were analysed blindly for the degree of activation of mast cells in control and IC patients. It was found that mast cells from IC patients averaged as high as 34 cells/mm2 as compared to less than 16/mm2 in controls. Electron microscopy revealed that over 90% of mast cells from IC patients were activated to various degrees. It is concluded that mast cell activation is a pathologic characteristic for IC.     

Interstitial cystitis: another IgG4–related inflammatory disease?

Interstitial cystitis (IC) is a disease of undetermined etiology and pathogenesis. Inflammation is thought to play a key role in many patients, characteristically with an increase in mast cells within the detrusor muscle of the bladder. We observed that some patients with IC had prominent plasma cells in bladder tissue, which elicited our interest in their possible pathogenic role in patients with IC. A total of 44 cases of IC were collected, including 42 bladder biopsies and 2 cystectomies. Patient age ranged from 18 to 92 years (average age of 49.5 years) and included 7 male and 37 female patients. The histology and immunostains for IgG, IgG4 and tryptase were examined, and the results were correlated with clinical and cystoscopic findings. Four cases showed a significant increase in IgG4-positive plasma cells, with greater than 30 IgG4 plasma cells per high-power field and an IgG4/IgG ratio greater than 0.5. In addition, statistically significant differences were found between IC with IgG4-positive plasma cells vs IgG4-negative cases. The IgG4-positive patients were of older age and had increased severe inflammation and decreased bladder capacity as compared with the IgG4-negative patients. We propose that a subset of patients with IC may have an IgG4-related disease, and further study including serum IgG4 measurement is required to better define this relationship.     

Neuronal Dual Leucine Zipper Kinase Mediates Inflammatory and Nociceptive Responses in Cyclophosphamide-Induced Cystitis

Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is implicated in neuropathic pain. We hypothesized that neuronal DLK is involved in the regulation of inflammation and nociceptive behavior in cystitis. Mice deficient in DLK in sensory neurons (cKO) were generated by crossing DLK floxed mice with mice expressing Cre recombinase under Advillin promoter. Cystitis was induced by cyclophosphamide (CYP) administration in mice. Nociceptive behavior, bladder inflammation, and pathology were assessed following cystitis induction in control and cKO mice. The role of DLK in CYP-induced cystitis was further determined by pharmacological inhibition of DLK with GNE-3511. Deletion of neuronal DLK attenuated CYP-induced pain-like nociceptive behavior and suppressed histamine release from mast cells, neuronal activation in the spinal cord, and bladder pathology. Mice deficient in neuronal DLK also showed reduced inflammation induced by CYP and reduced c-Jun activation in the dorsal root ganglia (DRG). Pharmacological inhibition of DLK with GNE-3511 recapitulated the effects of neuronal DLK depletion in CYP treatment mice. Our study suggests that DLK is a potential target for the treatment of neuropathic pain and bladder pathology associated with cystitis.     

Proliferation and transepithelial migration of mucosal mast cells in interstitial cystitis.

The distribution and abundance of mast cells, as well as their fixation, staining and ultrastructural properties, were studied in the urinary bladders of 16 patients with interstitial cystitis (IC) and in 14 normal subjects. Tissues were fixed in both standard formaldehyde solution and a special fixative, IFAA, optimized for the preservation of mucosal mast cells. An expansion of two distinct mast cell populations was observed in IC. One of these, comprising formaldehyde-sensitive cells, was found only in the mucosa underlying lesions of IC. They were most numerous in the lamina propria but were also frequent in the epithelial layer as well as in the bladder washings, indicating a migratory capacity for these cells. The other mast cell population was visualized equally well irrespective of fixation and staining procedure. In control subjects, such cells were found both in the lamina propria and detrusor muscle, but not in the epithelium nor in bladder washings. In lesions of IC they were increased in the detrusor muscle only. Both types of mast cell contained granules with the highly characteristic lamellar arrays and scrolls, distinguishing human mast cell granules from those of blood basophils. The proliferation and intraepithelial distribution of mucosal mast cells are unusual findings, but prominent features of helminth responses and human mucosal allergic reactions. These findings thus suggest that the mucosal mast cell-IgE system may be involved in the pathogenesis and/or aetiology of IC.     

Alterations in the immunohistochemical distribution patterns of vascular endothelial growth factor receptors Flk1 and Flt1 in bleomycin-induced rat lung fibrosis

To investigate the role of vascular endothelial growth factor (VEGF) in fibrogenesis, the distribution patterns of the VEGF receptors Flt1 and Flk1 were studied by immunohistochemistry, double immunofluorescence, and immunoelectron microscopy in normal (n=2) and bleomycin-treated (n=21) adult rats. Lungs were studied at 5, 24, 28, 35, and 42 days after treatment (p.t.). Flt1, Flk1, and VEGF immunoreactivity localised predominantly to the pulmonary epithelium. In control lungs, Flt1 immunoreactivity was present in ciliated bronchial epithelium and type 2 pneumocytes, Flk1 in Clara cells, and VEGF in Clara cells and type 2 pneumocytes. Flk1 localised to mast cells, present in the peribronchovascular and pleural interstitium only. Flt1- and Flk1-mRNAs were observed in Clara cells and type 2 pneumocytes. Bleomycin-induced fibrogenesis was characterised by a decrease in Flk1 immunoreactivity of Clara cells, and an increase in VEGF-immunoreactive myofibroblasts and type 2 pneumocytes by day 5 p.t., followed by a progressive accumulation of Flk1-immunoreactive mast cells by day 24 p.t. in fibrotic lesions containing VEGF-immunoreactive myofibroblasts. After 42 days, fibrotic regions were densely populated by mast cells. Since mast cells are known to be chemotactically attracted by VEGF, we suggest that VEGF/Flk1 represents the molecular link between proliferation of myofibroblasts, accumulation of mast cells, and the burst of fibrosis at sites of initial lesions in bleomycin-induced fibrosis. Received: 27 August 1998 / Accepted: 31 March 1999     

Highly specific detection of muscarinic M3 receptor,G protein interaction and intracellular trafficking in human detrusor using Proximity Ligation Assay (PLA)

Purpose

Muscarinic acetylcholine receptors (mAChRs) regulate a number of important physiological functions. Alteration of mAChR expression or function has been associated in the etiology of several pathologies including functional bladder disorders (e.g bladder pain syndrome/interstitial cystitis – BPS/IC). In a previous study we found specific mAChR expression patterns associated with BPS/IC, while correlation between protein and gene expression was lacking. Posttranslational regulatory mechanisms, e.g. altered intracellular receptor trafficking, could explain those differences. In addition, alternative G protein (GP) coupling could add to the pathophysiology via modulation of muscarinic signaling. In our proof-of-principle study, we addressed these questions in situ. We established PLA in combination with confocal laserscanning microscopy (CLSM) and 3D object reconstruction for highly specific detection and analysis of muscarinic 3 receptors (M3), G protein (GP) coupling and intracellular trafficking in human detrusor samples.

Nerve fibre proliferation in interstitial cystitis

Summary The aetiology of pain in interstitial cystitis is not understood, although it has been reported to be due to release of mediators from mast cell granules. Cystolysis and intravesical instillation of dimethyl sulphoxide have been shown to relieve pain in this condition. We have studied the nerve population within the bladder wall using immunohistochemical stains for protein gene product 9.5. A group of 18 cases of chronic interstitial cystitis and 12 controls; neuropathic bladder (n=1), chronic bacterial cystitis (n=3), systemic lupus erythematosus cystitis (n=2) and normals (n=6), were investigated. There were significantly more nerve fibres within the sub-urothelial and detrusor muscle layers in chronic interstitial cystitis than there were in normals. Patients with chronic cystitis of other aetiology did not have a significant increase in nerve fibre density within the bladder wall suggesting a specific association between nerve fibre proliferation and interstitial cystitis. Cystolysis is shown to deplete selectively the submucosal nerve plexuses without altering the nerve density within detrusor muscle. This finding explains the desensitisation of the bladder without impairment of detrusor function after this procedure.     

Lower urinary tract function in childhood; normal development and common functional disturbances

This review aims to provide researchers and clinicians involved with the adult lower urinary tract with background knowledge regarding the early development of bladder function and its most common disturbances in childhood. Bladder development begins in weeks 4–6 and the detrusor muscle is formed during weeks 9–12 of gestation. Higher CNS centres are involved in micturition at birth, and the infant usually wakes up, at least briefly, to void. Voiding during the first years of life is often incomplete, owing to detrusor‐sphincter dyscoordination, but this disappears when bladder control is attained. Approximately 5–10% of 7‐year‐old children suffer from daytime incontinence and/or nocturnal enuresis, and a few per cent of them will not outgrow it. Daytime incontinence in childhood is usually attributable to detrusor overactivity, although it is unclear to what extent it is the detrusor or the micturition reflex per se that is overactive. Enuresis – nocturnal incontinence – is caused by either nocturnal polyuria and/or nocturnal detrusor overactivity, in both cases combined with high arousal thresholds. Bladder problems in childhood constitute a risk factor for the development or persistence of bladder problems in adulthood.     

RDP58 inhibits T cell-mediated bladder inflammation in an autoimmune cystitis model

Interstitial cystitis (IC) is a chronic inflammatory condition of the urinary bladder with a strong autoimmune component. Currently, the major challenge in IC treatment is the development of effective therapies. RDP58 is a novel d-amino acid decapeptide with potent immunosuppressive activity. In this study, we investigated whether RDP58 was effective as an intravesical agent for treating bladder autoimmune inflammation in a transgenic mouse model (URO-OVA mice). URO-OVA mice were adoptively transferred with syngeneic activated splenocytes of OT-I mice transgenic for the OVA-specific CD8(+) TCR for cystitis induction and treated intravesically with RDP58 at days 0 and 3. Compared with controls, the RDP58-treated bladders showed markedly reduced histopathology and expressions of mRNAs and proteins of TNF-alpha, NGF and substance P. To determine whether the inhibition of bladder inflammation by RDP58 was due to the interference with effector T cells, we treated the cells with RDP58 in vitro. Cells treated with RDP58 showed reduced production of TNF-alpha and IFN-gamma as well as apoptotic death. Collectively, these results indicate that RDP58 is effective for treating T cell-mediated experimental autoimmune cystitis and may serve as a useful intravesical agent for the treatment of autoimmune-associated bladder inflammation such as IC.     

Does the mast cell have an intrinsic role in the pathogenesis of interstitial cystitis?

In order to examine the role of mast cells in the inflammatory bladder disease interstitial cystitis, mast cells isolated from the human bladder of normal and diseased tissue were challenged with a range of secretagogues. Calcium ionophore A23187 and anti-IgE caused histamine release from all bladder mast cells in a dose-related manner. Mast cells from the diseased tissue were far more responsive than those from the normal tissue. Mast cells from the muscle of normal bladder were responsive towards substance P and compound 48/80. However, mast cells from interstitial cystitis bladder did not release significant amounts of histamine with these two secretagogues.     

Mast cell activation in sterile bladder and prostate inflammation

Sterile inflammation of the bladder has often been associated with interstitial cystitis (IC), a urologic condition of unknown etiology, predominantly affecting young and middle-aged females, for which no effective therapy is known. Recent reports have indicated that IC is associated with an increased number of bladder mast cells. Here we report the case of a middle-aged man with chronic sterile hematuria, dysuria and lower abdominal pain associated with a high number of bladder and prostate mast cells. Following therapeutic transurethral resection of the trigone area, bladder neck and prostate, samples of bladder and prostate were examined with light and electron microscopy and contained many mast cells (about 150 cells/mm2) which were not degranulated. Nevertheless, mast cells contained many altered granules and urinary levels of histamine were elevated, implying secretion without exocytosis. These findings are discussed in the context of the pathophysiology of IC and possible therapeutic interventions.     

Ribonucleotide reductase M2 subunit is a novel diagnostic marker and a potential therapeutic target in bladder cancer

Morikawa T, Maeda D, Kume H, Homma Y & Fukayama M
(2010) Histopathology 57, 885–892 Ribonucleotide reductase M2 subunit is a novel diagnostic marker and a potential therapeutic target in bladder cancer Aims: To examine the immunohistochemical expression and function of ribonucleotide reductase M2 subunit (RRM2), a gemcitabine‐related molecule, in bladder cancer. Methods and results: One hundred and seventeen bladder specimens on a tissue microarray were immunostained for RRM2. Positive RRM2 staining was observed in none of 14 examples of non‐neoplastic urothelium, none of four low‐grade urothelial carcinoma (UC), 69 of 83 (83%) high‐grade UC, three of three (100%) squamous cell carcinoma and 12 of 13 (92%) lymph node metastasis of UC. RRM2 overexpression was associated significantly with muscularis propria invasion in UC patients who had undergone radical cystectomy (P = 0.005). Immunohistochemistry for RRM2 was then applied to small biopsy specimens of 15 cystitis with reactive atypia cases and 25 urothelial carcinoma in‐situ (CIS) cases. Positive RRM2 staining was found in one of 15 (6.7%) cystitis with reactive atypia cases and in 24 of 25 (96%) CIS cases. Finally, UM‐UC‐3 bladder cancer cells were transfected with RRM2 siRNAs and cell growth was evaluated. Knockdown of RRM2 protein markedly inhibited cell growth. Conclusions: We have shown frequent overexpression of RRM2 protein and its possible role in bladder cancer. Our results suggest that RRM2 is a novel diagnostic marker and a potential therapeutic target in bladder cancer.     

Conditioned medium derived from mesenchymal stem cells culture as a intravesical therapy for cystitis interstitials

The treatment of Interstinal Cystitisis (IC) is still challenge for urologist. Available therapies do not result in long-term control of symptoms and do not provide pain relive to patients. Unique abilities of mesenchymal stem cells (MSC) could be used to develop new treatment approaches for Interstitial Cystitis. Conditioned Medium (CM) derived from MSC culture is rich in plenty of growth factors, cytokines and trophic agents which were widely reported to enhance regeneration of urinary bladder in different conditions. This ready mixture of growth factors could be used to develop intravesical therapy for patients with IC. MSC-CM has anti-apoptotic, anti-inflammatory, supportive, angiogenic, immunosuppressive and immunomodulative properties and seems to be ideal substance to prevent IC recurrence and to create favorable environment for regeneration of damaged bladder wall.     

In vivo motor effects of loperamide on the rat urinary bladder

Bladder motility recordings were performed in anaesthetized rats and the effect of the peripherally active opiate agonist loperamide on urinary bladder function was studied. Regional intra-arterial administration of loperamide (0.01–2 mg kg^-1) induced weak bladder contraction per se. Loperamide caused an effective dose-dependent inhibition of bladder motility induced by regional injection of the receptor agonists acetylcholine (ACh) and substance P (SP), as well as by peripheral motor nerve stimulation (PNS). Pretreatment with naloxone (0.5 mg kg^-1) partially antagonized the inhibitory action of loperamide on the nerve-mediated detrusor contraction. However, the depression of the motor responses induced by the receptor agonists ACh and SP was not influenced. It is suggested that the demonstrated inhibitory effect of loperamide on bladder motility is partially mediated by peripheral opioid receptors. The main non-opioid part of the inhibition might be a direct smooth muscle action.     

Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device

Limited treatment options exist for patients who suffer from a painful bladder condition known as interstitial cystitis/bladder pain syndrome (IC/BPS). Whether given systemically (orally) or by short-duration (1 to 2 hours) exposure via intravesical instillation, therapeutic agents have exhibited poor efficacy because their concentrations in the bladder are low. A previous attempt to develop a drug delivery device for use in the bladder was unsuccessful, likely as a result of poor tolerability. A continuous lidocaine-releasing intravesical system (LiRIS) was designed to be retained in the bladder and release therapeutic amounts of the drug into urine over a period of 2 weeks. The device was tested in healthy volunteers and IC/BPS patients and was found to be well tolerated in both subject groups because of its small size and freedom of movement within the bladder. The 16 women with IC/BPS who were enrolled in the study met the National Institute of Diabetes and Digestive and Kidney Diseases criteria for bladder hemorrhages or Hunner's lesions. Subjects received either LiRIS 200 mg or LiRIS 650 mg for 2 weeks. Safety, efficacy, cystoscopic appearance of the bladder, and limited pharmacokinetic data were collected. Both doses were well tolerated, and clinically meaningful reductions were seen in pain, urgency, voiding frequency, and disease questionnaires. Cystoscopic examinations showed improvement on day 14 (day of removal) compared with day 1, including resolution of Hunner's lesions in five of six subjects with baseline lesions. Global response assessment showed an overall responder rate of 64% at day 14 and a sustained overall responder rate of 64% 2 weeks later. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed.     

Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis

Cha S‐I, Chang C S, Kim E K, Lee J W, Matthay M A, Golden J A, Elicker B M, Jones K, Collard H R & Wolters P J (2012) Histopathology  61, 98–106 Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis Aims: The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite recognition of their presence in the lungs of patients with pulmonary fibrosis. This study was performed to characterize the relationship of mast cells to fibrotic lung diseases. Methods and results: Lung tissues from patients with idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), systemic sclerosis (SSc)‐related interstitial lung disease (ILD) and normal individuals were subjected to chymase immunostaining and the mast cell density quantified. Eosinophils were quantified by immunostaining for eosinophil peroxidase. Changes in lung function were correlated with mast cell density. Lung tissue obtained from IPF patients had a higher density of chymase‐immunoreactive mast cells than that from patients with HP, SSc‐related ILD or normal lungs. IPF lung tissue had a higher density of eosinophils than normal lung. There was no correlation between mast cell density and eosinophil density in IPF lung. IPF patients with high mast cell density had a slower rate of decline in forced vital capacity (FVC) than IPF patients with low mast cell density. Conclusions: Mast cell density in IPF lungs is higher than in other fibrotic lung diseases and normal lungs. Increased mast cell density in IPF may predict slower disease progression.