Upregulation of neurotrophins and transforming growth factor‐β expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine‐associated cystitis

Jhang, Jia‐Fong; Wang, Hsiu-Jen; Hsu, Yung‐Hsiang; Birder, Lori A.; Kuo, Hann‐Chorng

doi:10.1002/nau.24139

Cited by 10 publications

(5 citation statements)

References 25 publications

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“…Our previous histopathology study also found nerve hyperplasia and increased collagen deposition in the bladder wall of ketamine cystitis [ 23 , 29 ]. Nerve hyperplasia and fibrosis are histological characteristics of these bladders, and we found that the expression of neurotrophins was significantly correlated with bladder capacity and pain according to the differing clinical severity of ketamine cystitis [ 30 ]. These findings indicate that the upregulation of neurotrophins, transforming growth factor-b, and activation of cell proliferation kinases play an important role in nerve hyperplasia and fibrosis mechanisms in these bladders.…”

Section: P Athophysiologymentioning

confidence: 99%

Pathophysiology, clinical presentation, and management of ketamine-induced cystitis

Jhang

Birder

Kuo

2023

Tzu Chi Medical Journal

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A BSTRACT Ketamine is illegally used as a recreational drug in many Asian countries. Long-term ketamine abusers often develop irritable bladder symptoms that gradually develop into more severe urinary frequency and urgency and eventually into a painful ulcerated bladder. These patients typically have reduced functional bladder capacity, increased bladder sensation, detrusor overactivity, severe urgency, urinary incontinence, and bladder contracture. Ketamine metabolites can cause severe inflammation of the urothelium, urothelial barrier deficits, vascular endothelial fibrinoid changes, increased oxidative stress, and bladder wall fibrosis. A decrease in bladder compliance, urinary tract infection, severe bladder pain with a full bladder, and painful micturition are also common symptoms. Finally, with continued abuse of ketamine, hydronephrosis, ureteral stricture, vesicoureteral reflux, and renal failure may develop. Cessation of ketamine is the mainstay of treatment. Lower urinary tract symptoms usually relapse if patients reuse ketamine after stopping. In cases of severe ketamine cystitis, only augmentation enterocystoplasty can relieve bladder pain and restore normal lower urinary tract function. This article reviews the underlying pathophysiology, clinical characteristics, and management of ketamine cystitis.

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Section: P Athophysiologymentioning

confidence: 99%

Pathophysiology, clinical presentation, and management of ketamine-induced cystitis

Jhang

Birder

Kuo

2023

Tzu Chi Medical Journal

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“…Besides urothelial damage and inflammation, stromal neurogenesis is another important finding 20,52,53 . Prominent nerve bundles and nerve hyperplasia in the deeper portion of the lamina propria or within the detrusor muscle are sometimes evident 20,52 .…”

Section: Evidencementioning

confidence: 99%

“…Neurotrophins are ordinarily present in the bladder and play an important role in the regulation of sensory afferent and urothelium 54 . Upregulation of neurotrophins and their receptors (nerve growth factor, brain‐derived neurotrophic factor, growth‐associated protein 43, and tropomyosin receptor kinase A and B) in bladder mucosa may explain nerve hyperplasia and pain in KC, whereas the increased nerve growth factor expression in the damaged urothelium might suggest a regenerative wound‐healing pattern of the epithelium 52,53,55 . However, different results of serum level of neurotrophins in chronic ketamine abusers have been reported.…”

Section: Evidencementioning

confidence: 99%

What urologists need to know about ketamine‐induced uropathy: A systematic review

Castellani

Pirola

Gubbiotti

et al. 2020

Neurourology and Urodynamics

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Aims: Ketamine is a general anesthetic. Dissociative effects and low cost led ketamine becoming an illegal recreational drug in young adults. Ketamineinduced uropathy (KIU) is one of the complications observed in abusers. This study aimed to provide a systematic literature review on KIU clinical presentation, pathophysiology, and treatments. Methods: We performed the literature search in PubMed, Web of Science, Scopus, and Embase using the terms ketamine and bladder. English papers on human and animal studies were accepted. Results: A total of 75 papers were selected. Regular ketamine users complain about severe storage symptoms and pelvic pain. Hydronephrosis may develop in long-term abusers and is correlated to the contracted bladder, ureteral stenosis, or vesicoureteral reflux due to ureteral involvement and/or bladder fibrosis. Cystoscopy shows ulcerative cystitis. Ketamine in urine might exert direct toxicity to the urothelium, disrupting its barrier function and enhancing cell apoptosis. The presence of ketamine/ions in the bladder wall result in neurogenic/IgE-mediated inflammation, stimulation of the inducible nitric oxide synthase-cytokines-cyclooxygenase pathway with persistent inflammation and fibrosis. Abstinence is the first therapeutic step. Anti-inflammatory drugs, analgesics and anticholinergics, intravesical instillation of hyaluronic acid, hydrodistension and intravesical injection of botulin toxin-A were helpful in patients with early-stage KIU. In patients with end-stage disease, the control of intractable symptoms and the increase of bladder capacity were the main recommendations to perform augmentation enterocystoplasty.Conclusions: KIU is becoming a worldwide health concern, which should be taken into account in the differential diagnosis of ulcerative cystitis. K E Y W O R D S cystitis, inflammation, ketamine, lower urinary tract symptoms, substance-related disorders, urinary tract 1050 | CASTELLANI ET AL.

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“…Bladder fibrosis is a late-stage presentation of bladder outflow tract obstruction (BOO), spinal cord injury (SCI), radiation, or ketamine-induced cystitis [1][2][3]. Bladder fibrosis is characterized by the excessive deposition of the extracellular matrix (ECM), which is composed of collagen (type-I and -III), elastin, and fibronectin.…”

Section: Introductionmentioning

confidence: 99%

Activation of TRPA1 in Bladder Suburothelial Myofibroblasts Counteracts TGF-β1-Induced Fibrotic Changes

Zhao

Ding

Wang

et al. 2023

IJMS

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The activation of the transient receptor potential ankyrin 1 (TRPA1) channel has anti-fibrotic effects in the lung and intestine. Suburothelial myofibroblasts (subu−MyoFBs), a specialized subset of fibroblasts in the bladder, are known to express TRPA1. However, the role of the TRPA1 in the development of bladder fibrosis remains elusive. In this study, we use the transforming growth factor-β1 (TGF-β1) to induce fibrotic changes in subu−MyoFBs and assess the consequences of TRPA1 activation utilizing RT-qPCR, western blotting, and immunocytochemistry. TGF-β1 stimulation increased α-SMA, collagen type I alpha 1 chain(col1A1), collagen type III (col III), and fibronectin expression, while simultaneously suppressing TRPA1 in cultured human subu−MyoFBs. The activation of TRPA1, with its specific agonist allylisothiocyanate (AITC), inhibited TGF-β1-induced fibrotic changes, and part of these inhibition effects could be reversed by the TRPA1 antagonist, HC030031, or by reducing TRPA1 expression via RNA interference. Furthermore, AITC reduced spinal cord injury-induced fibrotic bladder changes in a rat model. The increased expression of TGF-β1, α-SMA, col1A1 and col III, and fibronectin, and the downregulation of TRPA1, were also detected in the mucosa of fibrotic human bladders. These findings suggest that TRPA1 plays a pivotal role in bladder fibrosis, and the negative cross talk between TRPA1 and TGF-β1 signaling may represent one of the mechanisms underlying fibrotic bladder lesions.

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Upregulation of neurotrophins and transforming growth factor‐β expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine‐associated cystitis

Cited by 10 publications

References 25 publications

Pathophysiology, clinical presentation, and management of ketamine-induced cystitis

Pathophysiology, clinical presentation, and management of ketamine-induced cystitis

What urologists need to know about ketamine‐induced uropathy: A systematic review

Activation of TRPA1 in Bladder Suburothelial Myofibroblasts Counteracts TGF-β1-Induced Fibrotic Changes

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