Abnormal Sensory Protein Expression and Urothelial Dysfunction in Ketamine-Related Cystitis in Humans Yao Chou Tsai1,2, Lori Birder3, Hann-Chorng Kuo2,4.

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Abnormal Sensory Protein Expression and Urothelial Dysfunction in Ketamine-Related Cystitis in Humans Yao Chou Tsai1,2, Lori Birder3, Hann-Chorng Kuo2,4 1Division of Urology, Department of Surgery, Taipei Tzu Chi General Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan 2Department of Urology, School of Medicine, Tzu Chi University, Hualien, Taiwan 3Department of Medicine and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 4Department of Urology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan

PURPOSE The aim of this study was to analyze patterns of sensory protein expression and urothelial dysfunction in ketamine-related cystitis (KC) in humans.

METHODS Biopsies of bladder mucosa were performed in 29 KC patients during cystoscopy. Then specimens were analyzed for tryptase, zonula occludens-1 (ZO-1), E-cadherin, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) with immunofluorescence staining and quantification. In addition, 10 healthy control bladder specimens were analyzed and compared with the KC specimens. Another 16 whole bladder specimens obtained from partial cystectomy were also analyzed for the muscarinic receptors M2 and M3, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), β-3 adrenergic receptors (β3-ARs), and the P2X3 receptor by western blotting. In addition, 3 normal control bladder specimens were analyzed and compared with the KC specimens.

RESULTS The KC bladder mucosa revealed significantly less expression of ZO-1 and E-cadherin, and greater expression of TUNEL and tryptase activity than the control samples. The expression of M3 and β3-AR in the KC specimens was significantly greater than in the controls. The expression of iNOS, eNOS, M2, and P2X3 was not significantly different between the KC and control specimens.

CONCLUSIONS The bladder tissue of KC patients revealed significant urothelial dysfunction, which was associated with mast-cell mediated inflammation, increased urothelial cell apoptosis, and increased expression of the M3 and β3-AR.

Table 1. Urothelial expressions of apoptosis, mast cell acitivity, E-cadherin, ZO-1, and TGF-β in biopsy specimens of ketamine related cystitis and normal control

Table 2. The urothelial sensory protein expression in Ketamine cystitis and normal control

Fig. 1. Representative images from a biopsy taken from a patient with ketamine-related cystitis (KC) versus a control noninflamed bladder (immunohistochemistry, ×400). For terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), the target cells are labeled in green (arrows) and the white dotted line indicates the boundary of the urothelium; for mast cells, the target cells are labeled in green (arrows) and the white dotted line indicates the boundary of the urothelium; for E-cadherin, the target adhesion glycoprotein is labeled in green and the white dotted line indicates the boundary of the urothelium; for zonula occludens-1 (ZO-1), the target junction protein is labeled in green. The sample size was n=10 for the normal samples and n=29 for the KC samples. 2). No significant differences in expression were observed in the other sensory proteins that were evaluated.