Abstract
Simple SummaryLong-term ketamine abuse may increase urinary frequency, nocturia, urgency, bladder pain, dysuria, and sometimes hematuria. Evaluation of the pathophysiological mechanism of bladder voiding dysfunction in ketamine-induced cystitis (KIC) patients is a critical step for therapy. This study uses autophagy inducer (rapamycin, mTOR inhibitor) and inhibitor (wortmannin, PI3K-III inhibitor) to identify the role of autophagy in bladder angiogenesis alteration and bladder hyperactivity improvement.The present study attempts to elucidate whether autophagy alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity—thereby influencing bladder function in ketamine-induced cystitis (KIC). In our methodology, female Sprague-Dawley (S-D) rats were randomly divided into the control group, the ketamine group, the ketamine+rapamycin group, and the ketamine+wortmannin group. The bladder function, contractile activity of detrusor smooth muscle, distribution of autophagosome and autolysosome, total white blood cells (WBCs) and leukocyte differential counts, the expressions of autophagy-associated protein, angiogenesis markers, and signaling pathway molecules involved in KIC were tested, respectively. The data revealed that treatment with ketamine significantly results in bladder overactivity, enhanced interstitial fibrosis, impaired endothelium, induced eosinophil-mediated inflammation, swelling, and degraded mitochondria and organelles, inhibited angiogenesis, and elevated the phosphorylation of Akt. However, treatment with rapamycin caused an inhibitory effect on vascular formation, removed ketamine metabolites, decreased the eosinophil-mediated inflammation, and ameliorated bladder hyperactivity, leading to improve bladder function in KIC. Moreover, wortmannin treatment reduced basophil-mediated inflammatory response, improved bladder angiogenesis by increasing capillary density and VEGF expression, to reverse antiangiogenic effect to repair KIC. In conclusion, these findings suggested that autophagy could modulate inflammatory responses and angiogenesis, which improved bladder function in KIC.
Highlights
Clinical studies have revealed that ketamine users may cause severe lower urinary tract symptoms (LUTSs), resulting in increased urinary frequency, nocturia, urgency, bladder pain, dysuria, and sometimes hematuria
The bladder weight of the ketamine group and the ketamine+wortmannin group was significantly increased compared to the control group
The bladder weight of the ketamine+rapamycin group significantly reduced as compared with the ketamine group
Summary
Clinical studies have revealed that ketamine users may cause severe lower urinary tract symptoms (LUTSs), resulting in increased urinary frequency, nocturia, urgency, bladder pain, dysuria, and sometimes hematuria. These symptoms are very similar to those of interstitial cystitis/bladder pain syndrome (IC/BPS) [1,2,3]. Clinical ketamine-induced cystitis (KIC) patients show increases in bladder mast cell and eosinophil cell infiltration with increased serum immunoglobulin-E (IgE) levels associated with hypersensitivity and/or allergic reactions [6,7,8]. Pathological changes in the KIC animal model were denuded urothelium, neurogenic inflammation, abnormal apoptosis, bladder wall thickening, and infiltration of mast cells, eosinophils, lymphocytes, as well as plasma cells [8]. The pathophysiological mechanism of bladder voiding dysfunction in KIC patients is still elusive
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