Clinical significance of interleukin‑6 and inducible nitric oxide synthase in ketamine‑induced cystitis

Huang,Chi‑Jung; Lee,Fa‑Kung; Chen,Shao‑Kuan; Chien,Chih‑Cheng; Wu,Sheng‑Tang; Wang,Yen‑Chieh

doi:10.3892/ijmm.2017.3264

Clinical significance of interleukin‑6 and inducible nitric oxide synthase in ketamine‑induced cystitis

Authors:
- Chi‑Jung Huang
- Fa‑Kung Lee
- Shao‑Kuan Chen
- Chih‑Cheng Chien
- Sheng‑Tang Wu
- Yen‑Chieh Wang
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Affiliations: Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C., School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 24205, Taiwan, R.O.C., Division of Urology, Department of Surgery, Tri‑Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C.
Published online on: November 17, 2017 https://doi.org/10.3892/ijmm.2017.3264
Pages: 836-844
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ketamine is an ionotropic glutamatergic N‑methyl‑D‑aspartate receptor antagonist, which is widely used among recreational drug abusers. Ketamine abusers exhibit substantially reduced bladder capacity, which can lead to urinary frequency. The molecular pathogenesis of ketamine‑induced cystitis has been scarcely reported. Given previous clinical findings, it may be hypothesized that pathological alterations in smooth muscle cells (SMCs) of the urinary bladder serve a crucial role in the mechanism underlying cystitis. In the present study, two lineages of SMCs, one from differentiated foreskin‑derived fibroblast‑like stromal cells and the other from cultured normal aortic SMCs, were used to study ketamine‑induced molecular alterations. Polymerase chain reaction was used to study the effects of ketamine on oxidative stress. The effects of adjuvant chemotherapy with cyclophosphamide (CTX) were also investigated. The results indicated that the expression levels of interleukin‑6 and inducible nitric oxide synthase (iNOS) were decreased, whereas collagen expression and deposition were increased in ketamine‑treated SMCs. Conversely, treatment with CTX restored the expression of iNOS, which may prevent or limit oxidative damage. In conclusion, the present study demonstrated that ketamine may induce several molecular alterations in SMCs and these changes may be associated with the clinical symptoms observed in ketamine abusers. In addition, the specific chemotherapeutic agent CTX may reverse these ketamine‑induced aberrations.

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1	Zarate C, Duman RS, Liu G, Sartori S, Quiroz J and Murck H: New paradigms for treatment-resistant depression. Ann NY Acad Sci. 1292:21–31. 2013. View Article : Google Scholar : PubMed/NCBI
2	Naughton M, Clarke G, O'Leary OF, Cryan JF and Dinan TG: A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 156:24–35. 2014. View Article : Google Scholar : PubMed/NCBI
3	Kavalali ET and Monteggia LM: How does ketamine elicit a rapid antidepressant response. Curr Opin Pharmacol. 20:35–39. 2015. View Article : Google Scholar
4	Jha AK, Bhardwaj N, Yaddanapudi S, Sharma RK and Mahajan JK: A randomized study of surgical site infiltration with bupivacaine or ketamine for pain relief in children following cleft palate repair. Paediatr Anaesth. 23:401–406. 2013. View Article : Google Scholar : PubMed/NCBI
5	Tawfic QA: A review of the use of ketamine in pain management. J Opioid Manag. 9:379–388. 2013. View Article : Google Scholar : PubMed/NCBI
6	Ricaurte GA and McCann UD: Recognition and management of complications of new recreational drug use. Lancet. 365:2137–2145. 2005. View Article : Google Scholar : PubMed/NCBI
7	Wang YC, Chen SK and Lin CM: Breaking the drug addiction cycle is not easy in ketamine abusers. Int J Urol. 17:496author reply 497. 2010. View Article : Google Scholar : PubMed/NCBI
8	Jansen KL and Darracot-Cankovic R: The nonmedical use of ketamine, part two: A review of problem use and dependence. J Psychoactive Drugs. 33:151–158. 2001. View Article : Google Scholar : PubMed/NCBI
9	Lim DK: Ketamine associated psychedelic effects and dependence. Singapore Med J. 44:31–34. 2003.PubMed/NCBI
10	Slikker W Jr, Liu F, Rainosek SW, Patterson TA, Sadovova N, Hanig JP, Paule MG and Wang C: Ketamine-induced toxicity in neurons differentiated from neural stem cells. Mol Neurobiol. 52:959–969. 2015. View Article : Google Scholar : PubMed/NCBI
11	Gray T and Dass M: Ketamine cystitis: An emerging diagnostic and therapeutic challenge. Br J Hosp Med (Lond). 73:576–579. 2012. View Article : Google Scholar
12	Gu D, Huang J, Yin Y, Shan Z, Zheng S and Wu P: Long-term ketamine abuse induces cystitis in rats by impairing the bladder epithelial barrier. Mol Biol Rep. 41:7313–7322. 2014. View Article : Google Scholar : PubMed/NCBI
13	Shahani R, Streutker C, Dickson B and Stewart RJ: Ketamine-associated ulcerative cystitis: A new clinical entity. Urology. 69:810–812. 2007. View Article : Google Scholar : PubMed/NCBI
14	Chu PS, Ma WK, Wong SC, Chu RW, Cheng CH, Wong S, Tse JM, Lau FL, Yiu MK and Man CW: The destruction of the lower urinary tract by ketamine abuse: A new syndrome. BJU Int. 102:1616–1622. 2008. View Article : Google Scholar : PubMed/NCBI
15	Colebunders B and Van Erps P: Cystitis due to the use of ketamine as a recreational drug: A case report. J Med Case Reports. 2:2192008. View Article : Google Scholar :
16	Chu PS, Kwok SC, Lam KM, Chu TY, Chan SW, Man CW, Ma WK, Chui KL, Yiu MK, Chan YC, et al: 'Street ketamine'-associated bladder dysfunction: A report of ten cases. Hong Kong Med J. 13:311–313. 2007.PubMed/NCBI
17	Chen CH, Lee MH, Chen YC and Lin MF: Ketamine-snorting associated cystitis. J Formos Med Assoc. 110:787–791. 2011. View Article : Google Scholar
18	Cheung RY, Lee JH, Chan SS, Liu DW and Choy KW: A pilot study of urine cytokines in ketamine-associated lower urinary tract symptoms. Int Urogynecol J Pelvic Floor Dysfunct. 25:1715–1719. 2014. View Article : Google Scholar
19	Smart C, Kabir M and Pati J: Treatment of ketamine-associated cystitis with chondroitin sulphate. Br J Nurs. 22:S4S6S8–9. 2013. View Article : Google Scholar : PubMed/NCBI
20	Chuang SM, Liu KM, Li YL, Jang MY, Lee HH, Wu WJ, Chang WC, Levin RM and Juan YS: Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder. Neurourol Urodyn. 32:1137–1143. 2013. View Article : Google Scholar : PubMed/NCBI
21	Gu D, Huang J, Shan Z, Yin Y, Zheng S and Wu P: Effects of long-term ketamine administration on rat bladder protein levels: A proteomic investigation using two-dimensional difference gel electrophoresis system. Int J Urol. 20:1024–1031. 2013.PubMed/NCBI
22	Baker SC, Stahlschmidt J, Oxley J, Hinley J, Eardley I, Marsh F, Gillatt D, Fulford S and Southgate J: Nerve hyperplasia: A unique feature of ketamine cystitis. Acta Neuropathol Commun. 1:642013. View Article : Google Scholar : PubMed/NCBI
23	Jhang JF, Hsu YH, Jiang YH and Kuo HC: Elevated serum IgE may be associated with development of ketamine cystitis. J Urol. 192:1249–1256. 2014. View Article : Google Scholar : PubMed/NCBI
24	Mami I, Tavernier Q, Bouvier N, Aboukamis R, Desbuissons G, Rabant M, Poindessous V, Laurent-Puig P, Beaune P, Tharaux PL, et al: A novel extrinsic pathway for the unfolded protein response in the kidney. J Am Soc Nephrol. 27:2670–2683. 2016.PubMed/NCBI
25	de Oliveira L, Spiazzi CM, Bortolin T, Canever L, Petronilho F, Mina FG, Dal-Pizzol F, Quevedo J and Zugno AI: Different sub-anesthetic doses of ketamine increase oxidative stress in the brain of rats. Prog Neuropsychopharmacol Biol Psychiatry. 33:1003–1008. 2009. View Article : Google Scholar : PubMed/NCBI
26	Toma JG, Akhavan M, Fernandes KJ, Barnabé-Heider F, Sadikot A, Kaplan DR and Miller FD: Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 3:778–784. 2001. View Article : Google Scholar : PubMed/NCBI
27	Fernandes KJ, McKenzie IA, Mill P, Smith KM, Akhavan M, Barnabé-Heider F, Biernaskie J, Junek A, Kobayashi NR, Toma JG, et al: A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol. 6:1082–1093. 2004. View Article : Google Scholar : PubMed/NCBI
28	Huang HI, Chen SK, Ling QD, Chien CC, Liu HT and Chan SH: Multilineage differentiation potential of fibroblast-like stromal cells derived from human skin. Tissue Eng Part A. 16:1491–1501. 2010. View Article : Google Scholar
29	Wang CC, Weng TI, Wu ET, Wu MH, Yang RS and Liu SH: Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide. Toxicol Sci. 131:302–310. 2012. View Article : Google Scholar : PubMed/NCBI
30	Moore KA, Sklerov J, Levine B and Jacobs AJ: Urine concentrations of ketamine and norketamine following illegal consumption. J Anal Toxicol. 25:583–588. 2001. View Article : Google Scholar : PubMed/NCBI
31	Ho YH, Wang CC, Hsiao YT, Ko WK and Wu SM: Analysis of ten abused drugs in urine by large volume sample stacking-sweeping capillary electrophoresis with an experimental design strategy. J Chromatogr A. 1295:136–141. 2013. View Article : Google Scholar : PubMed/NCBI
32	Tam YH, Ng CF, Pang KK, Yee CH, Chu WC, Leung VY, Wong GL, Wong VW, Chan HL and Lai PB: One-stop clinic for ketamine-associated uropathy: Report on service delivery model, patients' characteristics and non-invasive investigations at baseline by a cross-sectional study in a prospective cohort of 318 teenagers and young adults. BJU Int. 114:754–760. 2014. View Article : Google Scholar : PubMed/NCBI
33	Ng CM, Ma WK, To KC and Yiu MK: The Chinese version of the pelvic pain and urgency/frequency symptom scale: A useful assessment tool for street-ketamine abusers with lower urinary tract symptoms. Hong Kong Med J. 18:123–130. 2012.PubMed/NCBI
34	Chung SD, Wang CC and Kuo HC: Augmentation enterocystoplasty is effective in relieving refractory ketamine-related bladder pain. Neurourol Urodyn. 33:1207–1211. 2014. View Article : Google Scholar
35	Lin HC, Lee HS, Chiueh TS, Lin YC, Lin HA, Lin YC, Cha TL and Meng E: Histopathological assessment of inflammation and expression of inflammatory markers in patients with ketamine-induced cystitis. Mol Med Rep. 11:2421–2428. 2015. View Article : Google Scholar :
36	Shen CH, Wang ST, Lee YR, Liu SY, Li YZ, Wu JD, Chen YJ and Liu YW: Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamine injected mice. Mol Med Rep. 11:887–895. 2015. View Article : Google Scholar
37	Andersson KE and Arner A: Urinary bladder contraction and relaxation: Physiology and pathophysiology. Physiol Rev. 84:935–986. 2004. View Article : Google Scholar : PubMed/NCBI
38	Ibeawuchi CU, Ajayi OI and Ebeigbe AB: Vascular effect of ketamine in isolated rabbit aortic smooth muscle. Niger J Physiol Sci. 23:85–88. 2008.
39	Ozturk AM, Ergun MA, Demir T, Gungor I, Yilmaz A and Kaya K: Ketamine is toxic to chondrocyte cell cultures. Bone Joint J. 96-B:989–994. 2014. View Article : Google Scholar : PubMed/NCBI
40	Chang HC, Chen TL and Chen RM: Cytoskeleton interruption in human hepatoma HepG2 cells induced by ketamine occurs possibly through suppression of calcium mobilization and mitochondrial function. Drug Metab Dispos. 37:24–31. 2009. View Article : Google Scholar
41	Ma J, Nishimura H, Fogo A, Kon V, Inagami T and Ichikawa I: Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int. 53:937–944. 1998. View Article : Google Scholar : PubMed/NCBI
42	Juan YS, Lee YL, Long CY, Wong JH, Jang MY, Lu JH, Wu WJ, Huang YS, Chang WC and Chuang SM: Translocation of NF-κB and expression of cyclooxygenase-2 are enhanced by ketamine-induced ulcerative cystitis in rat bladder. Am J Pathol. 185:2269–2285. 2015. View Article : Google Scholar : PubMed/NCBI
43	Song M, Yu HY, Chun JY, Shin DM, Song SH, Choo MS and Song YS: The fibrosis of ketamine, a noncompetitive N-methyl-d-aspartic acid receptor antagonist dose-dependent change in a ketamine-induced cystitis rat model. Drug Chem Toxicol. 39:206–212. 2016. View Article : Google Scholar
44	Chen CZ and Raghunath M: Focus on collagen: In vitro systems to study fibrogenesis and antifibrosis state of the art. Fibrogenesis Tissue Repair. 2:72009. View Article : Google Scholar : PubMed/NCBI
45	Borg BB, Seetharam A, Subramanian V, Basha HI, Lisker-Melman M, Korenblat K, Anderson CD, Shenoy S, Chapman WC, Crippin JS, et al: Immune response to extra-cellular matrix collagen in chronic hepatitis C-induced liver fibrosis. Liver Transpl. 17:814–823. 2011. View Article : Google Scholar : PubMed/NCBI
46	Challa AA, Vukmirovic M, Blackmon J and Stefanovic B: Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo. PLoS One. 7:e429892012. View Article : Google Scholar : PubMed/NCBI
47	Muñoz-Cánoves P, Scheele C, Pedersen BK and Serrano AL: Interleukin-6 myokine signaling in skeletal muscle: A double-edged sword. FEBS J. 280:4131–4148. 2013. View Article : Google Scholar
48	Yang C, Jiang RY, Shen J, Hong T, Liu N, Ding LC, Wang DM, Chen LJ, Xu B and Zhu B: Ketamine attenuates the lipopolysaccharide-induced inflammatory response in cultured N2a cells. Mol Med Rep. 8:217–220. 2013. View Article : Google Scholar : PubMed/NCBI
49	Tang SH, Yu JG, Li JJ and Sun JY: Neuroprotective effect of ketamine on acute spinal cord injury in rats. Genet Mol Res. 14:3551–3556. 2015. View Article : Google Scholar : PubMed/NCBI
50	Lee GL, Wu JY, Yeh CC and Kuo CC: TLR4 induces CREB-mediated IL-6 production via upregulation of F-spondin to promote vascular smooth muscle cell migration. Biochem Biophys Res Commun. 473:1205–1210. 2016. View Article : Google Scholar : PubMed/NCBI
51	Hiram R, Rizcallah E, Marouan S, Sirois C, Sirois M, Morin C, Fortin S and Rousseau E: Resolvin E1 normalizes contractility, Ca²⁺ sensitivity and smooth muscle cell migration rate in TNF-α-and IL-6-pretreated human pulmonary arteries. Am J Physiol Lung Cell Mol Physiol. 309:L776–L788. 2015.PubMed/NCBI
52	Cascella R, Ragazzo M, Strafella C, Missiroli F, Borgiani P, Angelucci F, Marsella LT, Cusumano A, Novelli G, Ricci F, et al: Age-related macular degeneration: Insights into inflammatory genes. J Ophthalmol. 582842:2014.PubMed/NCBI
53	Ye ZW, Zhang J, Townsend DM and Tew KD: Oxidative stress, redox regulation and diseases of cellular differentiation. Biochim Biophys Acta. 1850:1607–1621. 2015. View Article : Google Scholar :
54	Dijkstra G, Blokzijl H, Bok L, Homan M, van Goor H, Faber KN, Jansen PL and Moshage H: Opposite effect of oxidative stress on inducible nitric oxide synthase and haem oxygenase-1 expression in intestinal inflammation: Anti-inflammatory effect of carbon monoxide. J Pathol. 204:296–303. 2004. View Article : Google Scholar : PubMed/NCBI
55	Soyer T, Boybeyi Ö and Atasoy P: Selective inhibition of nitric oxide synthase causes increased muscle thickness in rat esophagus. J Pediatr Surg. 50:1112–1114. 2015. View Article : Google Scholar : PubMed/NCBI
56	Al-Azemi M, Refaat B, Amer S, Ola B, Chapman N and Ledger W: The expression of inducible nitric oxide synthase in the human fallopian tube during the menstrual cycle and in ectopic pregnancy. Fertil Steril. 94:833–840. 2010. View Article : Google Scholar
57	Dobrek Ł and Thor PJ: Bladder urotoxicity pathophysiology induced by the oxazaphosphorine alkylating agents and its chemoprevention. Postepy Hig Med Dosw Online. 66:592–602. 2012. View Article : Google Scholar
58	Yilmaz N, Emmungil H, Gucenmez S, Ozen G, Yildiz F, Balkarli A, Kimyon G, Coskun BN, Dogan I, Pamuk ON, et al: Incidence of cyclophosphamide-induced urotoxicity and protective effect of mesna in rheumatic diseases. J Rheumatol. 42:1661–1666. 2015. View Article : Google Scholar : PubMed/NCBI
59	Gray KJ, Engelmann UH, Johnson EH and Fishman IJ: Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. J Urol. 136:497–500. 1986. View Article : Google Scholar : PubMed/NCBI
60	Wang N, Yu HY, Shen XF, Gao ZQ, Yang C, Yang JJ and Zhang GF: The rapid antidepressant effect of ketamine in rats is associated with downregulation of pro-inflammatory cytokines in the hippocampus. Ups J Med Sci. 120:241–248. 2015. View Article : Google Scholar
61	Souza-Fiho MV, Lima MV, Pompeu MM, Ballejo G, Cunha FQ and Ribeiro RdeA: Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Am J Pathol. 150:247–256. 1997.PubMed/NCBI
62	Ozguven AA, Yılmaz O, Taneli F, Ulman C, Vatansever S and Onag A: Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide. Indian J Pharmacol. 46:147–151. 2014. View Article : Google Scholar : PubMed/NCBI