Bladder urothelium converts bacterial lipopolysaccharide information into neural signaling via an ATP-mediated pathway to enhance the micturition reflex for rapid defense

Ueda, Nasuo; Kondo, Makoto; Takezawa, Kentaro; Kiuchi, Hiroshi; Sekii, Yosuke; Inagaki, Yusuke; Soda, Tetsuji; Fukuhara, Shinichiro; Fujita, Kazutoshi; Uemura, Mamoru; Imamura, Ryoichi; Miyagawa, Yasushi; Nonomura, Norio; Shimada, Shoichi

doi:10.1038/s41598-020-78398-9

Cited by 15 publications

(10 citation statements)

References 74 publications

(196 reference statements)

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“…It is important to highlight that the IC/BPS is a non-bacterial inflammation of the bladder wall, only the symptoms are similar to bacterial cystitis. Usually the cystitis is caused by Gram negative bacterial infection and the signaling pathway starts with activation by lipopolysaccharide (LPS) that is the common virulence factor [ 39 ]. The LPS targets the Toll-like receptors (TLRs) [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of lavender and eucalyptus essential oils on the in vitro cell culture model of bladder pain syndrome using T24 cells

Horváth

Pandur

Sipos

et al. 2022

BMC Complement Med Ther

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Background Interstitial cystitis (IC) has a chronic chemical irritation and inflammation of non-bacterial origin in the bladder wall leading to various severe symptoms. There is evidence that chronic inflammation is significantly associated with abnormal urothelial barrier function, epithelial dysfunction. This is the underlying cause of urothelial apoptosis and sterile inflammation. Method The anti-inflammatory effects of lavender and eucalyptus essential oils (EOs) and their main components (linalool and eucalyptol) were investigated in the T24 human bladder epithelial cell line on TNFα stimulated inflammation, at 3 types of treatment schedule. The mRNA of pro-inflammatory cytokines (IL-1β, IL-6, IL-8) were measured by Real Time PCR. Human IL-8 ELISA measurement was performed as well at 3 types of treatment schedule. The effects of lavender and eucalyptus EOs and their main components were compared to the response to NFκB inhibitor ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile). Result There is no significant difference statistically, but measurements show that lavender EOs are more effective than eucalyptus EO. Long time treatment (24 h) of both lavender EO and linalool showed higher effect in decreasing pro-inflammatory cytokine mRNA expression than ACHP inhibitor following TNFα pre-treatment. Moreover, both lavender EOs were found to be significantly more effective in decreasing IL-8 secretion of T24 cells after TNFα pre-treatment compared to the ACHP NFκB-inhibitor. Conclusion The lavender EOs may be suitable for use as an adjunct to intravesical therapy of IC. Their anti-inflammatory effect could well complement glycosaminoglycan-regenerative therapy in the urinary bladder after appropriate pharmaceutical formulation.

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Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of lavender and eucalyptus essential oils on the in vitro cell culture model of bladder pain syndrome using T24 cells

Horváth

Pandur

Sipos

et al. 2022

BMC Complement Med Ther

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“…In addition to its roles in physiological bladder functions, ATP likely contributes to bladder dysfunctions that are characterized with urinary urgency and increased voiding frequency, with or without urge incontinence. For example, ATP is increased in the urine in patients with overactive bladder (OAB) syndrome [ 11 , 12 ], interstitial cystitis and bladder pain syndrome [ 13 , 14 , 15 ], and bladder infection and inflammation [ 16 , 17 , 18 ]. Conversely, decreased intravesical ATP has been found in patients with refractory detrusor overactivity and bacteriuria [ 19 ] and in patients with underactive bladder syndrome [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Urinary ATP Levels Are Controlled by Nucleotidases Released from the Urothelium in a Regulated Manner

et al. 2022

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Adenosine 5′-triphosphate (ATP) is released in the bladder lumen during filling. Urothelial ATP is presumed to regulate bladder excitability. Urinary ATP is suggested as a urinary biomarker of bladder dysfunctions since ATP is increased in the urine of patients with overactive bladder, interstitial cystitis or bladder pain syndrome. Altered urinary ATP might also be associated with voiding dysfunctions linked to disease states associated with metabolic syndrome. Extracellular ATP levels are determined by ATP release and ATP hydrolysis by membrane-bound and soluble nucleotidases (s-NTDs). It is currently unknown whether s-NTDs regulate urinary ATP. Using etheno-ATP substrate and HPLC-FLD detection techniques, we found that s-NTDs are released in the lumen of ex vivo mouse detrusor-free bladders. Capillary immunoelectrophoresis by ProteinSimple Wes determined that intraluminal solutions (ILS) collected at the end of filling contain ENTPD3 > ENPP1 > ENPP3 ≥ ENTPD2 = NT5E = ALPL/TNAP. Activation of adenylyl cyclase with forskolin increased luminal s-NTDs release whereas the AC inhibitor SQ22536 had no effect. In contrast, forskolin reduced and SQ22536 increased s-NTDs release in the lamina propria. Adenosine enhanced s-NTDs release and accelerated ATP hydrolysis in ILS and lamina propria. Therefore, there is a regulated release of s-NTDs in the bladder lumen during filling. Aberrant release or functions of urothelial s-NTDs might cause elevated urinary ATP in conditions with abnormal bladder excitability.

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“…It may be interesting to compare the effects of 5-HT1D and 5-HT4 receptors activation on mechanosensory transduction in the bladder, since both are enriched in the uroepithelium ( Matsumoto-Miyai et al, 2016 ). Matsumoto-Miyai et al (2016) reported that application of 5-HT to the mucosal side caused inhibition of stretch-induced ATP release and such effect was dependent on 5-HT 1D R but not 5-HT 4 R. ATP has been the most extensively studied signaling molecule released by the urothelium in response to mechanical stretch or chemical cues such as bacterial lipopolysaccharides (LPS) ( Ueda et al, 2020 ). Multiple P2 purinergic receptors have been detected in the bladder, which may mediate diverse effects of extracellular ATP.…”

Section: Discussionmentioning

confidence: 99%

Activation of uroepithelial 5-HT4R inhibits mechanosensory activity of murine bladder afferent nerves

Liu

et al. 2022

Front. Physiol.

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Serotonin (5-HT) is known to act via multiple 5-HT receptors at spinal and supraspinal levels to regulate micturition. However, the contribution of peripheral 5-HT and its receptors in bladder physiology and pathology is not very well understood, despite evidence showing expression of multiple 5-HT receptors in the bladder wall and 5-HT may activate bladder afferent nerves. The current study was designed to investigate the possible role of 5-HT4R in modulation of the sensitivity of bladder afferents to bladder filling. Immunofluorescent staining showed abundant 5-HT4R immunoreactivity largely confined to the uroepithelium in wild type (WT) but not 5-HT4R−/− mice. In the ex vivo bladder-pelvic nerve preparation, intravesical application of the 5-HT4R agonist RS67333 (1–30 μm) caused concentration-dependent decreases of the pelvic nerve response to bladder filling. Such effect was not observed in the presence of 5-HT4R antagonist GR125487 or in 5-HT4R−/− preparations. A cohort of 5-HT4R−/− and WT control mice were treated with intraperitoneal injections of cyclophosphamide (CYP) (75 mg/kg, three times at 2 days interval) to induce chronic cystitis. Void spot analysis showed that CYP-treated 5-HT4R−/− mice urinated more frequently than their CYP-treated WT counterparts. Concomitantly, bladder afferents of CYP-treated 5-HT4R−/− mice displayed exaggerated sensitivity to bladder filling in comparison with the CYP-treated WT controls. These data suggest that 5-HT4R expressed on uroepithelial cells plays an inhibitory role in mechanosensory transduction in the bladder. Loss of 5-HT4R-mediated inhibition may enhance bladder afferent sensitivity and exacerbate bladder overactivity in pathological conditions. We propose that 5-HT4R agonists might be exploited for the treatment of overactive and painful bladder symptoms.

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Bladder urothelium converts bacterial lipopolysaccharide information into neural signaling via an ATP-mediated pathway to enhance the micturition reflex for rapid defense

Cited by 15 publications

References 74 publications

Anti-inflammatory effects of lavender and eucalyptus essential oils on the in vitro cell culture model of bladder pain syndrome using T24 cells

Anti-inflammatory effects of lavender and eucalyptus essential oils on the in vitro cell culture model of bladder pain syndrome using T24 cells

Urinary ATP Levels Are Controlled by Nucleotidases Released from the Urothelium in a Regulated Manner

Activation of uroepithelial 5-HT4R inhibits mechanosensory activity of murine bladder afferent nerves

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