1887

Chapter 23 : Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract

Authors: Lori A. Birder1, David J. Klumpp2
VIEW AFFILIATIONS HIDE AFFILIATIONS
Affiliations: 1: Departments of Medicine and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; 2: Departments of Urology and Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60610
Content Type: Monograph
Publication Year: 2017

Category: Microbial Genetics and Molecular Biology; Clinical Microbiology

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Preview Magnify
Zoom in
Zoomout

Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817404/9781555817398_Chap23-1.gif /docserver/preview/fulltext/10.1128/9781555817404/9781555817398_Chap23-2.gif

Abstract:

The bladder wall contains the mucosal layer, the muscularis propria, and the adventitia/serosa. The urinary-bladder mucosa is defined as the portion of the lamina propria (LP) closest to the muscularis propria and contains the urothelium, a basement membrane, and the LP ( ).

Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555817404.chap23-1,webId=/content/author/10.1128/9781555817404.chap23-1,properties={foaf_givenname=Lori A., foaf_name=Lori A. Birder, foaf_surname=Birder, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555817404.chap23-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555817404.chap23-2,webId=/content/author/10.1128/9781555817404.chap23-2,properties={foaf_givenname=David J., foaf_name=David J. Klumpp, foaf_surname=Klumpp, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555817404.chap23-aff2]]}]]
Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
/content/10.1128/9781555817404.chap23.fig23-1
Figure 1

Opposing neural control during bladder filling and voiding. Circuits associated with filling (red) and voiding (green). During filling, receptor-mediated sensory signals from the bladder (blue arrow) are conveyed via the pelvic nerve, eliciting sphincter contraction and detrusor relaxation to retain urine. During voiding, sphincter relaxation and bladder contraction are achieved by inhibitory circuits that suppress the filling state and active circuits that promote detrusor contraction and thus urination ( ).

10.1128/9781555817404/fig23-1_thmb.gif
10.1128/9781555817404/fig23-1.gif
Image of Figure 1
Figure 1

Opposing neural control during bladder filling and voiding. Circuits associated with filling (red) and voiding (green). During filling, receptor-mediated sensory signals from the bladder (blue arrow) are conveyed via the pelvic nerve, eliciting sphincter contraction and detrusor relaxation to retain urine. During voiding, sphincter relaxation and bladder contraction are achieved by inhibitory circuits that suppress the filling state and active circuits that promote detrusor contraction and thus urination ( ).

Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817404.chap23.fig23-2
Figure 2

Inflammatory pain. Factors within the inflammatory microenvironment can trigger pain responses. These factors may be released by damaged cells at the site of injury or by leukocytes. Such inflammatory mediators can trigger action potentials in sensory neurons or reduce firing thresholds for other environmental or physiologic stimuli.

10.1128/9781555817404/fig23-2_thmb.gif
10.1128/9781555817404/fig23-2.gif
Image of Figure 2
Figure 2

Inflammatory pain. Factors within the inflammatory microenvironment can trigger pain responses. These factors may be released by damaged cells at the site of injury or by leukocytes. Such inflammatory mediators can trigger action potentials in sensory neurons or reduce firing thresholds for other environmental or physiologic stimuli.

Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817404.chap23.fig23-3
Figure 3

UPEC induces pain separable from other facets of UTI pathogenesis. FimH acts as a tethered toxin that mediates urothelial apoptosis and consequent bladder-barrier dysfunction. LPS plays dual roles through its interactions with TLR4. In addition to the well-characterized role as a trigger for inflammation, LPS mediates pelvic-pain responses. Reproduced from ( ), with permission.

10.1128/9781555817404/fig23-3_thmb.gif
10.1128/9781555817404/fig23-3.gif
Image of Figure 3
Figure 3

UPEC induces pain separable from other facets of UTI pathogenesis. FimH acts as a tethered toxin that mediates urothelial apoptosis and consequent bladder-barrier dysfunction. LPS plays dual roles through its interactions with TLR4. In addition to the well-characterized role as a trigger for inflammation, LPS mediates pelvic-pain responses. Reproduced from ( ), with permission.

Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817404.chap23.fig23-4
Figure 4

LPS O-antigen acts as a rheostat to modulate UTI pain. Mice exhibited allodynia that varied with O-antigen. The acute-pain phenotype of UPEC strain NU14 was rendered chronic by deleting or the entire O-antigen gene cluster, but was suppressed by expressing 83972 O-antigen genes. K-12 strain SΦ874 induced chronic pain that was suppressed by expressing O-antigen O2a. Adapted from ( ), with permission.

10.1128/9781555817404/fig23-4_thmb.gif
10.1128/9781555817404/fig23-4.gif
Image of Figure 4
Figure 4

LPS O-antigen acts as a rheostat to modulate UTI pain. Mice exhibited allodynia that varied with O-antigen. The acute-pain phenotype of UPEC strain NU14 was rendered chronic by deleting or the entire O-antigen gene cluster, but was suppressed by expressing 83972 O-antigen genes. K-12 strain SΦ874 induced chronic pain that was suppressed by expressing O-antigen O2a. Adapted from ( ), with permission.

Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817404.chap23.fig23-5
Figure 5

Chronic-pain pathway and ASB analgesia. A peripheral three-receptor cascade, consisting of TLR4, TRPV1, and CCR2, mediates development of chronic pain that is associated with central sensitization of the sacral spinal cord receiving bladder sensory input due to altered sensory input (green) or inhibitory control (red). Analgesic activity of ASB disrupts pain in the periphery and/or spinal cord.

10.1128/9781555817404/fig23-5_thmb.gif
10.1128/9781555817404/fig23-5.gif
Image of Figure 5
Figure 5

Chronic-pain pathway and ASB analgesia. A peripheral three-receptor cascade, consisting of TLR4, TRPV1, and CCR2, mediates development of chronic pain that is associated with central sensitization of the sacral spinal cord receiving bladder sensory input due to altered sensory input (green) or inhibitory control (red). Analgesic activity of ASB disrupts pain in the periphery and/or spinal cord.

Citation: Birder L, Klumpp D. 2017. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract, p 565-588. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0023-2016
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817404.chap23
1. Birder L,, Andersson KE . 2013. Urothelial signaling. Physiol Rev 93 : 653– 680.[PubMed] [CrossRef]
2. Khandelwal P,, Abraham SN,, Apodaca G . 2009. Cell biology and physiology of the uroepithelium. Am J Physiol Renal Physiol 297 : F1477– 1501.[PubMed] [CrossRef]
3. Sun TT,, Liang FX,, Wu XR . 1999. Uroplakins as markers of urothelial differentiation. Adv Exp Med Biol 462 : 7– 18.[PubMed] [CrossRef]
4. Wu XR,, Kong XP,, Pellicer A,, Kreibich G,, Sun TT . 2009. Uroplakins in urothelial biology, function, and disease. Kidney Int 75 : 1153– 1165.[PubMed] [CrossRef]
5. Acharya P,, Beckel J,, Ruiz WG,, Wang E,, Rojas R,, Birder L,, Apodaca G . 2004. Distribution of the tight junction proteins ZO-1, occludin, and claudin-4, -8, and -12 in bladder epithelium. Am J Physiol Renal Physiol 287 : F305– 318.[PubMed] [CrossRef]
6. Carattino MD,, Prakasam HS,, Ruiz WG,, Clayton DR,, McGuire M,, Gallo LI,, Apodaca G . 2013. Bladder filling and voiding affect umbrella cell tight junction organization and function. Am J Physiol Renal Physiol 305 : F1158– 1168.[PubMed] [CrossRef]
7. Sun TT . 2006. Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healing. Am J Physiol Renal Physiol 291 : F9– 21.[PubMed] [CrossRef]
8. Fry CH,, Young JS,, Jabr RI,, McCarthy C,, Ikeda Y,, Kanai AJ . 2012. Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists. Am J Physiol Renal Physiol 302 : F1447– 1454.[PubMed] [CrossRef]
9. Truschel ST,, Ruiz WG,, Shulman T,, Pilewski J,, Sun TT,, Zeidel ML,, Apodaca G . 1999. Primary uroepithelial cultures. A model system to analyze umbrella cell barrier function. J Biol Chem 274 : 15020– 15029.[PubMed] [CrossRef]
10. Andersson KE . 2002. Bladder activation: afferent mechanisms. Urology 59( 5 Suppl 1) : 43– 50.[PubMed] [CrossRef]
11. Heppner TJ,, Layne JJ,, Pearson JM,, Sarkissian H,, Nelson MT . 2011. Unique properties of muscularis mucosae smooth muscle in guinea pig urinary bladder. Am J Physiol Regul Integr Comp Physiol 301 : R351– 362.[PubMed] [CrossRef]
12. Koh BH,, Roy R,, Hollywood MA,, Thornbury KD,, McHale NG,, Sergeant GP,, Hatton WJ,, Ward SM,, Sanders KM,, Koh SD . 2012. Platelet-derived growth factor receptor-α cells in mouse urinary bladder: a new class of interstitial cells. J Cell Mol Med 16 : 691– 700.[PubMed] [CrossRef]
13. McCloskey KD . 2010. Interstitial cells in the urinary bladder–localization and function. Neurourol Urodyn 29 : 82– 87.[PubMed] [CrossRef]
14. Johnston L,, Woolsey S,, Cunningham RM,, O’Kane H,, Duggan B,, Keane P,, McCloskey KD . 2010. Morphological expression of KIT positive interstitial cells of Cajal in human bladder. J Urol 184 : 370– 377.[PubMed] [CrossRef]
15. Cheng S,, Scigalla FP,, Speroni di Fenizio P,, Zhang ZG,, Stolzenburg JU,, Neuhaus J . 2011. ATP enhances spontaneous calcium activity in cultured suburothelial myofibroblasts of the human bladder. PLoS One 6 : e25769. doi:10.1371/journal.pone.0025769 [CrossRef]
16. Nile CJ,, de Vente J,, Gillespie JI . 2010. Stretch independent regulation of prostaglandin E(2) production within the isolated guinea-pig lamina propria. BJU Int 105 : 540– 548.[PubMed] [CrossRef]
17. Fowler CJ,, Griffiths D,, de Groat WC . 2008. The neural control of micturition. Nat Rev Neurosci 9 : 453– 466.[PubMed] [CrossRef]
18. Kanai A,, Andersson KE . 2010. Bladder afferent signaling: recent findings. J Urol 183 : 1288– 1295.[PubMed] [CrossRef]
19. Zagorodnyuk VP,, Brookes SJ,, Spencer NJ . 2010. Structure-function relationship of sensory endings in the gut and bladder. Auton Neurosci 153 : 3– 11.[PubMed] [CrossRef]
20. Zagorodnyuk VP,, Gibbins IL,, Costa M,, Brookes SJ,, Gregory SJ . 2007. Properties of the major classes of mechanoreceptors in the guinea pig bladder. J Physiol 585 : 147– 163.[PubMed] [CrossRef]
21. Birder L,, Wyndaele JJ . 2013. From urothelial signalling to experiencing a sensation related to the urinary bladder. Acta Physiol (Oxf) 207 : 34– 39.[PubMed] [CrossRef]
22. De Wachter S,, Wyndaele JJ . 2008. How sudden is a compelling desire to void? An observational cystometric study on the suddenness of this sensation. BJU Int 101 : 1000– 1003.[PubMed] [CrossRef]
23. Xu L,, Gebhart GF . 2008. Characterization of mouse lumbar splanchnic and pelvic nerve urinary bladder mechanosensory afferents. J Neurophysiol 99 : 244– 253.[PubMed] [CrossRef]
24. Snellings AE,, Yoo PB,, Grill WM . 2012. Urethral flow-responsive afferents in the cat sacral dorsal root ganglia. Neurosci Lett 516 : 34– 38.[PubMed] [CrossRef]
25. Cook SP,, McCleskey EW . 2000. ATP, pain and a full bladder. Nature 407 : 951– 952.[PubMed] [CrossRef]
26. Cockayne DA,, Hamilton SG,, Zhu QM,, Dunn PM,, Zhong Y,, Novakovic S,, Malmberg AB,, Cain G,, Berson A,, Kassotakis L,, Hedley L,, Lachnit WG,, Burnstock G,, McMahon SB,, Ford AP . 2000. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407 : 1011– 1015.[PubMed] [CrossRef]
27. Chai TC,, Keay S . 2004. New theories in interstitial cystitis. Nat Clin Pract Urol 1 : 85– 89.[PubMed] [CrossRef]
28. de Groat WC,, Yoshimura N . 2009. Afferent nerve regulation of bladder function in health and disease. Handb Exp Pharmacol 4 : 91– 138.[PubMed] [CrossRef]
29. Liu HT,, Tyagi P,, Chancellor MB,, Kuo HC . 2010. Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity. BJU Int 106 : 1681– 1685.[PubMed] [CrossRef]
30. Ochodnicky P,, Cruz CD,, Yoshimura N,, Cruz F . 2012. Neurotrophins as regulators of urinary bladder function. Nat Rev Urol 9 : 628– 637.[PubMed] [CrossRef]
31. Bradesi S . 2010. Role of spinal cord glia in the central processing of peripheral pain perception. Neurogastroenterol Motil 22 : 499– 511.[PubMed] [CrossRef]
32. Gosselin RD,, Suter MR,, Ji RR,, Decosterd I . 2010. Glial cells and chronic pain. Neuroscientist 16 : 519– 531.[PubMed] [CrossRef]
33. Grist M,, Chakraborty J . 1994. Identification of a mucin layer in the urinary bladder. Urology 44 : 26– 33.[PubMed] [CrossRef]
34. Prakasam HS,, Gallo LI,, Li H,, Ruiz WG,, Hallows KR,, Apodaca G . 2014. A1 adenosine receptor-stimulated exocytosis in bladder umbrella cells requires phosphorylation of ADAM17 Ser-811 and EGF receptor transactivation. Mol Biol Cell 25 : 3798– 3812.[PubMed] [CrossRef]
35. Bishop BL,, Duncan MJ,, Song J,, Li G,, Zaas D,, Abraham SN . 2007. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat Med 13 : 625– 630.[PubMed] [CrossRef]
36. Romih R,, Korosec P,, de Mello W Jr,, Jezernik K . 2005. Differentiation of epithelial cells in the urinary tract. Cell Tissue Res 320 : 259– 268.[PubMed] [CrossRef]
37. Hicks RM,, Ketterer B,, Warren RC . 1974. The ultrastructure and chemistry of the luminal plasma membrane of the mammalian urinary bladder: a structure with low permeability to water and ions. Philos Trans R Soc Lond B Biol Sci 268 : 23– 38.[PubMed] [CrossRef]
38. Martin H . 1972. [Comparative histological and clinical studies on the glomerula of plasmacytoma kidneys using the semi-thin section technic]. Folia Haematol Int Mag Klin Morphol Blutforsch 98 : 195– 206.[PubMed]
39. Gandhi D,, Molotkov A,, Batourina E,, Schneider K,, Dan H,, Reiley M,, Laufer E,, Metzger D,, Liang F,, Liao Y,, Sun TT,, Aronow B,, Rosen R,, Mauney J,, Adam R,, Rosselot C,, Van Batavia J,, McMahon A,, McMahon J,, Guo JJ,, Mendelsohn C . 2013. Retinoid signaling in progenitors controls specification and regeneration of the urothelium. Dev Cell 26 : 469– 482.[PubMed] [CrossRef]
40. Varley CL,, Stahlschmidt J,, Lee WC,, Holder J,, Diggle C,, Selby PJ,, Trejdosiewicz LK,, Southgate J . 2004. Role of PPARgamma and EGFR signalling in the urothelial terminal differentiation programme. J Cell Sci 117 : 2029– 2036.[PubMed] [CrossRef]
41. Kreft ME,, Romih R,, Kreft M,, Jezernik K . 2009. Endocytotic activity of bladder superficial urothelial cells is inversely related to their differentiation stage. Differentiation 77 : 48– 59.[PubMed] [CrossRef]
42. Kreft ME,, Jezernik K,, Kreft M,, Romih R . 2009. Apical plasma membrane traffic in superficial cells of bladder urothelium. Ann N Y Acad Sci 1152 : 18– 29.[PubMed] [CrossRef]
43. de Boer WI,, Vermeij M,, Diez de Medina SG,, Bindels E,, Radvanyi F,, van der Kwast T,, Chopin D . 1996. Functions of fibroblast and transforming growth factors in primary organoid-like cultures of normal human urothelium. Lab Invest 75 : 147– 156.[PubMed]
44. Bassuk JA,, Cockrane K,, Mitchell ME . 2003. Induction of urothelial cell proliferation by fibroblast growth factor-7 in RAG1-deficient mice. Adv Exp Med Biol 539 : 623– 633.[PubMed] [CrossRef]
45. Varley CL,, Stahlschmidt J,, Smith B,, Stower M,, Southgate J . 2004. Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells. Am J Pathol 164 : 1789– 1798.[PubMed] [CrossRef]
46. Shin K,, Lee J,, Guo N,, Kim J,, Lim A,, Qu L,, Mysorekar IU,, Beachy PA . 2011. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472 : 110– 114.[PubMed] [CrossRef]
47. Robinson D,, Cardozo L . 2011. Estrogens and the lower urinary tract. Neurourol Urodyn 30 : 754– 757.[PubMed] [CrossRef]
48. Apodaca G,, Kiss S,, Ruiz W,, Meyers S,, Zeidel M,, Birder L . 2003. Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol 284 : F966– 976.[PubMed] [CrossRef]
49. Parsons CL,, Lilly JD,, Stein P . 1991. Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 145 : 732– 735.[PubMed]
50. Georgopoulos NT,, Kirkwood LA,, Walker DC,, Southgate J . 2010. Differential regulation of growth-promoting signalling pathways by E-cadherin. PLoS One 5 : e13621. doi:10.1371/journal.pone.0013621 [PubMed] [CrossRef]
51. Aberg KM,, Radek KA,, Choi EH,, Kim DK,, Demerjian M,, Hupe M,, Kerbleski J,, Gallo RL,, Ganz T,, Mauro T,, Feingold KR,, Elias PM . 2007. Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest 117 : 3339– 3349.[PubMed] [CrossRef]
52. Rostand KS,, Esko JD . 1997. Microbial adherence to and invasion through proteoglycans. Infect Immun 65 : 1– 8.[PubMed]
53. Schilling JD,, Hultgren SJ,, Lorenz RG . 2002. Recent advances in the molecular basis of pathogen recognition and host responses in the urinary tract. Int Rev Immunol 21 : 291– 304.[PubMed] [CrossRef]
54. Thumbikat P,, Berry RE,, Schaeffer AJ,, Klumpp DJ . 2009. Differentiation-induced uroplakin III expression promotes urothelial cell death in response to uropathogenic E. coli . Microbes Infect 11 : 57– 65.[PubMed] [CrossRef]
55. Thumbikat P,, Berry RE,, Zhou G,, Billips BK,, Yaggie RE,, Zaichuk T,, Sun TT,, Schaeffer AJ,, Klumpp DJ . 2009. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog 5 : e1000415. doi:10.1371/journal.ppat.1000415 [PubMed] [CrossRef]
56. Wood MW,, Breitschwerdt EB,, Nordone SK,, Linder KE,, Gookin JL . 2012. Uropathogenic E. coli promote a paracellular urothelial barrier defect characterized by altered tight junction integrity, epithelial cell sloughing and cytokine release. J Comp Pathol 147 : 11– 19.[PubMed] [CrossRef]
57. Brady CM,, Apostolidis A,, Yiangou Y,, Baecker PA,, Ford AP,, Freeman A,, Jacques TS,, Fowler CJ,, Anand P . 2004. P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 46 : 247– 253.[PubMed] [CrossRef]
58. Ikeda Y,, Fry C,, Hayashi F,, Stolz D,, Griffiths D,, Kanai A . 2007. Role of gap junctions in spontaneous activity of the rat bladder. Am J Physiol Renal Physiol 293 : F1018– 1025.[PubMed] [CrossRef]
59. Bossé Y,, Paré PD,, Seow CY . 2008. Airway wall remodeling in asthma: from the epithelial layer to the adventitia. Curr Allergy Asthma Rep 8 : 357– 366.[PubMed] [CrossRef]
60. Burnstock G . 2001. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22 : 182– 188.[PubMed] [CrossRef]
61. Du S,, Araki I,, Mikami Y,, Zakoji H,, Beppu M,, Yoshiyama M,, Takeda M . 2007. Amiloride-sensitive ion channels in urinary bladder epithelium involved in mechanosensory transduction by modulating stretch-evoked adenosine triphosphate release. Urology 69 : 590– 595.[PubMed] [CrossRef]
62. Hawthorn MH,, Chapple CR,, Cock M,, Chess-Williams R . 2000. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro . Br J Pharmacol 129 : 416– 419.[PubMed] [CrossRef]
63. Hendrix S . 2008. Neuroimmune communication in skin: far from peripheral. J Invest Dermatol 128 : 260– 261.[PubMed] [CrossRef]
64. Igawa Y,, Aizawa N,, Homma Y . 2010. Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder. Korean J Urol 51 : 811– 818.[PubMed] [CrossRef]
65. Ikeda Y,, Kanai A . 2008. Urotheliogenic modulation of intrinsic activity in spinal cord-transected rat bladders: role of mucosal muscarinic receptors. Am J Physiol Renal Physiol 295 : F454– 461.[PubMed] [CrossRef]
66. Knight GE,, Bodin P,, De Groat WC,, Burnstock G . 2002. ATP is released from guinea pig ureter epithelium on distension. Am J Physiol Renal Physiol 282 : F281– 288.[PubMed] [CrossRef]
67. Lowe EM,, Anand P,, Terenghi G,, Williams-Chestnut RE,, Sinicropi DV,, Osborne JL . 1997. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol 79 : 572– 577.[PubMed] [CrossRef]
68. Pandita RK,, Mizusawa H,, Andersson KE . 2000. Intravesical oxyhemoglobin initiates bladder overactivity in conscious, normal rats. J Urol 164 : 545– 550.[PubMed] [CrossRef]
69. Yamaguchi O,, Chapple CR . 2007. Beta3-adrenoceptors in urinary bladder. Neurourol Urodyn 26( 6 Suppl) : 752– 756.[PubMed] [CrossRef]
70. Hille B . 1992. Ionic Channels of Excitable Membranes, 2nd ed. Sinauer Associates, Sunderland, MA.
71. Parsons CL,, Stein PC,, Bidair M,, Lebow D . 1994. Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis. Neurourol Urodyn 13 : 515– 520.[PubMed] [CrossRef]
72. Parsons CL,, Greenberger M,, Gabal L,, Bidair M,, Barme G . 1998. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 159 : 1862– 1866; discussion 1866–1867.[PubMed]
73. Elliott TS,, Reed L,, Slack RC,, Bishop MC . 1985. Bacteriology and ultrastructure of the bladder in patients with urinary tract infections. J Infect 11 : 191– 199.[CrossRef]
74. Elliott TS,, Slack RC,, Bishop MC . 1985. Bladder changes associated with urinary tract infections. Lancet 1 : 1509. [PubMed] [CrossRef]
75. Fukushi Y,, Orikasa S,, Kagayama M . 1979. An electron microscopic study of the interaction between vesical epitherlium and E. coli . Invest Urol 17 : 61– 68.[PubMed]
76. McTaggart LA,, Rigby RC,, Elliott TS . 1990. The pathogenesis of urinary tract infections associated with Escherichia coli, Staphylococcus saprophyticus and S. epidermidis . J Med Microbiol 32 : 135– 141.[PubMed] [CrossRef]
77. Orikasa S,, Hinman F Jr . 1977. Reaction of the vesical wall to bacterial penetration: resistance to attachment, desquamation, and leukocytic activity. Invest Urol 15 : 185– 193.[PubMed]
78. Mulvey MA,, Lopez-Boado YS,, Wilson CL,, Roth R,, Parks WC,, Heuser J,, Hultgren SJ . 1998. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli . Science 282 : 1494– 1497.[PubMed] [CrossRef]
79. Klumpp DJ,, Weiser AC,, Sengupta S,, Forrestal SG,, Batler RA,, Schaeffer AJ . 2001. Uropathogenic Escherichia coli potentiates type 1 pilus-induced apoptosis by suppressing NF-kappaB. Infect Immun 69 : 6689– 6695.[PubMed] [CrossRef]
80. Mudge CS,, Klumpp DJ . 2005. Induction of the urothelial differentiation program in the absence of stromal cues. J Urol 174 : 380– 385.[PubMed] [CrossRef]
81. Billips BK,, Forrestal SG,, Rycyk MT,, Johnson JR,, Klumpp DJ,, Schaeffer AJ . 2007. Modulation of host innate immune response in the bladder by uropathogenic Escherichia coli . Infect Immun 75 : 5353– 5360.[PubMed] [CrossRef]
82. Billips BK,, Schaeffer AJ,, Klumpp DJ . 2008. Molecular basis of uropathogenic Escherichia coli evasion of the innate immune response in the bladder. Infect Immun 76 : 3891– 3900.[PubMed] [CrossRef]
83. Hunstad DA,, Justice SS,, Hung CS,, Lauer SR,, Hultgren SJ . 2005. Suppression of bladder epithelial cytokine responses by uropathogenic Escherichia coli . Infect Immun 73 : 3999– 4006.[PubMed] [CrossRef]
84. Orth K,, Palmer LE,, Bao ZQ,, Stewart S,, Rudolph AE,, Bliska JB,, Dixon JE . 1999. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285 : 1920– 1923.[PubMed] [CrossRef]
85. Mulvey MA,, Hultgren SJ . 2000. Cell biology. Bacterial spelunkers. Science 289 : 732– 733.[PubMed] [CrossRef]
86. Klumpp DJ,, Rycyk MT,, Chen MC,, Thumbikat P,, Sengupta S,, Schaeffer AJ . 2006. Uropathogenic Escherichia coli induces extrinsic and intrinsic cascades to initiate urothelial apoptosis. Infect Immun 74 : 5106– 5113.[PubMed] [CrossRef]
87. Wu XR,, Sun TT,, Medina JJ . 1996. In vitro binding of type 1 fimbriated Esherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc Natl Acad Sci U S A 93 : 9630– 9635.[PubMed] [CrossRef]
88. Liang FX,, Riedel I,, Deng FM,, Zhou G,, Xu C,, Wu XR,, Kong XP,, Moll R,, Sun TT . 2001. Organization of uroplakin subunits: transmembrane topology, pair formation and plaque composition. Biochem J 355 : 13– 18.[PubMed] [CrossRef]
89. Thumbikat P,, Berry RE,, Schaeffer AJ,, Klumpp DJ . 2008. Differentiation-induced uroplakin III expression promotes urothelial cell death in response to uropathogenic E. coli . Microbes Infect 11 : 57– 65.[PubMed] [CrossRef]
90. Scholz J,, Woolf CJ . 2007. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10 : 1361– 1368.[PubMed] [CrossRef]
91. Agace WW,, Hedges SR,, Ceska M,, Svanborg C . 1993. Interleukin-8 and the neutrophil response to mucosal gram-negative infection. J Clin Invest 92 : 780– 785.[PubMed] [CrossRef]
92. Schaeffer AJ,, Matulewicz RS,, Klumpp DJ, . 2016. Infections of the urinary tract, p 237– 303. In Wein AJ,, Kavoussi LR,, Partin AW,, Peters CA (ed), Campbell-Walsh Urology, 11th ed, vol 1. Elsevier, Philadelphia, PA.
93. Laird JM,, Souslova V,, Wood JN,, Cervero F . 2002. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 22 : 8352– 8356.[PubMed]
94. Rudick CN,, Billips BK,, Pavlov VI,, Yaggie RE,, Schaeffer AJ,, Klumpp DJ . 2010. Host-pathogen interactions mediating pain of urinary tract infection. J Infect Dis 201 : 1240– 1249.[PubMed] [CrossRef]
95. Bjorling DE,, Wang ZY,, Boldon K,, Bushman W . 2008. Bacterial cystitis is accompanied by increased peripheral thermal sensitivity in mice. J Urol 179 : 759– 763.[PubMed] [CrossRef]
96. Rudick CN,, Jiang M,, Yaggie RE,, Pavlov VI,, Done J,, Heckman CJ,, Whitfield C,, Schaeffer AJ,, Klumpp DJ . 2012. O-antigen modulates infection-induced pain states. PLoS One 7 : e41273. doi:10.1371/journal.pone.0041273 [PubMed]
97. Batchelor RA,, Haraguchi GE,, Hull RA,, Hull SI . 1991. Regulation by a novel protein of the bimodal distribution of lipopolysaccharide in the outer membrane of Escherichia coli . J Bacteriol 173 : 5699– 5704.[PubMed]
98. Kos V,, Cuthbertson L,, Whitfield C . 2009. The Klebsiella pneumoniae O2a antigen defines a second mechanism for O antigen ATP-binding cassette transporters. J Biol Chem 284 : 2947– 2956.[PubMed] [CrossRef]
99. Neuhard J,, Thomassen E . 1976. Altered deoxyribonucleotide pools in P2 eductants of Escherichia coli K-12 due to deletion of the dcd gene. J Bacteriol 126 : 999– 1001.[PubMed]
100. Stemler KM,, Crock LW,, Lai HH,, Mills JC,, Gereau RW IV,, Mysorekar IU . 2013. Protamine sulfate induced bladder injury protects from distention induced bladder pain. J Urol 189 : 343– 351.[PubMed] [CrossRef]
101. Zucker RS,, Regehr WG . 2002. Short-term synaptic plasticity. Annu Rev Physiol 64 : 355– 405.[PubMed] [CrossRef]
102. Rosen JM,, Klumpp DJ . 2014. Mechanisms of pain from urinary tract infection. Int J Urol 21( Suppl 1) : 26– 32.[PubMed] [CrossRef]
103. Rudick CN,, Taylor AK,, Yaggie RE,, Schaeffer AJ,, Klumpp DJ . 2014. Asymptomatic bacteriuria Escherichia coli are live biotherapeutics for UTI. PLoS One 9 : e109321. doi:10.1371/journal.pone.0109321 [PubMed] [CrossRef]
104. Sasaki M . 2004. Feed-forward and feedback regulation of bladdercontractility by Barrington’s nucleus in cats. J Physiol 557 : 287– 305.[PubMed] [CrossRef]
105. Lai H,, Gereau RW IV,, Luo Y,, O’Donnell M,, Rudick CN,, Pontari M,, Mullins C,, Klumpp DJ . 2015. Animal models of urologic chronic pelvic pain syndromes: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network. Urology 85 : 1454– 1465.[PubMed] [CrossRef]
106. Rudick CN,, Bryce PJ,, Guichelaar LA,, Berry RE,, Klumpp DJ . 2008. Mast cell-derived histamine mediates cystitis pain. PLoS One 3 : e2096. doi:10.1371/journal.pone.0002096 [PubMed] [CrossRef]
107. Rudick CN,, Chen MC,, Mongiu AK,, Klumpp DJ . 2007. Organ cross talk modulates pelvic pain. Am J Physiol Regul Integr Comp Physiol 293 : R1191– 1198.[PubMed] [CrossRef]
108. Rudick CN,, Pavlov VI,, Chen MC,, Klumpp DJ . 2012. Gender specific pelvic pain severity in neurogenic cystitis. J Urol 187 : 715– 724.[PubMed] [CrossRef]
109. Yang W,, Rudick CN,, Hoxha E,, Allsop SA,, Dimitrakoff JD,, Klumpp DJ . 2012. Ca2+/calmodulin-dependent protein kinase II is associated with pelvic pain of neurogenic cystitis. Am J Physiol Renal Physiol 303 : F350– 356.[PubMed] [CrossRef]
110. Jasmin L,, Janni G,, Manz HJ,, Rabkin SD . 1998. Activation of CNS circuits producing a neurogenic cystitis: evidence for centrally induced peripheral inflammation. J Neurosci 18 : 10016– 10029.[PubMed]
111. Arms L,, Vizzard MA . 2011. Neuropeptides in lower urinary tract function. Handb Exp Pharmacol 202 : 395– 423.[PubMed] [CrossRef]
112. Lai HH,, Qiu CS,, Crock LW,, Morales ME,, Ness TJ,, Gereau RW IV . 2011. Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder. Pain 152 : 2117– 2124.[PubMed] [CrossRef]
113. Crock LW,, Stemler KM,, Song DG,, Abbosh P,, Vogt SK,, Qiu CS,, Lai HH,, Mysorekar IU,, Gereau RW IV . 2012. Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception. Mol Pain 8 : 20. [PubMed] [CrossRef]
114. Han JS,, Neugebauer V . 2004. Synaptic plasticity in the amygdala in a visceral pain model in rats. Neurosci Lett 361 : 254– 257.[PubMed] [CrossRef]
115. Crock LW,, Kolber BJ,, Morgan CD,, Sadler KE,, Vogt SK,, Bruchas MR,, Gereau RW IV . 2012. Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain. J Neurosci 32 : 14217– 14226.[PubMed] [CrossRef]

Back to top
This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error