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Article ; Online: Role of neurogenic inflammation in local communication in the visceral mucosa.

Birder, Lori A / Kullmann, F Aura

2018 Volume 40, Issue 3, Page(s) 261–279

Abstract: Intense research has focused on the involvement of the nervous system in regard to cellular mechanisms underlying neurogenic inflammation in the pelvic viscera. Evidence supports the neural release of inflammatory factors, trophic factors, and ... ...

Abstract	Intense research has focused on the involvement of the nervous system in regard to cellular mechanisms underlying neurogenic inflammation in the pelvic viscera. Evidence supports the neural release of inflammatory factors, trophic factors, and neuropeptides in the initiation of inflammation. However, more recently, non-neuronal cells including epithelia, endothelial, mast cells, and paraneurons are likely important participants in nervous system functions. For example, the urinary bladder urothelial cells are emerging as key elements in the detection and transmission of both physiological and nociceptive stimuli in the lower urinary tract. There is mounting evidence that these cells are involved in sensory mechanisms and can release mediators. Further, localization of afferent nerves next to the urothelium suggests these cells may be targets for transmitters released from bladder nerves and that chemicals released by urothelial cells may alter afferent excitability. Modifications of this type of communication in a number of pathological conditions can result in altered release of epithelial-derived mediators, which can activate local sensory nerves. Taken together, these and other findings highlighted in this review suggest that neurogenic inflammation involves complex anatomical and physiological interactions among a number of cell types in the bladder wall. The specific factors and pathways that mediate inflammatory responses in both acute and chronic conditions are not well understood and need to be further examined. Elucidation of mechanisms impacting on these pathways may provide insights into the pathology of various types of disorders involving the pelvic viscera.
MeSH term(s)	Animals ; Humans ; Neurogenic Inflammation/metabolism ; Urinary Bladder/metabolism ; Urothelium/metabolism
Language	English
Publishing date	2018-03-26
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2316828-6
ISSN	1863-2300 ; 1863-2297
ISSN (online)	1863-2300
ISSN	1863-2297
DOI	10.1007/s00281-018-0674-0
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Article: Aging-Associated Changes in Oxidative Stress Negatively Impacts the Urinary Bladder Urothelium.

de Rijk, Mathijs M / Wolf-Johnston, Amanda / Kullmann, Aura F / Taiclet, Stephanie / Kanai, Anthony J / Shiva, Sruti / Birder, Lori A

International neurourology journal

2022 Volume 26, Issue 2, Page(s) 111–118

Abstract: Purpose: Lower urinary tract symptoms are known to significantly increase with age, negatively impacting quality of life and self-reliance. The urothelium fulfills crucial tasks, serving as a barrier protecting the underlying bladder tissue from the ... ...

Abstract	Purpose: Lower urinary tract symptoms are known to significantly increase with age, negatively impacting quality of life and self-reliance. The urothelium fulfills crucial tasks, serving as a barrier protecting the underlying bladder tissue from the harsh chemical composition of urine, and exhibits signaling properties via the release of mediators within the bladder wall that affect bladder functioning. Aging is associated with detrimental changes in cellular health, in part by increasing oxidative stress in the bladder mucosa, and more specifically the urothelium. This, in turn, may impact urothelial mitochondrial health and bioenergetics. Methods: We collected mucosal tissue samples from both young (3-4 months old) and aged (25-30 months old) rats. Tissue was evaluated for p21-Arc, nitrotyrosine, and cytochrome C expression by western immunoblotting. Urothelial cells were cultured for single-cell imaging to analyze basal levels of reactive oxygen species and the mitochondrial membrane potential. Mitochondrial bioenergetics and cellular respiration were investigated by the Seahorse assay, and measurements of adenosine triphosphate release were made using the luciferin-luciferase assay. Results: Aging was associated with a significant increase in biomarkers of cellular senescence, oxidative stress, and basal levels of reactive oxygen species. The mitochondrial membrane potential was significantly lower in urothelial cell cultures from aged animals, and cultures from aged animals showed a significant decrease in mitochondrial bioenergetics. Conclusion: Aging-related increases in oxidative stress and excessive reactive oxygen species may be contributing factors underlying lower urinary tract symptoms in older adults. The mechanisms outlined in this study could be utilized to identify novel pharmaceutical targets to improve aging-associated bladder dysfunction.
Language	English
Publishing date	2022-06-30
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2584447-7
ISSN	2093-6931 ; 2093-4777
ISSN (online)	2093-6931
ISSN	2093-4777
DOI	10.5213/inj.2142224.112
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Article: The aging bladder insights from animal models.

Birder, Lori A / Kullmann, Aura F / Chapple, Christopher R

Asian journal of urology

2017 Volume 5, Issue 3, Page(s) 135–140

Abstract: Alterations in bladder function with aging are very common and are very likely to represent an increasing healthcare problem in the years to come with the general aging of the population. In this review the authors describe the prevalence of lower ... ...

Abstract	Alterations in bladder function with aging are very common and are very likely to represent an increasing healthcare problem in the years to come with the general aging of the population. In this review the authors describe the prevalence of lower urinary tract symptoms (LUTS) and comment upon potential mechanisms which may be responsible for the increasing prevalence of lower LUTS with increasing age, based on laboratory studies. It is clear that there is a complex interplay between the various components of the neural innervation structure of the bladder in leading to changes with age, which are likely to underpin the LUTS which are seen in the aging bladder.
Language	English
Publishing date	2017-05-26
Publishing country	Singapore
Document type	Journal Article ; Review
ZDB-ID	2831144-9
ISSN	2214-3882
ISSN	2214-3882
DOI	10.1016/j.ajur.2017.03.004
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Article ; Online: Pharmacodynamic evaluation of Lys

Kullmann, F Aura / Katofiasc, M / Thor, K B / Marson, Lesley

Naunyn-Schmiedeberg's archives of pharmacology

2017 Volume 390, Issue 2, Page(s) 163–173

Abstract: The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor ( ... ...

Abstract	The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK
MeSH term(s)	Animals ; Colon/drug effects ; Colon/innervation ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Feasibility Studies ; Female ; Gastrointestinal Motility/drug effects ; Indoles/pharmacology ; Muscle Contraction/drug effects ; Neurokinin A/analogs & derivatives ; Neurokinin A/pharmacology ; Peptide Fragments/pharmacology ; Piperidines/pharmacology ; Pressure ; Rats, Sprague-Dawley ; Receptors, Neurokinin-2/drug effects ; Receptors, Neurokinin-2/metabolism ; Spinal Cord Injuries/drug therapy ; Spinal Cord Injuries/metabolism ; Spinal Cord Injuries/physiopathology ; Time Factors ; Urinary Bladder/drug effects ; Urinary Bladder/innervation ; Urodynamics/drug effects
Chemical Substances	GR 159897 ; Indoles ; Peptide Fragments ; Piperidines ; Receptors, Neurokinin-2 ; neurokinin A (4-10), Lys(5)-MeLeu(9)-Nle(10)- ; Neurokinin A (86933-74-6)
Language	English
Publishing date	2017-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	121471-8
ISSN	1432-1912 ; 0028-1298
ISSN (online)	1432-1912
ISSN	0028-1298
DOI	10.1007/s00210-016-1317-4
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Ud II Zs.5: Show issues

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Article ; Online: Implantation accuracy of novel polyimide stereotactic electroencephalographic depth electrodes-a human cadaveric study.

Kullmann, Aura / Akberali, Farida / Van Gompel, Jaime J / McGovern, Robert A / Marsh, W Richard / Kridner, Debra / Diaz-Botia, Camilo A / Park, Michael C

Frontiers in medical technology

2024 Volume 6, Page(s) 1320762

Abstract: Introduction: Stereoelectroencephalography (sEEG) is a minimally invasive procedure that uses depth electrodes stereotactically implanted into brain structures to map the origin and propagation of seizures in epileptic patients. Implantation accuracy of ...

Abstract	Introduction: Stereoelectroencephalography (sEEG) is a minimally invasive procedure that uses depth electrodes stereotactically implanted into brain structures to map the origin and propagation of seizures in epileptic patients. Implantation accuracy of sEEG electrodes plays a critical role in the safety and efficacy of the procedure. This study used human cadaver heads, simulating clinical practice, to evaluate (1) neurosurgeon's ability to implant a new thin-film polyimide sEEG electrode according to the instructions for use (IFU), and (2) implantation accuracy. Methods: Four neurosurgeons (users) implanted 24 sEEG electrodes into two cadaver heads with the aid of the ROSA robotic system. Usability was evaluated using a questionnaire that assessed completion of all procedure steps per IFU and user errors. For implantation accuracy evaluation, planned electrode trajectories were compared with post-implantation trajectories after fusion of pre- and postoperative computer tomography (CT) images. Implantation accuracy was quantified using the Euclidean distance for entry point error (EPE) and target point error (TPE). Results: All sEEG electrodes were successfully placed following the IFU without user errors, and post-implant survey of users showed favorable handling characteristics. The EPE was 1.28 ± 0.86 mm and TPE was 1.61 ± 0.89 mm. Long trajectories (>50 mm) had significantly larger EPEs and TPEs than short trajectories (<50 mm), and no differences were found between orthogonal and oblique trajectories. Accuracies were similar or superior to those reported in the literature when using similar experimental conditions, and in the same range as those reported in patients. Discussion: The results demonstrate that newly developed polyimide sEEG electrodes can be implanted as accurately as similar devices in the marker without user errors when following the IFU in a simulated clinical environment. The human cadaver ex-vivo test system provided a realistic test system, owing to the size, anatomy and similarity of tissue composition to that of the live human brain.
Language	English
Publishing date	2024-02-22
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-3129
ISSN (online)	2673-3129
DOI	10.3389/fmedt.2024.1320762
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Article ; Online: Layer-dependent role of collagen recruitment during loading of the rat bladder wall.

Cheng, Fangzhou / Birder, Lori A / Kullmann, F Aura / Hornsby, Jack / Watton, Paul N / Watkins, Simon / Thompson, Mark / Robertson, Anne M

Biomechanics and modeling in mechanobiology

2017 Volume 17, Issue 2, Page(s) 403–417

Abstract: In this work, we re-evaluated long-standing conjectures as to the source of the exceptionally large compliance of the bladder wall. Whereas these conjectures were based on indirect measures of loading mechanisms, in this work we take advantage of ... ...

Abstract	In this work, we re-evaluated long-standing conjectures as to the source of the exceptionally large compliance of the bladder wall. Whereas these conjectures were based on indirect measures of loading mechanisms, in this work we take advantage of advances in bioimaging to directly assess collagen fibers and wall architecture during biaxial loading. A custom biaxial mechanical testing system compatible with multiphoton microscopy was used to directly measure the layer-dependent collagen fiber recruitment in bladder tissue from 9 male Fischer rats (4 adult and 5 aged). As for other soft tissues, the bladder loading curve was exponential in shape and could be divided into toe, transition and high stress regimes. The relationship between collagen recruitment and loading curves was evaluated in the context of the inner (lamina propria) and outer (detrusor smooth muscle) layers. The large extensibility of the bladder was found to be possible due to folds in the wall (rugae) that provide a mechanism for low resistance flattening without any discernible recruitment of collagen fibers throughout the toe regime. For more extensible bladders, as the loading extended into the transition regime, a gradual coordinated recruitment of collagen fibers between the lamina propria layer and detrusor smooth muscle layer was found. A second important finding was that wall extensibility could be lost by premature recruitment of collagen in the outer wall that cut short the toe region. This change was correlated with age. This work provides, for the first time, a mechanistic understanding of the role of collagen recruitment in determining bladder extensibility and capacitance.
MeSH term(s)	Animals ; Biomechanical Phenomena ; Collagen/metabolism ; Compliance ; Male ; Microscopy, Fluorescence, Multiphoton ; Mucous Membrane/metabolism ; Muscle, Smooth/metabolism ; Rats, Inbred F344 ; Stress, Mechanical ; Urinary Bladder/metabolism ; Weight-Bearing
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2017-10-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2093052-5
ISSN	1617-7940 ; 1617-7959
ISSN (online)	1617-7940
ISSN	1617-7959
DOI	10.1007/s10237-017-0968-5
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Zs.A 5966: Show issues

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Article ; Online: Urothelial Tight Junction Barrier Dysfunction Sensitizes Bladder Afferents.

Montalbetti, Nicolas / Rued, Anna C / Taiclet, Stefanie N / Birder, Lori A / Kullmann, F Aura / Carattino, Marcelo D

eNeuro

2017 Volume 4, Issue 3

Abstract: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, ... ...

Abstract	Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, the epithelial barrier that lines the interior of the bladder, contributes to the symptoms of IC/BPS. To examine the consequence of increased urothelial permeability on pelvic pain and afferent excitability, we overexpressed in the urothelium claudin 2 (Cldn2), a tight junction (TJ)-associated protein whose message is significantly upregulated in biopsies of IC/BPS patients. Consistent with the presence of bladder-derived pain, rats overexpressing Cldn2 showed hypersensitivity to von Frey filaments applied to the pelvic region. Overexpression of Cldn2 increased the expression of c-Fos and promoted the activation of ERK1/2 in spinal cord segments receiving bladder input, which we conceive is the result of noxious stimulation of afferent pathways. To determine whether the mechanical allodynia observed in rats with reduced urothelial barrier function results from altered afferent activity, we examined the firing of acutely isolated bladder sensory neurons. In patch-clamp recordings, about 30% of the bladder sensory neurons from rats transduced with Cldn2, but not controls transduced with GFP, displayed spontaneous activity. Furthermore, bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials from rats transduced with Cldn2 showed hyperexcitability in response to suprathreshold electrical stimulation. These findings suggest that as a result of a leaky urothelium, the diffusion of urinary solutes through the urothelial barrier sensitizes bladders afferents, promoting voiding at low filling volumes and pain.
Language	English
Publishing date	2017-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0381-16.2017
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Article ; Online: Urothelial proliferation and regeneration after spinal cord injury.

Kullmann, F Aura / Clayton, Dennis R / Ruiz, Wily G / Wolf-Johnston, Amanda / Gauthier, Christian / Kanai, Anthony / Birder, Lori A / Apodaca, Gerard

American journal of physiology. Renal physiology

2017 Volume 313, Issue 1, Page(s) F85–F102

Abstract: The basal, intermediate, and superficial cell layers of the urothelium undergo rapid and complete recovery following acute injury; however, the effects of chronic injury on urothelial regeneration have not been well defined. To address this discrepancy, ... ...

Abstract	The basal, intermediate, and superficial cell layers of the urothelium undergo rapid and complete recovery following acute injury; however, the effects of chronic injury on urothelial regeneration have not been well defined. To address this discrepancy, we employed a mouse model to explore urothelial changes in response to spinal cord injury (SCI), a condition characterized by life-long bladder dysfunction. One day post SCI there was a focal loss of umbrella cells, which are large cells that populate the superficial cell layer and normally express uroplakins (UPKs) and KRT20, but not KRT5, KRT14, or TP63. In response to SCI, regions of urothelium devoid of umbrella cells were replaced with small superficial cells that lacked KRT20 expression and appeared to be derived in part from the underlying intermediate cell layer, including cells positive for KRT5 and TP63. We also observed KRT14-positive basal cells that extended thin cytoplasmic extensions, which terminated in the bladder lumen. Both KRT14-positive and KRT14-negative urothelial cells proliferated 1 day post SCI, and by 7 days, cells in the underlying lamina propria, detrusor, and adventitia were also dividing. At 28 days post SCI, the urothelium appeared morphologically patent, and the number of proliferative cells decreased to baseline levels; however, patches of small superficial cells were detected that coexpressed UPKs, KRT5, KRT14, and TP63, but failed to express KRT20. Thus, unlike the rapid and complete restoration of the urothelium that occurs in response to acute injuries, regions of incompletely differentiated urothelium were observed even 28 days post SCI.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Cell Proliferation ; Disease Models, Animal ; Female ; Keratin-14/metabolism ; Keratin-15/metabolism ; Keratin-20/metabolism ; Mice, Inbred C57BL ; Phenotype ; Phosphoproteins/metabolism ; Regeneration ; Spinal Cord Injuries/metabolism ; Spinal Cord Injuries/pathology ; Spinal Cord Injuries/physiopathology ; Time Factors ; Trans-Activators/metabolism ; Urinary Bladder/innervation ; Urinary Bladder/metabolism ; Urinary Bladder/pathology ; Urinary Bladder/ultrastructure ; Urothelium/innervation ; Urothelium/metabolism ; Urothelium/pathology ; Urothelium/ultrastructure
Chemical Substances	Biomarkers ; Keratin-14 ; Keratin-15 ; Keratin-20 ; Krt1-14 protein, mouse ; Krt1-15 protein, mouse ; Krt20 protein, mouse ; Phosphoproteins ; Trans-Activators ; Trp63 protein, mouse
Language	English
Publishing date	2017-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00592.2016
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Article ; Online: Acute spinal cord injury is associated with mitochondrial dysfunction in mouse urothelium.

Kullmann, Aura F / Truschel, Steven T / Wolf-Johnston, Amanda S / McDonnell, Bronagh M / Lynn, A M / Kanai, Anthony John / Kessler, Thomas M / Apodaca, Gerard / Birder, Lori A

Neurourology and urodynamics

2019 Volume 38, Issue 6, Page(s) 1551–1559

Abstract: Aim: To characterize the effects of acute spinal cord injury (SCI) on mitochondrial morphology and function in bladder urothelium and to test the therapeutic efficacy of early treatment with the mitochondrially targeted antioxidant, MitoTempo.: ... ...

Abstract	Aim: To characterize the effects of acute spinal cord injury (SCI) on mitochondrial morphology and function in bladder urothelium and to test the therapeutic efficacy of early treatment with the mitochondrially targeted antioxidant, MitoTempo. Methods: We used a mouse model of acute SCI by spinal cord transection between the T8-T9 vertebrae with or without MitoTempo delivery at the time of injury followed by tissue processing at 3 days after SCI. Control, SCI, and SCI-MitoTempo-treated mice were compared in all experimental conditions. Assessments included analysis of markers of mitochondrial health including accumulation of reactive oxygen species (ROS), morphological changes in the ultrastructure of mitochondria by transmission electron microscopy, and Western blot analysis to quantify protein levels of markers for autophagy and altered mitochondrial dynamics. Results: SCI resulted in an increase in oxidative stress markers and ROS production, confirming mitochondrial dysfunction. Mitochondria from SCI mice developed large electron-dense inclusions and these aberrant mitochondria accumulated throughout the cytoplasm suggesting an inability to clear dysfunctional mitochondria by mitophagy. SCI mice also exhibited elevated levels of dynamin-related protein 1 (DRP1), consistent with a disruption of mitochondrial dynamics. Remarkably, treatment with MitoTempo reversed many of the SCI-induced abnormalities that we observed. Conclusions: Acute SCI negatively and severely affects mitochondrial health of bladder urothelium. Early treatment of SCI with MitoTempo may be a viable therapeutic agent to mitigate these deleterious effects.
MeSH term(s)	Acute Disease ; Animals ; Antioxidants/pharmacology ; Apoptosis ; Autophagy ; Dynamins/biosynthesis ; Dynamins/genetics ; Female ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mitochondrial Diseases/etiology ; Mitochondrial Diseases/metabolism ; Organophosphorus Compounds/pharmacology ; Oxidative Stress/drug effects ; Piperidines/pharmacology ; Reactive Oxygen Species/metabolism ; Spinal Cord Injuries/metabolism ; Urothelium/metabolism
Chemical Substances	Antioxidants ; MitoTEMPO ; Organophosphorus Compounds ; Piperidines ; Reactive Oxygen Species ; Dnm1l protein, mouse (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2019-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604904-7
ISSN	1520-6777 ; 0733-2467
ISSN (online)	1520-6777
ISSN	0733-2467
DOI	10.1002/nau.24037
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Article: Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo

Kullmann, F. Aura / David McKenna / Grace I. Wells / Karl B. Thor

Life sciences. 2014 Mar. 28, v. 100, no. 1

2014

Abstract: Bombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats ... ...

Abstract	Bombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats and in a diabetic rat model of voiding dysfunction.In vivo cystometry experiments were performed in adult female Sprague–Dawley rats under urethane anesthesia. Diabetes was induced by streptozotocin (STZ; 65mg/kg, i.p.) injection. Experiments were performed 9 and 20weeks post STZ-treatment. Drugs included neuromedin B (NMB; BB1 receptor preferring agonist), and gastrin-releasing peptide (GRP; BB2 receptor preferring agonist).NMB and GRP (0.01–100μg/kg in sham rats; 0.1–300μg/kg in STZ-treated rats, i.v.) increased micturition frequency, bladder contraction amplitude and area under the curve dose dependently in both sham and STZ-treated rats. In addition, NMB (3, 10μg/kg i.v.) triggered voiding in >80% of STZ-treated rats when the bladder was filled to a sub-threshold voiding volume. NMB and GRP increased mean arterial pressure and heart rate at the highest doses, 100 and 300μg/kg.Activation of bombesin receptors facilitated neurogenic bladder contractions in vivo. Single applications of agonists enhanced or triggered voiding in sham rats as well as in the STZ-treated rat model of diabetic voiding dysfunction. These results suggest that BB receptors may be targeted for drug development for conditions associated with poor detrusor contraction such as an underactive bladder condition.
Keywords	adults ; agonists ; anesthesia ; animal disease models ; bladder ; bombesin ; bombesin receptors ; diabetes ; females ; gastrin-releasing peptide ; heart rate ; peptides ; rats ; streptozotocin ; urethane
Language	English
Dates of publication	2014-0328
Size	p. 35-44.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2014.01.071
Database	NAL-Catalogue (AGRICOLA)

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