Changes in Adenosine Triphosphate-stimulated ATP Release Suggest Association Between Cytokine and Purinergic Signaling in Bladder Urothelial Cells

Sun, Yue; Keay, Susan; Lehrfeld, Todd J.; Chai, Toby C.

doi:10.1016/j.urology.2009.02.066

Cited by 29 publications

(32 citation statements)

References 18 publications

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“…It has been shown previously that bladder uroepithelial cells grown in vitro release ATP in response to stretch and exogenous ATP (29,30,31). These previous studies also reported an increased ATP release from uroepithelial cells from patients The black bars show estimated ATP levels generated by the infected cells and are calculated by subtracting the ATP levels generated by IA2 itself from the measured ATP levels in the coincubation experiments (cells plus IA2 [10 8 CFU/ml]).…”

Section: Discussionmentioning

confidence: 94%

“…In a healthy bladder, release of ATP from uroepithelial cells by stretch and distension mediates the sensation of bladder fullness by activation of P2X 3 receptors on suburothelial sensory nerves (5). Pathophysiological conditions cause enhanced bladder release of ATP as shown in patients diagnosed with interstitial cystitis (29,30,31). Although several studies have shown that pathology often results in augmented ATP release from the urothelium, there have not been any studies of ATP release from urothelium infected with bacteria.…”

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confidence: 99%

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Extracellular ATP and P2Y Receptor Activation Induce a Proinflammatory Host Response in the Human Urinary Tract

Säve

Persson

2010

Infect Immun

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Extracellular ATP is released from a variety of cells not only as a consequence of cell injury or cell death but also via nonlytic mechanisms (25). ATP has attracted increasing attention as a danger signal released during the initial phase of infection and inflammation in order to trigger innate immunity (18). In a healthy bladder, release of ATP from uroepithelial cells by stretch and distension mediates the sensation of bladder fullness by activation of P2X 3 receptors on suburothelial sensory nerves (5). Pathophysiological conditions cause enhanced bladder release of ATP as shown in patients diagnosed with interstitial cystitis (29,30,31). Although several studies have shown that pathology often results in augmented ATP release from the urothelium, there have not been any studies of ATP release from urothelium infected with bacteria. Patients with bacteriuria have increased urinary levels of ATP (21), but it is not known whether the bacteria, host, or both produce ATP during infection. In their function as extracellular mediators, nucleotides activate P2 nucleotide receptors that include the ionotrophic P2X receptors (P2X 1 to P2X 7 ) and G-proteincoupled P2Y receptors (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 to P2Y 14 ) (33). In the urinary tract, extracellular ATP may communicate through P2X and P2Y receptors with different cells, such as uroepithelial cells, inflammatory cells, nerves, and myofibroblasts (5). Evidence that P2 receptors, in particular P2Y receptors, may regulate host immunity and modulate phagocytosis, chemotaxis, and cytokine production is now accumulating (14, 16). The P2Y receptor subtypes P2Y 1 , P2Y 2 , and P2Y 4 are expressed throughout the cat bladder urothelium (7), but P2Y receptor expression has not been examined in the human urothelium.Innate immunity is the first line of defense in the urinary tract and triggered by uropathogenic bacteria through activation of Toll-like receptors (TLRs) located on the uroepithelial cell surface (32). Lipopolysaccharide (LPS) is an established ligand for Toll-like receptor 4 (TLR4), but associated coeffector proteins, such as CD14 and MD2, are needed for LPS-induced stimulation of TLR4 (4, 27). TLR4 and CD14 expression by the human urinary tract epithelium remains controversial (3,23,24), and in vitro studies show that the TLR4 receptor can be activated in a LPS-independent manner by P-fimbriated uropathogenic Escherichia coli (UPEC) (12). Once activated, the uroepithelial cells play a central role in the host proinflammatory response through production of chemotactic substances, such as interleukin 6 (IL-6) and IL-8. Several lines of evidence demonstrate that IL-8 is essential for neutrophil transmigration across the infected urothelium and that neutrophils are important for clearance of bacterial infections in the urinary tract (32).

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

Extracellular ATP and P2Y Receptor Activation Induce a Proinflammatory Host Response in the Human Urinary Tract

Säve

Persson

2010

Infect Immun

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“…The urothelium, once thought to provide an impermeable barrier only, is now suggested to have "neuron-like" properties such as plasticity and sensory, transducive, and signaling capabilities, especially in the context of bladder inflammation (2,5,7,8,(61)(62)(63)(64). Urothelial cells share a number of similarities with sensory neurons, including the expression of receptors such as purinergic, norepinephrine, acetylcholine, neuropeptide-and protease-activated receptors, acid-sensing ion channels, neurotrophin receptors, and transient receptor potential channels (2,5,7,8,(61)(62)(63)(64). Because of functional receptor expression and secretion capabilities, urothelial-mediated communication with the detrusor smooth muscle, suburothelial plexus, and/or interstitial cells has been suggested (2,7).…”

Section: Discussionmentioning

confidence: 99%

Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

Arms

Vizzard

2011

American Journal of Physiology-Renal Physiology

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-AKT phosphorylation following peripheral nerve injury or inflammation may play a role in somatic pain processes and visceral inflammation. To examine such a role in micturition reflexes with bladder inflammation, we induced bladder inflammation in adult female Wistar rats (200 -300 g) by injecting cyclophosphamide (CYP) intraperitoneally at acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every third day for 10 days) time points. Western blot analyses of whole urinary bladders showed significant increases (P Յ 0.01) in phosphorylated (p) AKT at all time points; however, the magnitude of AKT phosphorylation varied with duration of CYP treatment. Immunohistochemical analyses of pAKT immunoreactivity (pAKT-IR) in cryostat bladder sections demonstrated duration-dependent, significant (P Յ 0.01) increases in pAKT-IR in both the urothelium and detrusor smooth muscle of CYP-inflamed bladders. Additionally, a suburothelial population of pAKT-IR macrophages (CD68-, MAC2-, and F4/ 80-positive) was present in chronic CYP-treated bladders. The functional role of pAKT in micturition was evaluated using open, conscious cystometry with continuous instillation of saline in conjunction with administration of an inhibitor of AKT phosphorylation, deguelin (1.0 g/10 l), or vehicle (1% DMSO in saline) in control (no inflammation) and CYP (48 h)-treated rats. Bladder capacity, void volume, and intercontraction void interval increased significantly (P Յ 0.05) following intravesical instillation of deguelin in CYP (48 h)-treated rats. These results demonstrate increased AKT phosphorylation in the urinary bladder with urinary bladder inflammation and that blockade of AKT phosphorylation in the urothelium improves overall bladder function. urothelium; cystometry; inflammation; deguelin THE SERINE-THREONINE PROTEIN kinase AKT is involved in cellular survival and protection from apoptosis in a number of tissues and organ systems (6,18,25). Recent studies have demonstrated additional roles for activated (phosphorylated; p) AKT in the initiation and maintenance of neuropathic pain and visceral inflammation (53,59,60,71). Immunohistochemical techniques demonstrate AKT activation in pain transducing C-fiber primary afferents and dorsal horn neurons following peripheral neuronal injury or tissue inflammation (26,58,59,60,71). In visceral inflammation, pAKT levels increase in the spinal cord dorsal horn following chemically induced colitis (53). Upstream regulators of pAKT include growth factors such as platelet-derived growth factor, epidermal growth factor, insulin, thrombin, nerve growth factor (NGF), and brainderived neurotrophic factor (BDNF) as well as other physiological stimuli (6,25,68).Diverse growth factors activate AKT (6, 31, 68), and growth factors are increased in the urinary bladder with inflammation (12,47,48,66,70). Specifically, recent studies by Chung et al.(16) demonstrated increases in pAKT levels with cyclophosphamide (CYP)-induced bladder inflammation and determined that inflammation-induced...

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“…The P2X3 receptor subunit was upregulated during stretch of cultured urothelial cells from patients with IC [645]; P2X2 and P2X3 receptor expression has been demonstrated on human bladder urothelial cells (as well as on afferent nerve terminals); the expression was greater in cells from IC bladder [63,662]. ATP-stimulated ATP release is augmented in IC bladder urothelial cells compared to healthy urothelial cells [648]. They showed further that ATP-stimulated release of ATP from healthy urothelial cells can be induced by treatment with epidermal growth factor and that P2X3 receptors are increased.…”

Section: Detrusor Overactivitymentioning

confidence: 99%

Purinergic signalling in the urinary tract in health and disease

Burnstock

2013

Purinergic Signalling

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Purinergic signalling is involved in a number of physiological and pathophysiological activities in the lower urinary tract. In the bladder of laboratory animals there is parasympathetic excitatory cotransmission with the purinergic and cholinergic components being approximately equal, acting via P2X1 and muscarinic receptors, respectively. Purinergic mechanosensory transduction occurs where ATP, released from urothelial cells during distension of bladder and ureter, acts on P2X3 and P2X2/3 receptors on suburothelial sensory nerves to initiate the voiding reflex, via low threshold fibres, and nociception, via high threshold fibres. In human bladder t h e p u r i n e rg i c c o m p o n e n t o f p a r a s y m p a t h e t i c cotransmission is less than 3 %, but in pathological conditions, such as interstitial cystitis, obstructed and neuropathic bladder, the purinergic component is increased to 40 %. Other pathological conditions of the bladder have been shown to involve purinoceptor-mediated activities, including multiple sclerosis, ischaemia, diabetes, cancer and bacterial infections. In the ureter, P2X7 receptors have been implicated in inflammation and fibrosis. Purinergic therapeutic strategies are being explored that hopefully will be developed and bring benefit and relief to many patients with urinary tract disorders.

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Changes in Adenosine Triphosphate-stimulated ATP Release Suggest Association Between Cytokine and Purinergic Signaling in Bladder Urothelial Cells

Cited by 29 publications

References 18 publications

Extracellular ATP and P2Y Receptor Activation Induce a Proinflammatory Host Response in the Human Urinary Tract

Extracellular ATP and P2Y Receptor Activation Induce a Proinflammatory Host Response in the Human Urinary Tract

Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

Purinergic signalling in the urinary tract in health and disease

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