Nerve Growth Factor and Its High-Affinity Receptor in Chronic Pancreatitis

Frieß, Helmut; Zhu, Z.; Mola, Fabio F. di; Kulli, Christoph; Graber, H.U.; Andrén‐Sandberg, Åke; Zimmermann, Arthur; Korc, Murray; Reinshagen, Max; Büchler, Markus W.

doi:10.1097/00000658-199911000-00002

Cited by 160 publications

(107 citation statements)

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“…In addition to the role of NGF in bladder function, it has also been identified as a key molecule in the signaling of pain during inflammation (1,17,23,24,26,61). Visceral inflammation is often accompanied by an increase in sensitivity of somatic structures to noxious stimuli, commonly called referred hyperalgesia (9,75).…”

Section: Increased Somatic Sensitivity After Rvsmentioning

confidence: 99%

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Merrill

Malley

Vizzard

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Merrill L, Malley S, Vizzard MA. Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression. Am J Physiol Regul Integr Comp Physiol 305: R147-R156, 2013. First published May 8, 2013 doi:10.1152/ajpregu.00089.2013.-Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly (P Յ 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly (P Յ 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly (P Յ 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly (P Յ 0.01) increased at all monofilament forces tested (0.1-4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly (P Յ 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity. micturition; stress; nerve growth factor; ELISA; somatic sensitivity STRESS CONTRIBUTES to symptom exacerbation in many disease states, including functional disorders of the urinary bladder such as overactive bladder (OAB) and interstitial cystitis (IC)/ bladder pain syndrome (BPS) (3,38,58,72). Urinary frequency is a common symptom among patients with OAB or IC/BPS, although the end result of frequent voiding may differ [reduce incontinence episodes (OAB) vs. reduce pain with bladder filling (IC/BPS)]. Patients with IC/BPS report symptom worsening during stress, as do patients with other disorders associated with IC/BPS including rheumatoid arthritis, psoriasis, and irritable bowel syndrome (47,72). Symptom worsening during stress may be due, in part, to disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol, through feedback on the HPA axis, normally acts to attenuate inflammation (47); however, abnormalities in the feedback may cause dysregulation of the inflammatory response. Therefore, patients...

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Section: Increased Somatic Sensitivity After Rvsmentioning

confidence: 99%

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Merrill

Malley

Vizzard

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…It does not cross-react with other neurotrophin receptors (Trk-B or Trk-C). These two antibodies have been characterized by immunocytochemistry and functional assay [17,19,47,48].…”

Section: Rna Preparation and Rt-pcr Analysis Of Ngf Gp140mentioning

confidence: 99%

NGF-withdrawal induces apoptosis in pancreatic beta cells in vitro

et al. 2001

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Beta cells originate from precursor cells in the pancreatic ducts, although the possibility of an early migration of the neuroectodermal cells to the endoderm has not been completely ruled out [1±3]. These cells share many similarities with neurons such as the expression of neuron-specific molecules, that is tyrosine hydroxylase or dopamine b-hydroxylase. They are electrically excitable like neurons and insulin release is a process resembling neurotransmitter release, involving cell depolarization and vesicle exocytosis [4]. Beta cells and neuronal cells could be sensitive to the same growth and differentiation factors since specific transcriptional activators (Islets1, Pax-6 and Beta2) are expressed in beta cells and neurons, whereas the transcriptional repressor factor NRSF/ Diabetologia (2001) Abstract Aims/hypothesis. Using primary cultures of human pancreatic islets, purified human pancreatic beta cells and the mouse bTC6-F7 cell line, we analysed the expression of nerve growth factor, (NGF/NGF) receptors in beta cells. To investigate whether NGF could sub-serve an autocrine antiapoptotic role in beta cells, we studied the effects of NGF withdrawal using a neutralizing monoclonal anti-NGF antibody.Methods. The expression of NGF and NGF receptors (gp140 Trk-A and p75 NTR ) were analysed by RT-PCR and immunofluorescence. Pulse-chase experiments and beta cell/PC12 co-cultures were used to investigate NGF production and secretion from beta cells. Possible apoptosis induced by NGF withdrawal was monitored by phosphatidylserine translocation, nucleosomal formation, DNA laddering and FACS analysis. Involvement of transcription/translation mechanisms were investigated as well as the gp140Trk-A required. Finally, signal transduction pathways typically involved in apoptotic mechanisms were analysed by western blot analysis.Results. We show that NGF and both NGF receptors, gp140Trk-A and p75 NTR are expressed in beta cells where NGF is produced and secreted in a biologically active form. NGF-withdrawal induces beta-cell transcription/translation independent apoptosis but mediated by gp140Trk-A. Analysis of signal transduction pathways revealed that NGF withdrawal inhibits the PI3-K, protein kinase B (AKT), Bad survival pathway and activates c-Jun kinase (JNK) whereas ERKs and p38 mitogen-activated protein kinase (MAPK) are not affected. Moreover, Bcl-XL, but not Bcl-2 protein expression are reduced. Conclusion/interpretaiton. We suggest that the integrity of the NGF/NGF receptor system and NGF bioavailability participate in controlling beta-cell survival in culture which represents a key issue for improving possibilities for transplantations in the treatment of diabetes. [Diabetologia (2001

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“…The process can lead to ischemia and local changes in the gut which by themselves can cause pain, but there is also destruction of the nerves, and therefore neuropathic pain features are likely prevalent (for review see 24). As outlined later in this chapter several recent articles have demonstrated upregulation of signalling molecules involved in inflammation and pronociceptive mediators, but also neurotropic factors in the pancreatic parenchyma in patients with CP (31). Increased neural density and hypertrophy, sprouting and neuritis of the intrapancreatic nerves, as well as activation of glia and immune cells have also been reported in pancreatic tissue from the patients (11).…”

Section: Pain Pathogenesismentioning

confidence: 99%

“…Systematic analysis of human CP tissues revealed that intrapancreatic nerves are enlarged in the resected inflammatory mass, irrespective of the etiology of the CP (30). These neuroplastic alterations during pancreatic neuropathy seem to have an impact on the clinical course of the disease, because the extent of neuroplasticity is closely correlated to the severity of pain in CP patients (31). On the other hand, neuro-inflammation is a characteristic feature of neuropathic pain syndromes (54).…”

Section: Morphological Alterationsmentioning

confidence: 99%

“…The tissue levels of nerve growth factor (NGF) and the glial-cell-line-derived neurotrophic factor family member artemin and neurturin in CP tissues have been demonstrated to correlate to the extent of neural hypertrophy and the degree of pain sensation in these patients (9,31). Similarly, overexpression of the neuronal chemokine fractalkine in CP tissues and pancreatic nerves is known to correlate to pancreatic neuritis, and to the severity and duration of the pain syndrome in CP (12).…”

Section: Morphological Alterationsmentioning

confidence: 99%

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