The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Robert Vink - One of the best experts on this subject based on the ideXlab platform.
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Neurogenic Inflammation after traumatic brain injury and its potentiation of classical Inflammation
Journal of Neuroinflammation, 2016Co-Authors: Frances Corrigan, Kimberley A. Mander, Anna V. Leonard, Robert VinkAbstract:Background The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body We suggest that this may be because classical Inflammation only represents part of the story, with activation of Neurogenic Inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions As such, the Neurogenic inflammatory response can exacerbate classical Inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroInflammation following TBI may require the inhibition of both classical and Neurogenic inflammatory pathways.
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Blocking Neurogenic Inflammation for the treatment of acute disorders of the central nervous system.
International journal of inflammation, 2013Co-Authors: Kate M. Lewis, Renée J. Turner, Robert VinkAbstract:Classical Inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of Neurogenic Inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical Inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of Neurogenic Inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and Neurogenic Inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.
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Neurogenic Inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats
Neuropeptides, 2004Co-Authors: Alan J Nimmo, Robert Vink, Ibolja Cernak, Deanne L Heath, C J BennettAbstract:The present study has used capsaicin-induced neuropeptide depletion to examine the role of Neurogenic Inflammation in the development of edema and functional deficits following traumatic brain injury (TBI). Adult, male rats were treated with capsaicin (neuropeptide-depleted) or equal volume vehicle (controls) 14 days prior to induction of moderate/severe diffuse TBI. Injury in vehicle treated control animals resulted in acute (4–5 h) edema formation, which was confirmed as being vasogenic in origin by diffusion weighted magnetic resonance imaging and the presence of increased permeability of the blood–brain barrier (BBB) to Evans blue dye. There was also a significant decline in brain magnesium concentration, as assessed by phosphorus magnetic resonance spectroscopy, and the development of profound motor and cognitive deficits. In contrast, capsaicin pre-treatment resulted in a significant reduction in post-traumatic edema formation (p<0.001), BBB permeability (p<0.001), free magnesium decline (p<0.01) and both motor and cognitive deficits (p<0.001). We conclude that Neurogenic Inflammation may play an integral role in the development of edema and functional deficits following TBI, and that neuropeptides may be a novel target for development of interventional pharmacological strategies.
Romina Nassini - One of the best experts on this subject based on the ideXlab platform.
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transient receptor potential ankyrin 1 channel localized to non neuronal airway cells promotes non Neurogenic Inflammation
PLOS ONE, 2012Co-Authors: Romina Nassini, Pamela Pedretti, Nadia Moretto, Camilla Fusi, Chiara Carnini, Fabrizio Facchinetti, Arturo R Viscomi, Anna Rita Pisano, Susan StokesberryAbstract:Background: The transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway Inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a Neurogenic mechanism. However the limited clinical evidence for the role of Neurogenic Inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway Inflammation is promoted by non-neuronal TRPA1. Methodology/Principal Findings: By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide substance P (SP), which is released from sensory nerve terminals by capsaicin, acrolein or CS), produced Neurogenic Inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue) in bronchoalveolar lavage (BAL) fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves. Conclusions: Our results demonstrate that, although either TRPV1 or TRPA1 activation causes airway Neurogenic Inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not Neurogenic. This finding suggests that non-neuronal TRPA1 in the airways is functional and potentially capable of contributing to inflammatory airway diseases. (Less)
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Nathalie Vergnolle, Nicolas Cenac, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
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cigarette smoke induced Neurogenic Inflammation is mediated by α β unsaturated aldehydes and the trpa1 receptor in rodents
Journal of Clinical Investigation, 2008Co-Authors: Eunice Andre, Romina Nassini, Serena Materazzi, Barbara Campi, Marcello Trevisani, Silvia Amadesi, Daniela Massi, Christophe Creminon, Natalya Vaksman, Maurizio CivelliAbstract:Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce Neurogenic Inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway Neurogenic Inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.
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The concept of Neurogenic Inflammation.
BJU international, 2008Co-Authors: Pierangelo Geppetti, Romina Nassini, Serena Materazzi, Silvia BenemeiAbstract:Neurogenic inflammatory responses have recently been linked to both acute and chronic pathological conditions in the urinary tract. Neurogenic Inflammation encompasses a series of vascular and non-vascular inflammatory responses, triggered by the activation of primary sensory neurons and the subsequent release of inflammatory neuropeptides, including substance P and calcitonin gene-related peptide. The reduction of Neurogenic inflammatory responses may be key in the mode of action of the adrenergic alpha(1)-adrenoceptor antagonists used to treat lower urinary tract symptoms (LUTS). Indeed, the alpha(1)-adrenoceptor antagonist alfuzosin inhibits expression of the oncogene c-fos- a marker of nociceptive pathway activation - evoked by cyclophosphamide in rats. Capsaicin ameliorates urinary bladder symptoms through its stimulatory action on the transient receptor potential vanilloid 1 (TRPV1) calcium channel, resulting in desensitization of bladder sensory nerve terminals. Involvement of the TRP cation channel, subfamily A, member 1 (TRPA1) has also been reported in models of Neurogenic Inflammation and nociception promoted by the cyclophosphamide metabolite, acrolein. Blockade by alfuzosin demonstrates the beneficial effects of alpha(1)-adrenoceptor antagonists on Neurogenic Inflammation via the transient receptor potential family of ionic channels. Consequently, these drugs may have an important role in reducing LUTS.
Nathalie Vergnolle - One of the best experts on this subject based on the ideXlab platform.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Nathalie Vergnolle, Nicolas Cenac, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
Serena Materazzi - One of the best experts on this subject based on the ideXlab platform.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Nathalie Vergnolle, Nicolas Cenac, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
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cigarette smoke induced Neurogenic Inflammation is mediated by α β unsaturated aldehydes and the trpa1 receptor in rodents
Journal of Clinical Investigation, 2008Co-Authors: Eunice Andre, Romina Nassini, Serena Materazzi, Barbara Campi, Marcello Trevisani, Silvia Amadesi, Daniela Massi, Christophe Creminon, Natalya Vaksman, Maurizio CivelliAbstract:Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce Neurogenic Inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway Neurogenic Inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.
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The concept of Neurogenic Inflammation.
BJU international, 2008Co-Authors: Pierangelo Geppetti, Romina Nassini, Serena Materazzi, Silvia BenemeiAbstract:Neurogenic inflammatory responses have recently been linked to both acute and chronic pathological conditions in the urinary tract. Neurogenic Inflammation encompasses a series of vascular and non-vascular inflammatory responses, triggered by the activation of primary sensory neurons and the subsequent release of inflammatory neuropeptides, including substance P and calcitonin gene-related peptide. The reduction of Neurogenic inflammatory responses may be key in the mode of action of the adrenergic alpha(1)-adrenoceptor antagonists used to treat lower urinary tract symptoms (LUTS). Indeed, the alpha(1)-adrenoceptor antagonist alfuzosin inhibits expression of the oncogene c-fos- a marker of nociceptive pathway activation - evoked by cyclophosphamide in rats. Capsaicin ameliorates urinary bladder symptoms through its stimulatory action on the transient receptor potential vanilloid 1 (TRPV1) calcium channel, resulting in desensitization of bladder sensory nerve terminals. Involvement of the TRP cation channel, subfamily A, member 1 (TRPA1) has also been reported in models of Neurogenic Inflammation and nociception promoted by the cyclophosphamide metabolite, acrolein. Blockade by alfuzosin demonstrates the beneficial effects of alpha(1)-adrenoceptor antagonists on Neurogenic Inflammation via the transient receptor potential family of ionic channels. Consequently, these drugs may have an important role in reducing LUTS.
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4 hydroxynonenal an endogenous aldehyde causes pain and Neurogenic Inflammation through activation of the irritant receptor trpa1
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Marcello Trevisani, Romina Nassini, Serena Materazzi, Eunice Andre, Barbara Campi, Jan Siemens, Diana M Bautista, Noritaka Imamachi, Riccardo Patacchini, Graeme S CottrellAbstract:TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and Neurogenic Inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensitivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous α,β-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, Inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in Neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and Neurogenic Inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.
Nicolas Cenac - One of the best experts on this subject based on the ideXlab platform.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Nathalie Vergnolle, Nicolas Cenac, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.
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a role for transient receptor potential vanilloid 4 in tonicity induced Neurogenic Inflammation
British Journal of Pharmacology, 2010Co-Authors: Serena Materazzi, Nathalie Vergnolle, Nicolas Cenac, Christophe Altier, Laurie Cellars, Kevin Chapman, Gerald W Zamponi, Romina NassiniAbstract:Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause Inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates Inflammation to hypotonic stimuli by a Neurogenic mechanism. Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro-inflammatory neuropeptides from peripheral tissues and on Inflammation were examined. Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co-expressed in some neurones with CGRP and substance P, mediators of Neurogenic Inflammation. Hypotonic solutions and 4α-phorbol 12,13-didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of Neurogenic Inflammation. Intraplantar injection of hypotonic solutions and 4α-phorbol 12,13-didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin. Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces Neurogenic Inflammation. This mechanism may mediate the generation and maintenance of Inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic Inflammation.