Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response

Mattoscio, Domenico; Evangelista, Virgilio; Cristofaro, Raimondo De; Recchiuti, Antonio; Pandolfi, Assunta; Silvestre, Sara Di; Manarini, Stefano; Martelli, Nicola; Rocca, Bianca; Petrucci, Giovanna; Angelini, Daniela F.; Battistini, Luca; Robuffo, Iole; Pensabene, Tiziana; Pieroni, Luisa; Furnari, Maria Lucia; Pardo, Francesca; Quattrucci, Serena; Lancellotti, Stefano; Davı̀, Giovanni; Romano, Mario

doi:10.1096/fj.10-159921

Cited by 69 publications

(70 citation statements)

References 37 publications

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“…In order to further our understanding of impaired eicosanoid class switching in CF we considered the roles played by various enzymes involved in eicosanoid biosynthesis (12-LO, LTA 4 H, 5-LO, 15-LO1 and 15-LO2). The activity of 12-LO in platelets from CF patients has been reported to be reduced [31]; however, in our study, 12-LO transcripts were detected at very low copy numbers in only 10 out of 25 airway samples tested, a finding which could possibly represent blood cell contamination from a friable and inflamed airway wall. Overexpression of LTA 4 H could result in a diversion phenomenon, routing the common immediate leukotriene A 4 away from LXA 4 synthesis towards LTB 4 synthesis giving rise to the reduced LXA 4 /LTB 4 ratio observed; however, expression was not significantly different in CF BAL than in control BAL.…”

Section: Discussioncontrasting

confidence: 89%

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

et al. 2014

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Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A 4 (LXA 4 ) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the ''class switch'' of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease.Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA 4 to leukotriene B 4 (LTB 4 ) is depressed in CF BAL (p,0.01), even in the absence of infection (p,0.001).Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p,0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA 4 /LTB 4 ratio (p50.01, r50.66) and with percentage macrophage composition of the BAL fluid (p,0.001, r50.82), which were absent in CF.Impoverished 15-LO2 expression and depression of the LXA 4 /LTB 4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung. @ERSpublications Reduced 15-LO2 expression in the lower airways of children with CF, associated with a depressed LXA 4 /LTB 4 ratio http://ow.ly/tzZWa This article has supplementary material available from

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Section: Discussioncontrasting

confidence: 89%

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

et al. 2014

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“…35 Therefore, one of the most common and important mechanisms of ATP release is simply cell rupture. Given that some purinergic receptors have an EC 50 for ATP as low as 1 mM it is clear that rupture of even a small number of cells can elicit a response in nearby viable cells. 13,36 Exocytosis.…”

Section: Atp Release Mechanismsmentioning

confidence: 99%

“…46 In addition to other ABC transporters, the CFTR has also been shown to mediate outward ATP currents. 47 This mechanism of ATP release potentially plays an important role in injured tissues as the CFTR is expressed in a number of relevant cell types including vascular endothelial cells, 48 red blood cells, 49 platelets, 50 and skeletal muscle.…”

Section: Atp Release Mechanismsmentioning

confidence: 99%

“…A 1 and A 3 receptors generally act through G i/o signaling while the A 2A and A 2B receptor subtypes signal through the counteracting G s system. Importantly, A 1 and A 3 receptors have a high affinity for adenosine (EC 50 < 500 nM), while A 2A receptors have lower affinities, and A 2B receptors have EC 50 's > 10 mM. 92 These opposing pathways play an important role in early inflammatory events.…”

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confidence: 99%

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Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

Rhett

Fann²,

Yost³

2014

Tissue Engineering Part B: Reviews

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Purinergic signaling is a ubiquitous and vital aspect of mammalian biology in which purines-mainly adenosine triphosphate (ATP)-are released from cells through loss of membrane integrity (cell death), exocytosis, or transport/diffusion across membrane channels, and exert paracrine or autocrine signaling effects through three subclasses of well-characterized receptors: the P1 adenosine receptors, the P2X ionotropic nucleotide receptors, and the P2Y metabotropic receptors. ATP and its metabolites are released by damaged and stressed cells in injured tissues. The early events of wound healing, hemostasis, and inflammation are highly regulated by these signals through activation of purinergic receptors on platelets and neutrophils. Recent data have demonstrated that ATP signaling is of particular importance to targeting leukocytes to sites of injury. This is particularly relevant to the subject of implanted medical devices, engineered tissues, and grafts as all these technologies elicit a wound healing response with varying degrees of encapsulation, rejection, extrusion, or destruction of the tissue or device. Here, we review the biology of purinergic signaling and focus on ATP release and response mechanisms that pertain to the early inflammatory phase of wound healing. Finally, therapeutic options are explored, including a new class of peptidomimetic drugs based on the ATP-conductive channel connexin43.

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“…Related studies show ATP currents in cells expressing the multiple drug resistance gene product P-glycoprotein, another member of the ABC transporter family, further supporting a functional role for this family of proteins in the release of ATP [88]. While the major focus of ATP release from CFTR has been in epithelial cell physiology, this transporter has been identified in vascular smooth muscle cells [95], endothelial cells [96] and circulating erythrocytes [28] and platelets [97] providing a potential conduit for ATP release into from these cells.…”

Section: Abc Transportersmentioning

confidence: 94%

Function and Regulation of Pannexin 1 Channels in the Vascular Endothelium

Lohman¹

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The nucleotide adenosine 5'-triphosphate (ATP) has classically been considered the cell's primary energy currency; however, a novel role for ATP as an extracellular autocrine/paracrine signaling molecule has evolved over the past century. Purinergic signaling is now known to regulate a plethora of physiological and pathophysiological processes in almost every organ system. In the vasculature, ATP and its metabolites elicit dual control over blood vessel tone and tissue perfusion, and purinergic signaling events have been implicated in vascular pathologies including atherosclerosis and inflammation.While the importance of extracellular ATP in the vascular system is well recognized, the mechanism(s) mediating the regulated release of the purine from vascular cells are less well understood and are a key target of current investigation. One such ATP-liberation mechanism has been ascribed to the recently identified pannexin (Panx) channels, namely Panx1. Initially, we characterized the expression and localization profiles of Panx isoforms across the systemic vasculature, identifying predominant representation by the Panx1 isoform in both smooth muscle (SMC) and endothelial cells (EC) comprising the blood vessel wall, with more heterogeneous expression profiles observed in specialized vascular systems including the heart, lung and kidney. In particular, the Panx1 isoform is highly expressed in ECs regardless of blood vessel type or size, while Panx1 expression is limited to SMCs of small arteries and arterioles. Panx1 forms hexameric channels in the plasma membrane of ECs, functioning to release ATP in response to a number of stimuli. However, prolonged Panx1 channel activity is extremely detrimental to cell viability. Here we report a novel negative regulatory mechanism that may govern the activity of Panx1 channels in ECs, by which the bioactive gas nitric oxide (NO) covalently modifies two cysteine (Cys) residues in the channel by a process termed S- reinforce the dual effect of purines on peripheral resistance and blood pressure. Purinergic Control of Vascular InflammationWhile the foundation for purinergic control of vascular functions was initially characterized extensively in the context of vascular reactivity and overall blood flow and pressure regulation, it has become increasingly clear that extracellular ATP also plays important regulatory roles in the vascular inflammatory response. Vascular inflammation can be characterized as acute (physiological) or chronic (pathological) in nature.The acute vascular inflammatory response is an innate process of inflammatory cell homing to infected or damaged tissues resulting from integrated cross-talk between circulating leukocytes and the vascular endothelium, primarily at the level of postcapillary venules [61]. This process has been highly studied and is now known to occur in a step-wise manner beginning with local recruitment, rolling (fast and slow), adhesion and final extravasation into the surrounding tissue (reviewed in [62...

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Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response

Cited by 69 publications

References 37 publications

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

Function and Regulation of Pannexin 1 Channels in the Vascular Endothelium

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Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response

Cited by 69 publications

References 37 publications

Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4ratio in children with cystic fibrosis

Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4ratio in children with cystic fibrosis

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

Function and Regulation of Pannexin 1 Channels in the Vascular Endothelium

Contact Info

Product

Resources

About

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis