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Journal ArticleDOI

Adenosine A2A receptor activation on CD4+ T lymphocytes and neutrophils attenuates lung ischemia–reperfusion injury

TL;DR: It is demonstrated that CD4+ T cells play a key role in mediating lung inflammation after ischemia-reperfusion, and ATL313 likely exerts its protective effect largely through activation of adenosine A(2A) receptors on CD4- T cells and neutrophils.
About: This article is published in The Journal of Thoracic and Cardiovascular Surgery.The article was published on 2010-02-01 and is currently open access. It has received 60 citations till now. The article focuses on the topics: Lung injury & T cell.
Citations
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Book ChapterDOI
TL;DR: It is apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.
Abstract: Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

1,565 citations


Cites background from "Adenosine A2A receptor activation o..."

  • ...…pharmacological depletion strategies, results in reduced neutrophil recruitment and associated injury after I/R (Caldwell et al., 2005; Horie et al., 1999; Martin et al., 2010; Osman et al., 2009; Park et al., 2002; Sharma et al., 2010; Uchida et al., 2010; Yang et al., 2009; Zwacka et al., 1997)....

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  • ...T cellmediated recruitment of neutrophils has been attributed to T cell secretion of IL-17 (Caldwell et al., 2005; Sharma et al., 2010), but other T-cell-derived factors, for example, IL-1, TNFa, likely also play a role....

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Journal ArticleDOI
TL;DR: How local purinergic signalling changes over time during tissue responses to injury or disease is reviewed, and the potential of targeting purInergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer is discussed.
Abstract: Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.

555 citations

Journal ArticleDOI
TL;DR: Methods for prevention of primary graft dysfunction after lung transplant are urgently needed, and understanding mechanisms of ischemia-reperfusion injury is critical for the development of novel and effective therapeutic approaches.
Abstract: Purpose of review Lungs are extremely susceptible to injury, and despite advances in surgical management and immunosuppression, outcomes for lung transplantation are the worst of any solid organ transplant. The success of lung transplantation is limited by high rates of primary graft dysfunction because of ischemia-reperfusion injury characterized by robust inflammation, alveolar damage, and vascular permeability. This review will summarize major mechanisms of lung ischemia-reperfusion injury with a focus on the most recent findings in this area. Recent findings Over the past 18 months, numerous studies have described strategies to limit lung ischemia-reperfusion injury in experimental settings, which often reveal mechanistic insight. Many of these strategies involved the use of various antioxidants, anti-inflammatory agents, mesenchymal stem cells, and ventilation with gaseous molecules. Further advancements have been achieved in understanding mechanisms of innate immune cell activation, neutrophil infiltration, endothelial barrier dysfunction, and oxidative stress responses. Summary Methods for prevention of primary graft dysfunction after lung transplant are urgently needed, and understanding mechanisms of ischemia-reperfusion injury is critical for the development of novel and effective therapeutic approaches. In doing so, both acute and chronic outcomes of lung transplant recipients will be significantly improved.

160 citations

Journal ArticleDOI
TL;DR: The current evidence for the anti-inflammatory effects of the A2AAR in different cell types is reviewed and possible molecular mechanisms mediating these effects are discussed, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways.
Abstract: The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2A adenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

108 citations


Cites background or methods from "Adenosine A2A receptor activation o..."

  • ...As in other tissues, A2AAR activation protects against inflammatory tissue damage in the lung caused by IRI[90,112,113]....

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  • ...Evidence for the specific cell types involved in this A2AAR-mediated response has been obtained using a mouse model of lung IRI in which ATL313 inhibited lung injury and reduced CD4 + T-cell activation and neutrophil recruitment[90]....

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  • ...Levels of inflammatory cytokines and chemokines (TNF, IL-17, KC, MCP-1, MIP-1, and RANTES) in BALF were also lower in the absence of neutrophils or CD4 + T cells, but could only be further reduced by ATL313 in neutrophil-depleted mice, indicating that suppression of neutrophil activity may be secondary to ligation of A2AARs on CD4 + T cells[90]....

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  • ...Activation of the A2AAR has been found to protect against inflammatory damage caused by ischaemia and reperfusion in a number of tissues including liver[88], kidney[89], lung[90], and heart[91]....

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Journal ArticleDOI
TL;DR: Studies of ventilator-induced lung injury revealed induction of the ADORA2B during ALI in vivo that was abolished following HIF inhibition or genetic deletion of Hif1a, and implicate HIF in the transcriptional control of pulmonary adenosine signaling during ALi.
Abstract: Although acute lung injury (ALI) contributes significantly to critical illness, resolution often occurs spontaneously through endogenous pathways. We recently found that mechanical ventilation increases levels of pulmonary adenosine, a signaling molecule known to attenuate lung inflammation. In this study, we hypothesized a contribution of transcriptionally controlled pathways to pulmonary adenosine receptor (ADOR) signaling during ALI. We gained initial insight from microarray analysis of pulmonary epithelia exposed to conditions of cyclic mechanical stretch, a mimic for ventilation-induced lung disease. Surprisingly, these studies revealed a selective induction of the ADORA2B. Using real-time RT-PCR and Western blotting, we confirmed an up to 9-fold induction of the ADORA2B following cyclic mechanical stretch (A549, Calu-3, or human primary alveolar epithelial cells). Studies using ADORA2B promoter constructs identified a prominent region within the ADORA2B promoter conveying stretch responsiveness. This region of the promoter contained a binding site for the transcription factor hypoxia-inducible factor (HIF)-1. Additional studies using site-directed mutagenesis or transcription factor binding assays demonstrated a functional role for HIF-1 in stretch-induced increases of ADORA2B expression. Moreover, studies of ventilator-induced lung injury revealed induction of the ADORA2B during ALI in vivo that was abolished following HIF inhibition or genetic deletion of Hif1a. Together, these studies implicate HIF in the transcriptional control of pulmonary adenosine signaling during ALI.

92 citations

References
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Journal ArticleDOI
01 Oct 2004-Immunity
TL;DR: Increasing evidence shows that IL-17 family members play an active role in inflammatory diseases, autoimmune diseases, and cancer, which places IL- 17 family members and their receptors as potential targets for future pharmacotherapy.

2,382 citations


"Adenosine A2A receptor activation o..." refers background in this paper

  • ...IL-17, produced largely by CD4þnatural killer T cells and T helper 17 cells, is a key cytokine for the recruitment, activation, and migration of neutrophils.(24) Thus, reduced levels of KC (a potent neutrophil chemokine) and MPO (ie, neutrophil infiltration) in the ATL313-treated groups are likely secondary to the inactivation of CD4þ T cells....

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Journal ArticleDOI
20 Dec 2001-Nature
TL;DR: It is suggested that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.
Abstract: Inappropriate or prolonged inflammation is the main cause of many diseases; for this reason it is important to understand the physiological mechanisms that terminate inflammation in vivo. Agonists for several Gs-protein-coupled receptors, including cell-surface adenosine purinergic receptors, can increase levels of immunosuppressive cyclic AMP in immune cells; however, it was unknown whether any of these receptors regulates inflammation in vivo. Here we show that A2a adenosine receptors have a non-redundant role in the attenuation of inflammation and tissue damage in vivo. Sub-threshold doses of an inflammatory stimulus that caused minimal tissue damage in wild-type mice were sufficient to induce extensive tissue damage, more prolonged and higher levels of pro-inflammatory cytokines, and death of male animals deficient in the A2a adenosine receptor. Similar observations were made in studies of three different models of inflammation and liver damage as well as during bacterial endotoxin-induced septic shock. We suggest that A2a adenosine receptors are a critical part of the physiological negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.

1,198 citations

Journal ArticleDOI
TL;DR: This work has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.
Abstract: Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.

1,072 citations

Journal ArticleDOI
TL;DR: The results suggest that IL-15 could represent a physiological trigger that leads to IL-17 production following bacterial infection, and this was concomitant with an increased number of T cells and macrophages, together with an increase of KC and Macrophage-inflammatory protein-2 levels in the lung tissue.
Abstract: IL-17 is a cytokine implicated in the regulation of inflammation. We investigated the role of this cytokine in neutrophil recruitment using a model of LPS-induced lung inflammation in mice. In the bronchoalveolar lavage, LPS induced a first influx of neutrophils peaking at day 1, followed by a second wave, peaking at day 2. IL-17 levels were increased during the late phase neutrophilia (day 2), and this was concomitant with an increased number of T cells and macrophages, together with an increase of KC and macrophage-inflammatory protein-2 levels in the lung tissue. Intranasal treatment with a neutralizing murine anti-IL-17 Ab inhibited the late phase neutrophilia. In the bronchoalveolar lavage cells, IL-17 mRNA was detected at days 1, 2, and 3 postchallenge, with a strong expression at day 2. This expression was associated with CD4(+) and CD8(+) cells, but also with neutrophils. When challenged with LPS, despite the absence of T cells, SCID mice also developed a neutrophilic response associated with IL-17 production. In BALB/c mice, IL-15 mRNA, associated mainly with neutrophils, was evidenced 1 day after LPS challenge. In vitro, IL-15 was able to induce IL-17 release from purified spleen CD4(+) cells, but not spleen CD8(+) or airway neutrophils. We have shown that IL-17, produced mainly by CD4(+) cells, but also by neutrophils, plays a role in the mobilization of lung neutrophils following bacterial challenge. In addition, our results suggest that IL-15 could represent a physiological trigger that leads to IL-17 production following bacterial infection.

558 citations


"Adenosine A2A receptor activation o..." refers result in this paper

  • ...This supports prior studies suggesting that neutrophils may also be a source of IL-17.(25) However,...

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  • ...This supports prior studies suggesting that neutrophils may also be a source of IL-17....

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