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Journal ArticleDOI

Protection from pulmonary ischemia-reperfusion injury by adenosine A2A receptor activation

26 Jun 2009-Respiratory Research (BioMed Central)-Vol. 10, Iss: 1, pp 58-58

TL;DR: Specific activation of A2AARs provides potent protection against lung IR injury via attenuation of inflammation, and occurs in the absence of circulating blood thereby indicating a protective role of A 2AAR activation on resident lung cells such as alveolar macrophages.

AbstractBackground: Lung ischemia-reperfusion (IR) injury leads to significant morbidity and mortality which remains a major obstacle after lung transplantation. However, the role of various subset(s) of lung cell populations in the pathogenesis of lung IR injury and the mechanisms of cellular protection remain to be elucidated. In the present study, we investigated the effects of adenosine A 2A receptor (A 2A AR) activation on resident lung cells after IR injury using an isolated, bufferperfused murine lung model. Methods: To assess the protective effects of A2AAR activation, three groups of C57BL/6J mice were studied: a sham group (perfused for 2 hr with no ischemia), an IR group (1 hr ischemia + 1 hr reperfusion) and an IR+ATL313 group where ATL313, a specific A 2A AR agonist, was included in the reperfusion buffer after ischemia. Lung injury parameters and pulmonary function studies were also performed after IR injury in A2AAR knockout mice, with or without ATL313 pretreatment. Lung function was assessed using a buffer-perfused isolated lung system. Lung injury was measured by assessing lung edema, vascular permeability, cytokine/chemokine activation and myeloperoxidase levels in the bronchoalveolar fluid. Results: After IR, lungs from C57BL/6J wild-type mice displayed significant dysfunction (increased airway resistance, pulmonary artery pressure and decreased pulmonary compliance) and significant injury (increased vascular permeability and edema). Lung injury and dysfunction after IR were significantly attenuated by ATL313 treatment. Significant induction of TNF-α, KC (CXCL1), MIP-2 (CXCL2) and RANTES (CCL5) occurred after IR which was also attenuated by ATL313 treatment. Lungs from A2AAR knockout mice also displayed significant dysfunction, injury and cytokine/ chemokine production after IR, but ATL313 had no effect in these mice. Conclusion: Specific activation of A 2A ARs provides potent protection against lung IR injury via attenuation of inflammation. This protection occurs in the absence of circulating blood thereby indicating a protective role of A2AAR activation on resident lung cells such as alveolar macrophages. Specific A 2A AR activation may be a promising therapeutic target for the prevention or treatment of pulmonary graft dysfunction in transplant patients.

Topics: Lung injury (73%), Pulmonary compliance (57%), Lung transplantation (57%), Lung (56%), Reperfusion injury (55%)

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Citations
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Journal ArticleDOI
TL;DR: The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described.
Abstract: Purinergic signaling plays important roles in control of vascular tone and remodeling. There is dual control of vascular tone by ATP released as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow (producing shear stress) or hypoxia acts on P2X and P2Y receptors on endothelial cells to produce nitric oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In this review, we stress the differences in neural and endothelial factors in purinergic control of different blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described. The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia, thrombosis and stroke, diabetes, and migraine, is discussed.

230 citations


Cites background from "Protection from pulmonary ischemia-..."

  • ...A2A receptor agonists attenuated cardiac dysfunction arising from pulmonary ischemia-reperfusion injury (Reece et al., 2005; Ellman et al., 2008; Gazoni et al., 2008; Sharma et al., 2009)....

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Journal ArticleDOI
TL;DR: Evidence indicates extracellular adenosine plays a role in orchestrating the resolution of pulmonary edema and inflammation during ALI.
Abstract: Acute lung injury (ALI) is a lung disease characterized by pulmonary edema and severe hypoxia. The past decade hosted a search for endogenous mechanisms controlling lung inflammation and pulmonary edema during ALI. As such, recent evidence indicates extracellular adenosine in orchestrating the resolution of pulmonary edema and inflammation during ALI.

101 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.

93 citations


Cites background from "Protection from pulmonary ischemia-..."

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

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Journal ArticleDOI
TL;DR: Key observations are discussed that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis.
Abstract: Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis.

92 citations


Cites background from "Protection from pulmonary ischemia-..."

  • ...These include reperfusion injury in the heart [11], liver [13], kidney [9], and lung [6]....

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Journal ArticleDOI
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.
Abstract: Objective Adenosine A 2A receptor activation potently attenuates lung ischemia–reperfusion injury. This study tests the hypothesis that adenosine A 2A receptor activation attenuates ischemia–reperfusion injury by inhibiting CD4+ T cell activation and subsequent neutrophil infiltration. Methods An in vivo model of lung ischemia–reperfusion injury was used. C57BL/6 mice were assigned to either sham group (left thoracotomy) or 7 study groups that underwent ischemia–reperfusion (1 hour of left hilar occlusion plus 2 hours of reperfusion). ATL313, a selective adenosine A 2A receptor agonist, was administered 5 minutes before reperfusion with or without antibody depletion of neutrophils or CD4+ T cells. After reperfusion, the following was measured: pulmonary function using an isolated, buffer-perfused lung system, T cell infiltration by immunohistochemistry, myeloperoxidase and proinflammatory cytokine/chemokine levels in bronchoalveolar lavage fluid, lung wet/dry weight, and microvascular permeability. Results ATL313 significantly improved pulmonary function and reduced edema and microvascular permeability after ischemia–reperfusion compared with control. Immunohistochemistry and myeloperoxidase content demonstrated significantly reduced infiltration of neutrophils and CD4+ T cells after ischemia–reperfusion in ATL313-treated mice. Although CD4+ T cell–depleted and neutrophil-depleted mice displayed significantly reduced lung injury, no additional protection occurred when ATL313 was administered to these mice. Expression of tumor necrosis factor-α, interleukin 17, KC, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and RANTES were significantly reduced in neutrophil- and CD4+ T cell–depleted mice and reduced further by ATL313 only in neutrophil-depleted mice. Conclusions These results demonstrate that CD4+ T cells play a key role in mediating lung inflammation after ischemia–reperfusion. ATL313 likely exerts its protective effect largely through activation of adenosine A 2A receptors on CD4+ T cells and neutrophils.

60 citations


Cites background from "Protection from pulmonary ischemia-..."

  • ...Our previous studies have shown that administration of a selective A2AAR agonist during reperfusion significantly reduces lung and heart IR injury in both in vivo and ex vivo animal models.(8,11,15) In a recent study, we(16) have...

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References
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Journal ArticleDOI
TL;DR: Better understanding of the mechanisms of ischemia-reperfusion injury, improvements in the technique of lung preservation, and the development of a new preservation solution specifically for the lung have been associated with a reduction in the incidence of primary graft failure from approximately 30 to 15% or less.
Abstract: Ischemia-reperfusion-induced lung injury is characterized by nonspecific alveolar damage, lung edema, and hypoxemia occurring within 72 hours after lung transplantation. The most severe form may lead to primary graft failure and remains a significant cause of morbidity and mortality after lung transplantation. Over the past decade, better understanding of the mechanisms of ischemia-reperfusion injury, improvements in the technique of lung preservation, and the development of a new preservation solution specifically for the lung have been associated with a reduction in the incidence of primary graft failure from approximately 30 to 15% or less. Several strategies have also been introduced into clinical practice for the prevention and treatment of ischemia-reperfusion-induced lung injury with various degrees of success. However, only three randomized, double-blinded, placebo-controlled trials on ischemia-reperfusion-induced lung injury have been reported in the literature. In the future, the development of new agents and their application in prospective clinical trials are to be expected to prevent the occurrence of this potentially devastating complication and to further improve the success of lung transplantation.

798 citations


"Protection from pulmonary ischemia-..." refers background in this paper

  • ...It is known that neutrophils progressively infiltrate the transplanted lung after reperfusion and contribute to injury by releasing oxygen free radicals [2]....

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  • ...Background Ischemia-reperfusion (IR)-induced lung injury remains the major cause of primary graft failure after lung transplantation [1,2]....

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Journal ArticleDOI
TL;DR: Novel adenosine receptor subtype-selective ligands have recently been developed that will help investigators to sort out how adenoine protects tissues from injury and to identify new therapeutic agents that hold promise for the treatment of inflammatory and ischemic diseases.
Abstract: Adenosine accumulation during ischemia and inflammation protects tissues from injury. In ischemic tissues adenosine accumulates due to inhibition of adenosine kinase, and in inflamed tissues adenos...

658 citations


"Protection from pulmonary ischemia-..." refers background in this paper

  • ...The attenuation of IR injury by A2AAR activation is postulated to involve a purinergic regulatory process whereby the A2AAR coupled to a stimulatory G protein leads to an increase in cyclic adenosine monophosphate (cAMP), thereby resulting in reduced cytokine release and inactivation of inflammatory cells [30,31]....

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Journal ArticleDOI
TL;DR: The observations reviewed here suggest that adenosine and agents that act throughadenosine are excellent candidates for development as anti-inflammatory agents.
Abstract: Adenosine receptors are present on most cells and organs, yet, although the physiological effects of adenosine were first described over 60 years ago, the potential therapeutic uses of adenosine ha...

635 citations


"Protection from pulmonary ischemia-..." refers background in this paper

  • ...Adenosine receptor sub-classification has shown specifically that activation of A2AAR produces antiinflammatory responses and prevents leukocyte adhesion [18,19]....

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TL;DR: The authors discuss the effects and implications of atelectasis in the perioperative period and illustrate how preventive measures may impact outcome and the impact of atElectasis and its prevention in acute lung injury.
Abstract: Atelectasis occurs in the dependent parts of the lungs of most patients who are anesthetized. Development of atelectasis is associated with decreased lung compliance, impairment of oxygenation, increased pulmonary vascular resistance, and development of lung injury. The adverse effects of atelectasis persist into the postoperative period and can impact patient recovery. This review article focuses on the causes, nature, and diagnosis of atelectasis. The authors discuss the effects and implications of atelectasis in the perioperative period and illustrate how preventive measures may impact outcome. In addition, they examine the impact of atelectasis and its prevention in acute lung injury.

514 citations


"Protection from pulmonary ischemia-..." refers background in this paper

  • ...Atelectasis and reexpansion has been shown to induce injury involving edema, free radical generation, and apoptosis [33,34]....

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TL;DR: Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis and results indicate that acute rejection is the most significant risk factor for development of obliteration and that obliteration responds to treatment with augmented immunosuppression when it is detected early by surveillance transbronchial biopsy.
Abstract: With a prevalence of 34% (55/162 at-risk recipients) and a mortality of 25% (14/55 affected recipients), obliterative bronchiolitis is the most significant long-term complication after pulmonary transplantation Because of its importance, we examined donor-recipient characteristics and antecedent clinical events to identify factors associated with development of obliterative bronchiolitis, which might be eliminated or modified to decrease its prevalence We also compared treatment outcome between recipients whose diagnosis was made early by surveillance transbronchial lung biopsy before symptoms or decline in pulmonary function were present versus recipients whose diagnosis was made later when symptoms or declines in pulmonary function were present Postoperative airway ischemia, an episode of moderate or severe acute rejection (grade III/IV), three or more episodes of histologic grade II (or greater) acute rejection, and cytomegalovirus disease were risk factors for development of obliterative bronchiolitis Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis: 81% (13/15) versus 33% (13/40); p

410 citations


"Protection from pulmonary ischemia-..." refers background in this paper

  • ...Pulmonary IR injury also entails the induction of pro-inflammatory cytokines and chemokines [9,10], and the contribution of TNF-α, IL-1β, IL-6 and KC (CXCL1) in the genesis and progression of lung IR injury has been demonstrated [5,11,12]....

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