Protection from pulmonary ischemia-reperfusion injury by adenosine A2A receptor activation
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.
Abstract: Background: 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.
Citations
More filters
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.
256 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)....
[...]
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.
113 citations
Cites background from "Protection from pulmonary ischemia-..."
...These include reperfusion injury in the heart [11], liver [13], kidney [9], and lung [6]....
[...]
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.
110 citations
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 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]....
[...]
TL;DR: This study is the first, to the authors' knowledge, to demonstrate that endothelial Panx1 plays a key role in mediating vascular permeability, inflammation, edema, leukocyte infiltration, and lung dysfunction after I/R.
Abstract: Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate ce...
75 citations
References
More filters
TL;DR: It is concluded that alveolar macrophages are an essential player in the initiation of acute lung I/R injury and are a major producer/initiator of TNF-alpha, MCP-1, and MIP-2.
Abstract: Lung ischemia-reperfusion (I/R) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribu...
176 citations
"Protection from pulmonary ischemia-..." refers background or methods or result in this paper
...We have previously demonstrated that alveolar macrophage activation [4] and alveolar type II epithelial cell activation [5] are associated with the induction of lung IR injury....
[...]
...For this study, we used an isolated, buffer-perfused mouse lung system (Hugo Sachs Elektronik, March-Huggstetten, Germany) as previously described by our laboratory [4]....
[...]
...Previous studies from our group and others have demonstrated a significant role of alveolar macrophages in the initiation of lung IR injury [4,46,47]....
[...]
...We have previously shown that a significant number of marginated neutrophils are retained in buffer-perfused lungs [4]....
[...]
...We have previously demonstrated the presence of marginated neutrophils in buffer-perfused mouse lungs [4]....
[...]
TL;DR: Tumor necrosis factor alpha and interleukin 1beta help regulate the development of lung ischemia-reperfusion injury and appear to promote injury by altering expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment.
145 citations
"Protection from pulmonary ischemia-..." refers background in this paper
...The pro-inflammatory cascade in lung IR injury involving TNF-α has also been previously documented by our group and others [12,49,50]....
[...]
TL;DR: Elevations in adenosine can directly impact lung inflammation and physiology, and this finding may have important implications in the regulation of pulmonary inflammation and airway hyperresponsiveness.
Abstract: Adenosine is a signaling nucleoside that is elevated in the lungs of asthmatics. We have engineered a mouse model that has elevated levels of adenosine as a result of the partial expression of the enzyme that metabolizes adenosine, adenosine deaminase (ADA). Mice with lowered levels of ADA enzymatic activity were generated by the ectopic expression of an ADA minigene in the gastrointestinal tract of otherwise ADA-deficient mice. These mice developed progressive lung inflammation and damage and died at 4-5 mo of age from respiratory distress. Associated with this phenotype was a progressive increase in lung adenosine levels. Examination of airway physiology at 6 wk of age revealed alterations in airway hyperresponsiveness. This was reversed following the lowering of adenosine levels using ADA enzyme therapy and also through the use of the adenosine receptor antagonist theophylline, implicating both the nucleoside and its receptors in airway physiological alterations. All four adenosine receptors were expressed in the lungs of both control and partially ADA-deficient mice. However, transcript levels for the A(1), A(2B), and A(3) adenosine receptors were significantly elevated in partially ADA-deficient lungs. There was a significant increase in alveolar macrophages, and monocyte chemoattractant protein-3 was found to be elevated in the bronchial epithelium of these mice, which may have important implications in the regulation of pulmonary inflammation and airway hyperresponsiveness. Collectively, these findings suggest that elevations in adenosine can directly impact lung inflammation and physiology.
140 citations
"Protection from pulmonary ischemia-..." refers background in this paper
...It is plausible that activation of other adenosine receptors (A1, A2B and A3), which are all expressed in the lung [40], may have significant, anti-inflammatory roles in the pathogenesis of IR....
[...]
TL;DR: It is demonstrated that endogenous or exogenous preischemic activation of A1 ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.
Abstract: Controversy exists regarding the effect of A1 adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A1 ARs in ...
138 citations
"Protection from pulmonary ischemia-..." refers background in this paper
...It is plausible that activation of other adenosine receptors (A1, A2B and A3), which are all expressed in the lung [40], may have significant, anti-inflammatory roles in the pathogenesis of IR. For example, it is well documented that A1AR plays a role in protecting the heart [41] and kidney [ 42 ] against IR injury....
[...]
TL;DR: The hypothesis that regulation of adenosine receptor expression, especially up-regulation of the A(2A)AR, is part of a delayed feedback mechanism initiated through NF-kappaB to terminate the activation of human and mouse macrophages is supported.
Abstract: The A2A adenosine receptor (A2AAR) mediates anti-inflammatory actions of adenosine in a variety of cell types. LPS (lipopolysaccharide) was reported to induce a small ( 100-fold increase in A2AAR mRNA. LPS-induced increases in mRNA for A2AAR and TNFα (tumour necrosis factor α) are reduced by 90% in IPMΦ pretreated with the NF-κB (nuclear factor κB) inhibitor, BAY 11-7082 {(E)3-[(4-methylphenyl)sulphonyl]-2-propenenitrile; 10 μM}. In Wehi-3 cells exposed to LPS, A2AAR and A2BAR transcripts are elevated by 290- and 10-fold respectively, the A1AR transcript is unchanged and the A3AR transcript is decreased by 67%. The induction of A2AAR mRNA by LPS is detectable after 1 h, reaches a peak at 6 h at 600 times control and remains elevated beyond 24 h. The ED50 (effective dose) of LPS is 2.3 ng/ml. A2AAR receptor number, measured by 125I-ZM241385 binding to whole cells, is undetectable in naive cells and increases linearly at a rate of 23 receptors·cell−1·min−1 to a Bmax of 348 fmol/mg (28000 receptors/cell) in 20 h. The increase in receptor number is correlated with an increase in the potency of an A2A agonist (4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester; referred to as ATL146e) to stimulate cAMP in these cells. After LPS pretreatment, the potency of the A2A agonist, ATL146e, to reduce TNFα release from IPMΦ was increased by 200-fold. The results support the hypothesis that regulation of adenosine receptor expression, especially up-regulation of the A2AAR, is part of a delayed feedback mechanism initiated through NF-κB to terminate the activation of human and mouse macrophages.
136 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]....
[...]