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.
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TL;DR: It is concluded that adenosine receptors find their definite involvement in DYP-mediated anti-oxidative and reno-protective effect against ischemia reperfusion-induced acute kidney injury (AKI) in rats.
Abstract: Dipyridamole (DYP) is an anti-platelet agent with marked vasodilator, anti-oxidant, and anti-inflammatory activity. The present study investigated the role of adenosine receptors in DYP-mediated protection against ischemia reperfusion-induced acute kidney injury (AKI) in rats. The rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h. The renal damage induced by ischemia reperfusion injury (IRI) was assessed by measuring creatinine clearance, blood urea nitrogen, uric acid, plasma potassium, fractional excretion of sodium, and microproteinuria in rats. The oxidative stress in renal tissues was assessed by quantification of thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The hematoxylin-eosin staining was carried out to observe histopathological changes in renal tissues. DYP (10 and 30 mg/kg, intraperitoneal, i.p.) was administered 30 min before subjecting the rats to renal IRI. In separate groups, caffeine (50 mg/kg, i.p.), an adenosinergic A1 and A2A receptor antagonist was administered with and without DYP treatment before subjecting the rats to renal IRI. The ischemia reperfusion-induced AKI was demonstrated by significant changes in serum as well as urinary parameters, enhanced oxidative stress, and histopathological changes in renal tissues. The administration of DYP demonstrated protection against AKI. The prior treatment with caffeine abolished DYP-mediated reno-protection suggesting role of A1 and A2A adenosine receptors in DYP-mediated reno-protection in rats. It is concluded that adenosine receptors find their definite involvement in DYP-mediated anti-oxidative and reno-protective effect against ischemia reperfusion-induced AKI.
8 citations
Cites background from "Protection from pulmonary ischemia-..."
...The activation of A2A receptors is documented to protect against IRI of various organs including heart, liver, lungs, as well as kidneys in various animal species (Day et al. 2004, 2006; Peart and Headrick, 2007; Sharma et al. 2009)....
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...The activation of A2A receptors is documented to reduce inflammation through cyclic adenosine monophosphate (cAMP)-mediated inhibition of cytokine release and inactivation of inflammatory cells (Day et al. 2005; Sharma et al. 2009; Okusa et al. 2011)....
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TL;DR: Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance and the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.
Abstract: The A2 adenosine receptors play an important role, among others, in the regulation of inflammatory process and glucose homeostasis in diabetes and obesity. Thus, the presented project evaluated of influence of the selective antagonist of A2A adenosine receptor-KD-64 as compared to the known non-selective antagonist-caffeine on these two particular processes. Two different inflammation models were induced namely local and systemic inflammation. Obesity was induced in mice by high-fat diet and the tested compounds (KD-64 and caffeine) were administrated for 21 days. KD-64 showed anti-inflammatory effect in both tested inflammation models and administered at the same dose as ketoprofen exerted stronger effect than this reference compound. Elevated levels of IL-6 and TNF-α observed in obese control mice were significantly lowered by the administration of KD-64 and were similar to the values observed in control non-obese mice. Interestingly, caffeine increased the levels of these parameters. In contrast to caffeine which had no influence on AlaT activity, KD-64 administration significantly lowered AlaT activity in the obese mice. Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance. Thus, the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.
8 citations
Cites background from "Protection from pulmonary ischemia-..."
...The adenosine A2A receptor is predominantly expressed on inflammatory cells, including neutrophils, mast cells, macrophages, monocytes, and platelets [29] and in many animal studies it has been demonstrated that its activation reduced inflammatory processes [29, 30] and improved molecular markers of inflammation....
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Book•
01 Jan 2015
TL;DR: Intuitively structured and comprehensive, The Vertebrate Blood-Gas Barrier in Health and Disease is ideal for researchers and clinicians interested in pneumology and angiology.
Abstract: This comprehensive volume on the blood-gas barrier (BGB) among vertebrates covers its structure and composition along with aspects of evolution, bioengineering, and morphometry. The book also discusses the embryological development of the BGB, including chronology of events and molecular control in vertebrates; modulation of the barrier function, including cyclic stretch-induced increases in alveolar epithelial permeability; mechanisms of lung vascular/epithelial permeability; transport mechanisms of the BGB, including sodium transport channels; factors affecting trans-barrier traffic of fluids, such as chronic elevation of pulmonary microvascular pressure; stress failure; regulation and repair in acute lung injury; chronic lung disease; and lung transportation. Ten authoritative chapters approach the blood-gas barrier holistically, from basic structure and development to pathology and treatment. Properties of the BGB are discussed in the earlier chapters, followed by prenatal and post-natal development and mechanisms of the healthy BGB. The latter half of the book delves into the pathology of the BGB, analyzing common afflictions and exploring options for treatment, including its alterations during lung transplantation. Intuitively structured and comprehensive, The Vertebrate Blood-Gas Barrier in Health and Disease is ideal for researchers and clinicians interested in pneumology and angiology
7 citations
TL;DR: In this article, the authors proposed that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.
Abstract: COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.
7 citations
15 Feb 2012
TL;DR: Improvements in surgical technique and perioperative care over the past two decades have led to a 30-fold increase in the number of lung transplant recipients worldwide and a promising future for lung transplantation.
Abstract: Lung transplantation provides a curative hope for many with end-stage pulmonary disease. Since the first attempt at human lung transplantation in 1963, scientific and surgical advancements have supported improved survival and quality of life for lung transplant recipients (Hardy, et al., 1963). Significant contributions in cardiopulmonary bypass, pharmacologic immunosuppression, and donor-recipient risk stratification have increased the success and associated clinical adoption of this treatment strategy. Continued research efforts in novel methods for organ preservation, donor graft selection, and recipient risk stratification support a promising future for lung transplantation. Improvements in surgical technique and perioperative care over the past two decades have led to a 30-fold increase in the number of lung transplant recipients worldwide to 2,769 patients in 2008 (Christie, et al., 2010). Since 1994, bilateral lung transplantation has supplanted single lung transplantation as the primary strategy for organ replacement to now account for 71% of lung transplants performed worldwide (Christie, et al., 2010). In 2010, the primary indications for lung transplantation included chronic obstructive pulmonary disease (35.5%), idiopathic pulmonary fibrosis (22.1%), and cystic fibrosis (16.0%) (Christie, et al., 2010). Despite this promising evolution and the increasing number of indications for lung transplantation, long-term survival has shown minimal improvement. Lung transplant outcomes remain the poorest of any solid organ transplant, with international survival estimates demonstrating a 21% one-year and 50% five-year mortality (Christie, et al., 2010). Lung ischemia-reperfusion (IR) injury following transplantation imposes a significant threat to graft and recipient survival (Diamond & Christie, 2010). IR injury is the main cause of primary graft failure and significantly increases the risk for acute rejection and long-term graft dysfunction (de Perrot, et al., 2003). Multivariate analysis of long-term graft function has implicated IR injury as an independent predictor for bronchiolitis obliterans syndrome (BOS), the most common cause of long-term morbidity and mortality after lung transplantation (Fiser, et al., 2002). IR-induced lung injury is characterized by nonspecific alveolar damage, lung edema, and hypoxemia occurring within 72 hours after lung transplantation (de Perrot, et al., 2003). The estimated incidence of IR injury is 41% following lung transplantation with an associated 30-day mortality of 40%, compared to 7% for
6 citations
References
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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.
857 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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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...
680 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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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...
650 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.
585 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.
412 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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