scispace - formally typeset
Search or ask a question
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.
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.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
TL;DR: A sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI are demonstrated.
Abstract: CCL5/RANTES, a chemoattractant for myeloid cells, is induced by hepatic ischemia/reperfusion injury (IRI). The roles of CCL5 in hepatic IRI were carried out by means of CCL5 immunodepletion, antagonistic competition by Met-CCL5, and treatment with recombinant murine CCL5 (rmCCL5). Depletion or inhibition of CCL5 reduced severity of hepatic IRI, whereas rmCCL5 treatment aggravated liver IRI as manifested in elevated serum alanine aminotransferase (ALT) and tissue myeloperoxidase (MPO) levels. Moreover, IRI severity was reduced in CCL5-knockout (CCL5-KO) mice versus wildtype (WT) mice, with drops in serum ALT level, intrahepatic MPO activity, and histological pathology. Bone marrow transplantion (BMT) studies show that myeloid cells and tissue cells are both required for CCL5-aggravated hepatic IRI. The profile of liver-infiltrating leukocyte subsets after hepatic reperfusion identified CD11b+ cells as the only compartment significantly reduced in CCL5-KO mice versus WT controls at early reperfusion phase. The role of CCL5 recruiting CD11b+ cells in early reperfusion was validated by in vitro transwell migration assay of murine primary macrophages (broadly characterized by their CD11b expression) in response to liver lysates after early reperfusion. Taken together, our results demonstrate a sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI.

24 citations

Journal ArticleDOI
TL;DR: Elevation of circulating sphingosine‐1‐phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation.

21 citations

Journal ArticleDOI
TL;DR: A COVID-19 patient with unresponsive respiratory failure was treated with adenosine for compassionate use and the results showed a rapid improvement of clinical conditions, with negativity of SARS-CoV2 detection.
Abstract: Coronavirus disease 2019 (COVID-19) patients can develop interstitial pneumonia, which, in turn, can evolve into acute respiratory distress syndrome (ARDS). This is accompanied by an inflammatory cytokine storm. severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has proteins capable of promoting the cytokine storm, especially in patients with comorbidities, including obesity. Since currently no resolutive therapy for ARDS has been found and given the scientific literature regarding the use of adenosine, its application has been hypothesized. Through its receptors, adenosine is able to inhibit the acute inflammatory process, increase the protection capacity of the epithelial barrier, and reduce the damage due to an overactivation of the immune system, such as that occurring in cytokine storms. These features are known in ischemia/reperfusion models and could also be exploited in acute lung injury with hypoxia. Considering these hypotheses, a COVID-19 patient with unresponsive respiratory failure was treated with adenosine for compassionate use. The results showed a rapid improvement of clinical conditions, with negativity of SARS-CoV2 detection.

20 citations


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

  • ...In lung inflammation, adenosine promotes the cellular response to hypoxia [88] and the reduction of extravasation of proteins and cytokines in the alveolus with decreased infiltrated neutrophils [89]....

    [...]

Journal ArticleDOI
TL;DR: The inhibition of eATP signaling downregulates the alloimmune response, expands Treg cells and promotes graft survival, and robust preclinical evidence and the recent advances in pharmacological research may lead to intriguing clinical applications.
Abstract: Purpose of review Purine nucleosides and nucleotides are released in the extracellular space following cell injury and act as paracrine mediators through a number of dedicated membrane receptors. In particular, extracellular ATP (eATP) significantly influences T-lymphocyte activation and phenotype. The purpose of this review is to discuss the role of ATP signaling in the T-cell-mediated alloimmune response. Recent findings In various animal models of solid transplantation, the purinergic axis has been targeted to prevent acute rejection and to promote long-term graft tolerance. The inhibition of ATP-gated P2X receptors has been shown to halt lymphocyte activation, to downregulate both Th1 and Th17 responses and to promote T-regulatory (Treg) cell differentiation. Similarly, the inhibition of ATP signaling attenuated graft-versus-host disease in mice undergoing hematopoietic cell transplantation. Significantly, different drugs targeting the purinergic system have been recently approved for human use and may be a viable therapeutic option for transplant patients. Summary The inhibition of eATP signaling downregulates the alloimmune response, expands Treg cells and promotes graft survival. This robust preclinical evidence and the recent advances in pharmacological research may lead to intriguing clinical applications.

20 citations

Journal ArticleDOI
TL;DR: In this article, the effects of the proinflammatory cytokine TNFα on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries were studied.
Abstract: The endothelial cell barrier regulates the passage of fluid between the bloodstream and underlying tissues, and barrier function impairment exacerbates the severity of inflammatory insults. To understand how inflammation alters vessel permeability, we studied the effects of the proinflammatory cytokine TNFα on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries. We found that TNFα specifically decreased the barrier function of venous endothelium without affecting that of arterial endothelium. On the basis of RNA expression profiling and protein analysis, we found that claudin-11 (CLDN11) was the predominant claudin in venous endothelial cells and that there was little, if any, CLDN11 in arterial endothelial cells. Consistent with a difference in claudin composition, TNFα increased the permselectivity of Cl- over Na+ in venous but not arterial endothelium. The vein-specific effects of TNFα also required the activation of Pannexin 1 (Panx1) channels and the CD39-mediated hydrolysis of ATP to adenosine, which subsequently stimulated A2A adenosine receptors. Moreover, the increase in vein permeability required the activation of the Ca2+ channel TRPV4 downstream of Panx1 activation. Panx1-deficient mice resisted the pathologic effects of sepsis induced by cecal ligation and puncture on life span and lung vascular permeability. These data provide a targetable pathway with the potential to promote vein barrier function and prevent the deleterious effects of vascular leak in response to inflammation.

19 citations

References
More filters
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.

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]....

    [...]

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

    [...]

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...

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]....

    [...]

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...

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]....

    [...]

Journal ArticleDOI
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]....

    [...]

Journal ArticleDOI
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]....

    [...]