Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung

Heller, Axel R.; Rothermel, Juliane; Weigand, Markus A.; Plaschke, Konstanze; Schmeck, Joachim; Wendel, Martina; Bardenheuer, Hubert J.; Koch, Thea

doi:10.1017/s026502150600144x

Cited by 22 publications

(26 citation statements)

References 49 publications

(79 reference statements)

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“…In an early study, pharmacologic blocking of A1AR attenuated LPS-induced lung injury in cats (24), suggesting a proinflammatory role of A1AR. In two recent studies with rodents, A1AR demonstrated protective effects in models of ischemia reperfusion-and endotoxin-induced lung injury (25,26). Both studies focused on the effects of A1AR on the formation of lung edema and are in line with our findings; leukocyte trafficking, however, was not considered in these studies.…”

Section: Discussionsupporting

confidence: 84%

“…In an early study, pharmacologic blocking of A1AR attenuated LPS-induced lung injury in cats (24). In more recent studies, protective effects of A1AR have been demonstrated in models of ischemia reperfusion-and endotoxin-induced lung injury (25,26). In adenosine deaminase (ADA)-deficient mice, which exhibit elevated adenosine levels, genetic removal of the A1AR resulted in enhanced pulmonary inflammation and alveolar destruction (23).…”

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confidence: 99%

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Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

Ngamsri

Wagner

Vollmer

et al. 2010

The Journal of Immunology

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Extracellular adenosine and adenosine receptors are critically involved in various inflammatory pathways. Adenosine receptor A1 (A1AR) has been implicated in mediating transmigration of leukocytes to sites of inflammation. This study was designed to characterize the role of A1AR in a murine model of LPS-induced lung injury. LPS-induced transmigration of polymorphonuclear cells (PMNs) and microvascular permeability was elevated in A1AR−/− mice. Pretreatment of wild-type mice with the specific A1AR agonist 2′Me–2-chloro-N6-cyclopentyladenosine attenuated PMN accumulation in the interstitium and alveolar space as well as microvascular permeability. Lower PMN counts in the lungs of pretreated wild-type mice were associated with reduced amounts of the chemotactic cytokines TNF-α, IL-6, and CXCL2/3 in the bronchoalveolar lavage. Pretreatment was only effective when A1AR was expressed on hematopoietic cells as demonstrated in chimeric mice. These findings were confirmed by in vitro transmigration assays demonstrating that chemokine-induced transmigration of PMNs was reduced when PMNs but not when pulmonary endothelial or alveolar epithelial cells were pretreated. 2′Me–2-chloro-N6-cyclopentyladenosine prevented pulmonary endothelial but not epithelial cells from LPS-induced cellular remodeling and cell retraction. Our data reveal what we believe to be a previously unrecognized distinct role of A1AR for PMN trafficking and endothelial integrity in a model of acute lung injury.

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 99%

Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

Ngamsri

Wagner

Vollmer

et al. 2010

The Journal of Immunology

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“…To the extent that endothelial mitochondria are responsible for the shedding response, as we show here, loss of mitochondrial function might be proinflammatory. Inflammatory conditions such as sepsis cause loss of lung mitochondrial function, as demonstrated by decreased lung ATP (59,60). Our findings indicate that in such conditions, therapy aimed at restoring endothelial mitochondrial function might protect against the deleterious effects of increasing inflammation.…”

Section: Figurementioning

confidence: 66%

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

et al. 2011

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Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca 2+ , and the purinergic receptor P 2 Y 2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor-1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca 2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca 2+ -dependent increase of mitochondrial H 2 O 2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α-induced microvascular inflammation.

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“…LPS caused expression of A 1 , A 2A , and A 2B and P2Y receptors to be increased, and A 3 receptors to be decreased, whereas highvolume ventilation reduced P2Y 4 mRNA levels (Riesenman et al, 2008). On the basis of a study of LPS administration in isolated and ventilated rabbit lungs, it was suggested that adenosine A 2 receptor-mediated stimulation might be beneficial during acute lung injury (Heller et al, 2007). Both A 2A receptors (Reutershan et al, 2007) and A 2B receptors (Eckle et al, 2008) have been claimed to be involved in the attenuation of acute lung injury.…”

Section: Lung Injurymentioning

confidence: 99%

Purinergic Signaling in the Airways

Burnstock

Brouns²,

Adriaensen³

et al. 2012

Pharmacol Rev

173

158

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Adenosine A1 and A2 receptor agonists reduce endotoxin-induced cellular energy depletion and oedema formation in the lung

Abstract: Adenosine A1- and A2-receptor agonists reduced LPS-induced vasoconstriction and oedema formation by maintenance of tissue energy content. Thus, adenosine receptor stimulation, in particular of the A2 receptor, might be beneficial during acute lung injury.

Cited by 22 publications

References 49 publications

Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

Purinergic Signaling in the Airways

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