Selective A<sub>2A</sub>adenosine receptor activation reduces skin pressure ulcer formation and inflammation

Peirce, Shayn M.; Skalak, Thomas C.; Rieger, Jayson M.; Macdonald, Timothy L.; Linden, Joel

doi:10.1152/ajpheart.2001.281.1.h67

Cited by 67 publications

(41 citation statements)

References 26 publications

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“…The A 2A AR agonist ATL-146e is also of interest for the treatment of sepsis 186 , inflammatory bowel disease 187 and for inclusion in drug-eluting stents to prevent restenosis after angioplasty. Selective activation of the A 2A AR has also been shown to reduce skin pressure, ulcer formation and inflammation 188 , and wound healing is accelerated 189 .…”

Section: Ars As Targets In Inflammatory Disordersmentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,289

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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Section: Ars As Targets In Inflammatory Disordersmentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,289

1,361

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“…In fact, adenosine is a potent anti-inflammatory agent with A 2A Rs triggering BOFF^signals in activated immune cells, which constitutes one of the most fundamental and immediate tissue-protecting mechanisms (reviewed in [295,296]). A 2A R agonists were even named Bthe most potent anti-inflammatory drug known to mankind.^Ac-cordingly, activation of A 2A Rs has been shown to confer a robust protection against tissue damage from ischemiaYreperfusion injury in different organ such as heart [297Y299], blood vessels [300], kidney [301,302], liver [303,304], lung [305,306], joints [307], skin [308,309], and even in the spinal cord [310,311] and in the brain following hemorrhage [312] or acute infection [313]. Thus, it is the activation (rather the blockade) of A 2A Rs that confers protection against damage triggered by inflammation in peripheral tissues, precisely the opposite of what is observed in the damaged adult brain.…”

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

484

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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“…Previous studies showed that hypoxic injury of skin was intimately associated with oxidative stress and inflammatory responses (Houwing et al, 2000;Peirce et al, 2001). Mounting evidence suggested that cyclooxygenase-2 (COX-2) and its product prostaglandin E 2 (PGE 2 ) played a pivotal role in inflammatory response (Birnbaum et al, 2005;Chi and Kim, 2005).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Mediates Chemical Hypoxia-Induced Injury and Inflammation by Activating NF-κb-COX-2 Pathway in HaCaT Cells

Liu

Ling

Mei-fen

et al. 2011

Molecules and Cells

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Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl 2 ), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms. Exposure of HaCaT cells to CoCl 2 reduced cell viability and caused overproduction of reactive oxygen species (ROS) and oversecretion of interleukin-6 (IL-6) and interleukin-8 (IL-8). Importantly, CoCl 2 exposure elicited overexpression of cyclooxygenase-2 (COX-2) and phosphorylation of nuclear factor-kappa B (NF-κB) p65 subunit. Inhibition of COX-2 by NS-398, a selective inhibitor of COX-2, significantly repressed the cytotoxicity, as well as secretion of IL-6 and IL-8 induced by CoCl 2 . Inhibition of NF-κB by PDTC (a selective inhibitor of NF-κB) or genetic silencing of p65 by RNAi (Si-p65), attenuated not only the cytotoxicity and secretion of IL-6 and IL-8, but also overexpression of COX-2 in CoCl 2 -treated HaCaT cells. Neutralizing anti-IL-6 or anti-IL-8 antibody statistically alleviated CoCl 2 -induced cytotoxicity in HaCaT cells. N-acetyl-L-cysteine (NAC), a well characterized ROS scavenger, obviously suppressed CoCl 2 -induced cytotoxicity in HaCaT cells, as well as secretion of IL-6 and IL-8. Additionally, NAC also repressed overexpression of COX-2 and phosphorylation of NF-B κ p65 subunit induced by CoCl 2 in HaCaT cells. In conclusion, our results demonstrated that oxidative stress mediates chemical hypoxia-induced injury and inflammatory response through activation of NF-κB-COX-2 pathway in HaCaT cells.

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Selective A_2Aadenosine receptor activation reduces skin pressure ulcer formation and inflammation

Cited by 67 publications

References 26 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Oxidative Stress Mediates Chemical Hypoxia-Induced Injury and Inflammation by Activating NF-κb-COX-2 Pathway in HaCaT Cells

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Selective A2Aadenosine receptor activation reduces skin pressure ulcer formation and inflammation

Cited by 67 publications

References 26 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Oxidative Stress Mediates Chemical Hypoxia-Induced Injury and Inflammation by Activating NF-κb-COX-2 Pathway in HaCaT Cells

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Selective A_2Aadenosine receptor activation reduces skin pressure ulcer formation and inflammation