Adenosine receptor agonists for promotion of dermal wound healing

Valls, María D.; Cronstein, Bruce N.; Montesinos, M. Carmen

doi:10.1016/j.bcp.2008.11.002

Cited by 95 publications

(77 citation statements)

References 74 publications

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“…Growing evidence suggests that adenosine plays a role in the pathogenesis of COPD and asthma (38)(39)(40)(41). Smokers demonstrate significantly increased adenosine concentrations in airway lining fluid, and patients with COPD exhibit enhanced adenosine receptor density in their lung parenchyma (42,43).…”

Section: Discussionmentioning

confidence: 99%

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Allen‐Gipson

Zimmerman²,

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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Adenosine concentrations are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease, where it balances between tissue repair and excessive airway remodeling. We previously demonstrated that the activation of the adenosine A 2A receptor promotes epithelial wound closure. However, the mechanism by which adenosine-mediated wound healing occurs after cigarette smoke exposure has not been investigated. The present study investigates whether cigarette smoke exposure alters adenosine-mediated reparative properties via its ability to induce a shift in the oxidant/ antioxidant balance. Using an in vitro wounding model, bronchial epithelial cells were exposed to 5% cigarette smoke extract, were wounded, and were then stimulated with either 10 mM adenosine or the specific A 2A receptor agonist, 59-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 10 mM), and assessed for wound closure. In a subset of experiments, bronchial epithelial cells were infected with adenovirus vectors encoding human superoxide dismutase and/or catalase or control vector. In the presence of 5% smoke extract, significant delay was evident in both adenosine-mediated and CPCA-mediated wound closure. However, cells pretreated with N-acetylcysteine (NAC), a nonspecific antioxidant, reversed smoke extract-mediated inhibition. We found that cells overexpressing mitochondrial catalase repealed the smoke extract inhibition of CPCA-stimulated wound closure, whereas superoxide dismutase overexpression exerted no effect. Kinase experiments revealed that smoke extract significantly reduced the A 2A -mediated activation of cyclic adenosine monophosphate-dependent protein kinase. However, pretreatment with NAC reversed this effect. In conclusion, our data suggest that cigarette smoke exposure impairs A 2A -stimulated wound repair via a reactive oxygen species-dependent mechanism, thereby providing a better understanding of adenosine signaling that may direct the development of pharmacological tools for the treatment of chronic inflammatory lung disorders.

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Section: Discussionmentioning

confidence: 99%

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Allen‐Gipson

Zimmerman²,

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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“…In particular, adenosine affects several early events in the wound-healing process such as vasodilatation, angiogenesis, matrix production, and inflammation [6,7], and thus, we have previously shown that topical application of selective adenosine A 2A receptor agonists accelerate healing of dermal wounds both in normal animals and in animals with impaired wound healing (reviewed in [6]). …”

Section: Introductionmentioning

confidence: 98%

Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator

Desai-Merchant

Cronstein

2015

Inflammation

Self Cite

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Impaired wound healing, as it occurs in diabetes mellitus or long-term corticoid treatment, is commonly associated with disability, diminished quality of life, and high economic costs. Selective agonists of the A2A receptor subtype of adenosine, an endogenous regulator of inflammation, promote tissue repair in animal models, both healthy and with impaired healing. Plasmin-mediated proteolysis of fibrin and other matrix proteins is essential for cell migration at sites of injury. Since adenosine A2A receptor activation increases plasminogen activator release from macrophages and mast cells, we studied the effect of a selective agonist, CGS-21680, on full-thickness excisional wound closure in wild-type, urokinase plasminogen activator (uPA)-deficient, and tissue plasminogen activator (tPA)-deficient mice. Wound closure was impaired in tPA- and uPA-deficient mice as compared with wild-type mice, and topical application of CGS-21680 significantly increased the rate at which wounds closed in wild-type mice and uPA-deficient mice, but not in tPA-deficient mice. Immunostaining of tissue sections showed that tPA was present in endothelial cells and histiocytes by day 3 post-wound and also by day 6. In contrast, uPA was more prominent in these cell types only by day 6 post-wound. Our results confirm that plasminogen activation contributes to wound repair and are consistent with the hypothesis that adenosine A2A receptor activation promotes wound closure by a mechanism that depends upon tPA, but not uPA. Moreover, our results suggest that topical adenosine A2A receptor agonists may be useful in promotion of wound closure in patients with impaired wound healing.

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“…In particular, activation of adenosine A 2A receptor plays an important role in promotion of wound healing (Montesinos et al, 2015), being especially relevant in the formation of new granulation tissue and revascularization of the wound bed (Montesinos and Valls, 2010;Valls et al, 2009). Although mice with a targeted disruption of this receptor subtype showed a defect in granulation tissue formation, wound re-epithelialization was hardly compromised (Montesinos et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Andrés

Terencio

Arasa

et al. 2017

Journal of Investigative Dermatology

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Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A 2B receptors, human epidermal keratinocytes also express A 2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists, we showed that physiological concentrations of adenosine activate A 2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling. In contrast, the selective activation of A 2A receptors by CGS-21680 induces keratinocyte proliferation via p38emitogen-activated protein kinase activation. Adenosine and selective A 2A and A 2B agonists presented anti-inflammatory profiles independent of adenosine receptors but mediated by membrane phosphatase activation. Finally, keratinocyte exposure to diverse inflammatory cytokines altered adenosine receptor expression by reducing A 2B and increasing A 2A , a pattern also observed in psoriatic epidermis. Because increased epidermal turnover and inflammatory response are characteristics of psoriatic disease, further studies are needed to assess the role and consequences of the altered adenosine receptor expression in lesional and nonlesional psoriatic keratinocytes.

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Adenosine receptor agonists for promotion of dermal wound healing

Cited by 95 publications

References 74 publications

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

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