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Wound healing is accelerated by agonists of adenosine A2 (G alpha s-linked) receptors.

Montesinos MC, Gadangi P, Longaker M, Sung J, Levine J, Nilsen D, Reibman J, Li M, Jiang CK, Hirschhorn R, Recht PA, Ostad E, Levin RI, Cronstein BN - J. Exp. Med. (1997)

Bottom Line: In rats rendered diabetic (streptozotocin-induced diabetes mellitus) wound healing was impaired as compared to nondiabetic rats; CGS-21680 significantly increased the rate of wound healing in both nondiabetic and diabetic rats.Indeed, the rate of wound healing in the CGS-21680-treated diabetic rats was greater than or equal to that observed in untreated normal rats.These results appear to constitute the first evidence that a small molecule, such as an adenosine receptor agonist, accelerates wound healing in both normal animals and in animals with impaired wound healing.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, New York University Medical Center, New York 10016, USA.

ABSTRACT
The complete healing of wounds is the final step in a highly regulated response to injury. Although many of the molecular mediators and cellular events of healing are known, their manipulation for the enhancement and acceleration of wound closure has not proven practical as yet. We and others have established that adenosine is a potent regulator of the inflammatory response, which is a component of wound healing. We now report that ligation of the G alpha s-linked adenosine receptors on the cells of an artificial wound dramatically alters the kinetics of wound closure. Excisional wound closure in normal, healthy mice was significantly accelerated by topical application of the specific A2A receptor agonist CGS-21680 (50% closure by day 2 in A2 receptor antagonists. In rats rendered diabetic (streptozotocin-induced diabetes mellitus) wound healing was impaired as compared to nondiabetic rats; CGS-21680 significantly increased the rate of wound healing in both nondiabetic and diabetic rats. Indeed, the rate of wound healing in the CGS-21680-treated diabetic rats was greater than or equal to that observed in untreated normal rats. These results appear to constitute the first evidence that a small molecule, such as an adenosine receptor agonist, accelerates wound healing in both normal animals and in animals with impaired wound healing.

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The effect of the adenosine A2A agonist CGS-21680 on  wound closure in normal and diabetic rats. Animals received a single injection of streptozotocin (60 mg/kg) followed 8 d later by excision of  three wounds (2 cm in diameter) on the dorsum of each rat. Wounds  were treated with carrier (1.5% methylcellulose/PBS, wt/vol) alone or  CGS-21680 (250 μg/ml) in carrier. The wounds were traced at the indicated intervals and the area was determined after computer digitization of  the wounds. Each point represents the mean (± SEM) of 9–21 wounds.
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Figure 4: The effect of the adenosine A2A agonist CGS-21680 on wound closure in normal and diabetic rats. Animals received a single injection of streptozotocin (60 mg/kg) followed 8 d later by excision of three wounds (2 cm in diameter) on the dorsum of each rat. Wounds were treated with carrier (1.5% methylcellulose/PBS, wt/vol) alone or CGS-21680 (250 μg/ml) in carrier. The wounds were traced at the indicated intervals and the area was determined after computer digitization of the wounds. Each point represents the mean (± SEM) of 9–21 wounds.

Mentions: Patients with diabetes mellitus suffer from impaired wound healing, and poor wound healing is responsible for significant morbidity and mortality in these patients. To determine whether an adenosine A2A receptor agonist might be useful in the promotion of wound healing in patients with diabetes, we studied the effect of topical application of the adenosine receptor agonist CGS-21680 to full-thickness wounds in rats rendered diabetic by a single injection of streptozotocin. As expected, streptozotocin-treated rats had high serum glucose concentrations (432 ± 25 mg/dl in the diabetic rats versus 156 ± 18.5 mg/dl in the nondiabetic; P <0.00001) and the wounds of the diabetic animals healed more slowly than those of the control animals (50% closure by day 9 versus by day 7, respectively; P <0.0001; Fig. 4). As with the normal young mice, topical application of CGS-21680 significantly promoted wound healing in the healthy nondiabetic rats (50% closure by day 4; P <0.0001, Fig. 4). More importantly, application of CGS-21680 increased the rate at which the diabetic animals closed their wounds (50% closure by day 6, P <0.0001, versus control diabetic rats, Fig. 4) but did not affect the serum glucose concentration (432 ± 31 mg/dl versus 407 ± 40 mg/dl in the control and CGS-21680–treated diabetic rats, respectively; P = NS). Indeed, the rate of wound healing in CGS-21680– treated diabetic animals was as good as or better than that in the untreated controls (Fig. 4).


Wound healing is accelerated by agonists of adenosine A2 (G alpha s-linked) receptors.

Montesinos MC, Gadangi P, Longaker M, Sung J, Levine J, Nilsen D, Reibman J, Li M, Jiang CK, Hirschhorn R, Recht PA, Ostad E, Levin RI, Cronstein BN - J. Exp. Med. (1997)

The effect of the adenosine A2A agonist CGS-21680 on  wound closure in normal and diabetic rats. Animals received a single injection of streptozotocin (60 mg/kg) followed 8 d later by excision of  three wounds (2 cm in diameter) on the dorsum of each rat. Wounds  were treated with carrier (1.5% methylcellulose/PBS, wt/vol) alone or  CGS-21680 (250 μg/ml) in carrier. The wounds were traced at the indicated intervals and the area was determined after computer digitization of  the wounds. Each point represents the mean (± SEM) of 9–21 wounds.
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Related In: Results  -  Collection

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Figure 4: The effect of the adenosine A2A agonist CGS-21680 on wound closure in normal and diabetic rats. Animals received a single injection of streptozotocin (60 mg/kg) followed 8 d later by excision of three wounds (2 cm in diameter) on the dorsum of each rat. Wounds were treated with carrier (1.5% methylcellulose/PBS, wt/vol) alone or CGS-21680 (250 μg/ml) in carrier. The wounds were traced at the indicated intervals and the area was determined after computer digitization of the wounds. Each point represents the mean (± SEM) of 9–21 wounds.
Mentions: Patients with diabetes mellitus suffer from impaired wound healing, and poor wound healing is responsible for significant morbidity and mortality in these patients. To determine whether an adenosine A2A receptor agonist might be useful in the promotion of wound healing in patients with diabetes, we studied the effect of topical application of the adenosine receptor agonist CGS-21680 to full-thickness wounds in rats rendered diabetic by a single injection of streptozotocin. As expected, streptozotocin-treated rats had high serum glucose concentrations (432 ± 25 mg/dl in the diabetic rats versus 156 ± 18.5 mg/dl in the nondiabetic; P <0.00001) and the wounds of the diabetic animals healed more slowly than those of the control animals (50% closure by day 9 versus by day 7, respectively; P <0.0001; Fig. 4). As with the normal young mice, topical application of CGS-21680 significantly promoted wound healing in the healthy nondiabetic rats (50% closure by day 4; P <0.0001, Fig. 4). More importantly, application of CGS-21680 increased the rate at which the diabetic animals closed their wounds (50% closure by day 6, P <0.0001, versus control diabetic rats, Fig. 4) but did not affect the serum glucose concentration (432 ± 31 mg/dl versus 407 ± 40 mg/dl in the control and CGS-21680–treated diabetic rats, respectively; P = NS). Indeed, the rate of wound healing in CGS-21680– treated diabetic animals was as good as or better than that in the untreated controls (Fig. 4).

Bottom Line: In rats rendered diabetic (streptozotocin-induced diabetes mellitus) wound healing was impaired as compared to nondiabetic rats; CGS-21680 significantly increased the rate of wound healing in both nondiabetic and diabetic rats.Indeed, the rate of wound healing in the CGS-21680-treated diabetic rats was greater than or equal to that observed in untreated normal rats.These results appear to constitute the first evidence that a small molecule, such as an adenosine receptor agonist, accelerates wound healing in both normal animals and in animals with impaired wound healing.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, New York University Medical Center, New York 10016, USA.

ABSTRACT
The complete healing of wounds is the final step in a highly regulated response to injury. Although many of the molecular mediators and cellular events of healing are known, their manipulation for the enhancement and acceleration of wound closure has not proven practical as yet. We and others have established that adenosine is a potent regulator of the inflammatory response, which is a component of wound healing. We now report that ligation of the G alpha s-linked adenosine receptors on the cells of an artificial wound dramatically alters the kinetics of wound closure. Excisional wound closure in normal, healthy mice was significantly accelerated by topical application of the specific A2A receptor agonist CGS-21680 (50% closure by day 2 in A2 receptor antagonists. In rats rendered diabetic (streptozotocin-induced diabetes mellitus) wound healing was impaired as compared to nondiabetic rats; CGS-21680 significantly increased the rate of wound healing in both nondiabetic and diabetic rats. Indeed, the rate of wound healing in the CGS-21680-treated diabetic rats was greater than or equal to that observed in untreated normal rats. These results appear to constitute the first evidence that a small molecule, such as an adenosine receptor agonist, accelerates wound healing in both normal animals and in animals with impaired wound healing.

Show MeSH
Related in: MedlinePlus