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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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Histologic analysis  of wounds in control and CGS-21680–treated mice. Wounds  were excised and mice were  treated with topical application  either of carrier or CGS-21680  in carrier. Analysis of fibroblast  density (A), matrix density (B),  epithelial closure (C), and inflammatory cell infiltrate (D) was  carried out blindly, as described.  Each point represents the mean  (± SEM) of six wounds on three  mice.
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Figure 3: Histologic analysis of wounds in control and CGS-21680–treated mice. Wounds were excised and mice were treated with topical application either of carrier or CGS-21680 in carrier. Analysis of fibroblast density (A), matrix density (B), epithelial closure (C), and inflammatory cell infiltrate (D) was carried out blindly, as described. Each point represents the mean (± SEM) of six wounds on three mice.

Mentions: The observation that both HUVEC and dermal fibroblasts express mRNA for both A2A and A2B receptors, the preliminary finding that adenosine A2 receptor occupancy increases the rate of fibroblast migration, and the previous demonstration that agents binding to adenosine A2 receptors may promote angiogenesis (3–6) all suggested that an adenosine A2 receptor agonist might accelerate wound healing in vivo. To test this hypothesis we studied the effect of the topical application of CGS-21680, the specific A2A agonist, on wound healing in healthy, young (6–8-wk-old) BALB/c mice. As shown in Fig. 2, wound closure was significantly more rapid in the CGS-21680–treated mice than the mice treated with carrier alone (50% wound closure by day 2 versus by day 6; P <0.00001, n = 10 wounds per group). Topical application of the adenosine A2 receptor antagonist DMPX (2.5 mg/ml) did not affect wound healing itself, but completely reversed the effects of CGS-21680 on the rate of wound closure (Fig. 2 A). Similarly, the more selective A2A receptor antagonist CSC also completely reversed the effect of CGS-21680 on wound healing (Fig. 2 B). Upon histologic examination of the wounds, fibroblast infiltration, matrix density, and reepithelialization were markedly enhanced in the CGS-21680–treated animals as compared to controls (Fig. 3). Surprisingly, in contrast to the demonstrated antiinflammatory effects mediated by adenosine A2 receptor occupancy (2), CGS-21680 did not affect the inflammatory infiltrate in the wound until day 10 after wounding. The change in inflammatory infiltrate observed so late in the course of wound closure may have resulted from earlier wound closure rather than any direct effect of CGS-21680 on inflammatory infiltrate in the wound. Topical application of CGS-21680 to open wounds had no obvious toxic effect on the mice.


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)

Histologic analysis  of wounds in control and CGS-21680–treated mice. Wounds  were excised and mice were  treated with topical application  either of carrier or CGS-21680  in carrier. Analysis of fibroblast  density (A), matrix density (B),  epithelial closure (C), and inflammatory cell infiltrate (D) was  carried out blindly, as described.  Each point represents the mean  (± SEM) of six wounds on three  mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199104&req=5

Figure 3: Histologic analysis of wounds in control and CGS-21680–treated mice. Wounds were excised and mice were treated with topical application either of carrier or CGS-21680 in carrier. Analysis of fibroblast density (A), matrix density (B), epithelial closure (C), and inflammatory cell infiltrate (D) was carried out blindly, as described. Each point represents the mean (± SEM) of six wounds on three mice.
Mentions: The observation that both HUVEC and dermal fibroblasts express mRNA for both A2A and A2B receptors, the preliminary finding that adenosine A2 receptor occupancy increases the rate of fibroblast migration, and the previous demonstration that agents binding to adenosine A2 receptors may promote angiogenesis (3–6) all suggested that an adenosine A2 receptor agonist might accelerate wound healing in vivo. To test this hypothesis we studied the effect of the topical application of CGS-21680, the specific A2A agonist, on wound healing in healthy, young (6–8-wk-old) BALB/c mice. As shown in Fig. 2, wound closure was significantly more rapid in the CGS-21680–treated mice than the mice treated with carrier alone (50% wound closure by day 2 versus by day 6; P <0.00001, n = 10 wounds per group). Topical application of the adenosine A2 receptor antagonist DMPX (2.5 mg/ml) did not affect wound healing itself, but completely reversed the effects of CGS-21680 on the rate of wound closure (Fig. 2 A). Similarly, the more selective A2A receptor antagonist CSC also completely reversed the effect of CGS-21680 on wound healing (Fig. 2 B). Upon histologic examination of the wounds, fibroblast infiltration, matrix density, and reepithelialization were markedly enhanced in the CGS-21680–treated animals as compared to controls (Fig. 3). Surprisingly, in contrast to the demonstrated antiinflammatory effects mediated by adenosine A2 receptor occupancy (2), CGS-21680 did not affect the inflammatory infiltrate in the wound until day 10 after wounding. The change in inflammatory infiltrate observed so late in the course of wound closure may have resulted from earlier wound closure rather than any direct effect of CGS-21680 on inflammatory infiltrate in the wound. Topical application of CGS-21680 to open wounds had no obvious toxic effect on the mice.

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