Nitric oxide enhances experimental wound healing in diabetes

Witte, Maria; Kiyama, Teruo; Barbul, Adrian

doi:10.1046/j.1365-2168.2002.02263.x

Cited by 158 publications

(151 citation statements)

References 33 publications

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“…Importantly, cutaneous gene transfer of eNOS or manganese superoxide dismutase was able to restore eNOS expression and NO level, resulting in accelerated wound healing in STZ mice (19). Similarly, application of NO donor molsidomine or NO-releasing poly(vinyl alcohol) hydrogel dressing can partially restore the impaired wound healing in STZ rats (26). These studies indicate that impairment of cutaneous NO function is an important contributor to wound healing delay in type 1 diabetes.…”

Section: Discussionmentioning

confidence: 76%

“…Consistently, dysfunction of cutaneous NO is involved in impaired wound healing. Recent studies including ours have shown that both eNOS expression and NO level were declined in STZ-induced diabetes (19,26). Importantly, cutaneous gene transfer of eNOS or manganese superoxide dismutase was able to restore eNOS expression and NO level, resulting in accelerated wound healing in STZ mice (19).…”

Section: Discussionmentioning

confidence: 97%

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Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes

Luo

Tai-ping²,

Wang³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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The present study tested the hypothesis that impaired SHH pathway results in delayed wound healing by suppressing cutaneous nitric oxide (NO) function in type 1 diabetes. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Although cutaneous SHH and Patched-1 (Ptc-1 encoded by PTCH, PTCH 1) proteins were increased significantly on day 4 after wounding compared with day 0 in normal mice, both were decreased significantly in STZ-induced diabetic mice. Topical application of SHH restored wound healing delay in STZ-induced diabetic mice, with a concomitant augmentation of both cutaneous constitutive nitric oxide synthase (NOS) activity and nitrite level. The effects of SHH on wound healing and cutaneous NO function were markedly inhibited by SHH receptor inhibitor cyclopamine. After 24-h treatment in vitro, SHH (5-20 g/ml) significantly increased cutaneous endothelial NOS protein expression, NOS activity and NO level in normal mice and STZ-induced diabetic mice in a concentration-dependent manner, an effect that was blunted by cyclopamine and NOS inhibitor N -nitro-L-arginine methyl ester. The phosphatidylinositol 3-kinase inhibitor LY-294002 significantly blunted the increase of NOS activity and NO level induced by SHH treatment in human umbilican vein endothelial cells. These results demonstrate that the SHH pathway is activated in a normal wound, and its reduction results in impaired NO function and wound healing in diabetes. Strategies aimed at augmenting the endogenous SHH pathway may provide an effective means in ameliorating delayed diabetic wound healing.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes

Luo

Tai-ping²,

Wang³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…In diabetic wound healing, a physiologic state consistent with decreased nitric oxide (NO) levels results, leading to an impaired inflammatory response, decreased collagen production, and decreased wound-breaking strength (Witte et al, 2002). Prior studies have also revealed the MMP levels are significantly elevated in chronic diabetic wounds, thus creating an imbalance in matrix breakdown and release of growth factors that are important for normal wound healing (Wysocki et al, 1993;Trengove et al, 1999;Lobmann et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…Impaired healing of diabetic wounds is thought to be related to diminished NO production (Witte et al, 2002;Schaffer et al, 1997). Because the level of NO in chronic wounds is low, and elevation of NO enhances wound healing, a number of other approaches have been tried to deliver NO therapeutically.…”

Section: Resultsmentioning

confidence: 99%

Role of Nitric Oxide in Extracellular Matrix Metabolism and Inflammation in Diabetic Wound Healing

Sylvia¹,

Myers²,

Seifert³

et al. 2011

Global Perspective on Diabetic Foot Ulcerations

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“…These agents have been studied in vitro, in airway and gastric epithelial wounds [3,4], and in vivo, in diabetic ulcers [5], and skin abscesses [6]. Yet, the molecular basis for the effect of NO donors in wound healing is poorly defined, and a better understanding of how NO functions to improve wound healing is needed.…”

Section: Introductionmentioning

confidence: 99%

Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase

Spitler

Schwappacher

et al. 2013

Cellular Signalling

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a b s t r a c t a r t i c l e i n f oNitric oxide (NO) donors have been shown to improve wound healing, but the mechanism is not well defined. Here we show that the novel NO donor nitrosyl-cobinamide (NO-Cbi) improved in vitro wound healing in several cell types, including an established line of lung epithelial cells and primary human lung fibroblasts. On a molar basis, NO-Cbi was more effective than two other NO donors, with the effective NO-Cbi concentration ranging from 3 to 10 μM, depending on the cell type. Improved wound healing was secondary to increased cell migration and not cell proliferation. The wound healing effect of NO-Cbi was mediated by cGMP, mainly through cGMPdependent protein kinase type I (PKGI), as determined using pharmacological inhibitors and activators, and siRNAs targeting PKG type I and II. Moreover, we found that Src and ERK were two downstream mediators of NO-Cbi's effect. We conclude that NO-Cbi is a potent inducer of cell migration and wound closure, acting via cGMP, PKG, Src, and extracellular signal regulated kinase (ERK).

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Nitric oxide enhances experimental wound healing in diabetes

Abstract: The nitric oxide donor molsidomine can at least partially reverse impaired healing associated with diabetes.

Cited by 158 publications

References 33 publications

Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes

Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes

Role of Nitric Oxide in Extracellular Matrix Metabolism and Inflammation in Diabetic Wound Healing

Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase

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