Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition

Kunkemoeller, Britta; Kyriakides, Themis R.

doi:10.1089/ars.2017.7263

Cited by 164 publications

(127 citation statements)

References 193 publications

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“…Thus, restoring the balance of ROS generation and scavenging is required for efficient and timely wound healing. [39,40] Elevated and sustained ROS has been detected in the wound of our study. Our present study also found that NaHS pretreatment decreased superoxide anion generation, reduced MDA content but increased total antioxidant capacity in the skin wound.…”

Section: H 2 S Inhibited Methylglyoxal-induced Cell Viability and Rossupporting

confidence: 51%

“…Although adequate oxygen is required to disinfect wounds, to initiate wound repair and to provide adequate fuel for healing, excessive ROS generation or impaired ROS scavenging is deleterious for wound healing. Thus, restoring the balance of ROS generation and scavenging is required for efficient and timely wound healing . Elevated and sustained ROS has been detected in the wound of our study.…”

Section: Discussionmentioning

confidence: 99%

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Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

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Hydrogen sulphide (H2S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 μmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T‐AOC), expression of vascular endothelial growth factor (VEGF), dynamin‐related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 μmol/L) pre‐administration for 4 hours, cell migration rate, DRP1, OPA1 and α–smooth muscle actin (α‐SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T‐AOC in the wound. NaHS also promoted skin fibroblasts migration and α‐SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.

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Section: H 2 S Inhibited Methylglyoxal-induced Cell Viability and Rossupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

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“…Approximately 43,000,000 patients suffer from diabetic wounds worldwide with the number expected to increase . One of the most serious complications of diabetes is impaired wound healing, which leads to the development of chronic wounds in the lower extremities in 15–25% of diabetes patients . Chronic wounds represent a relevant clinical and socioeconomic burden.…”

mentioning

confidence: 99%

Modulation of vascular endothelial growth factor and mitogen‐activated protein kinase‐related pathway involved in extracorporeal shockwave therapy accelerate diabetic wound healing

Chen

Chang

Wang

et al. 2018

Wound Repair Regeneration

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Extracorporeal shockwave therapy (ESWT) has a significant positive effect to accelerate chronic wound healing. This study investigated whether the vascular endothelial growth factor (VEGF)–related pathway has involved in ESWT enhancement of diabetic wound healing. A dorsal skin defect (area, 6 × 5 cm) in a streptozotocin‐induced diabetes rodent model was used. Thirty‐two male Wistar rats were divided into four groups. Group I consisted of nondiabetic control; group II, diabetic control without treatment; group III, diabetic rats received ESWT; and group IV, rats received Avastin (a VEGF monoclonal antibody) on day 0 (post‐wounding immediately) to day 7 and ESWT on day 3 and day 7. The wound healing was assessed clinically. The VEGF, endothelial nitric oxide synthase (eNOS), and Ki‐67 were analyzed with immunohistochemical staining. The mRNA expression of mitogen‐activated protein kinase–related genes was measured by real‐time quantitative real‐time polymerase chain reaction. The results revealed wound size was significantly reduced in the ESWT‐treated rats as compared to the diabetic control (p < 0.01). The positive effect of ESWT‐increasing wound healing was significantly suppressed in pretreatment of the Avastin group. Histological findings revealed significant increase in neo‐vessels in the ESWT group as compared to the control. In immunohistochemical stain, significant increases in VEGF, eNOS, and Ki‐67 expressions were noted in the ESWT group as compared to that in controls. However, Avastin suppressed the shockwave effect and down‐regulation of VEGF, eNOS, and Ki‐67 expressions in the Avastin‐ESWT group as compared to that in the ESWT alone group. We found that highly mRNA expression of Kras, Raf1, Mek1, Jnkk, Jnk, and Jun at early stage in the ESWT group, as compared to the diabetic control. These evidences indicated treatment with multiple sessions of ESWT significantly enhanced diabetic wound healing associated with increased neovascularization and tissue regeneration. The bio‐mechanism of ESWT‐enhanced wound healing is correlated with VEGF and mitogen‐activated protein kinase–mediated pathway.

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“…Diabetes and ulceration were reported to be associated with increased deposition of FN in ECM and linked with the occurrence of FN modified by glycation and/or hypoxia. Such structural modification may cause its reduced functionality . The lack of EDA‐FN as well as a low concentration of functional EDA‐FN may lead to exacerbation of vascular damage and delay in normal tissue remodelling .…”

Section: Discussionmentioning

confidence: 99%

Time‐dependent changes in extra‐domain A‐fibronectin concentration and relative amounts of fibronectin‐fibrin complexes in plasma of patients with peripheral arterial disease after endovascular revascularisation

Pupek

Krzyżanowska-Gołąb

Kotschy³

et al. 2018

International Wound Journal

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Fibronectin (FN) may be involved in time- and stage-dependent and inter-related controlled processes of inflammation, coagulation, and wound healing accompanying peripheral arterial disease (PAD). In the present study, FN and FN-containing extra-domain A (EDA-FN), macromolecular FN-fibrin complexes, and FN monomer were analysed in the plasma of 142 PAD patients, including 37 patients with restenosis, for 37 months after revascularisation. FN concentration increased significantly in the plasma of PAD patients within 7 to 12 months after revascularisation, whereas the high concentration of EDA-FN was maintained up to 24 months, significantly higher in the group 7 to 12 months after revascularisation with recurrence of stenosis and lower in the PAD groups 1 to 3 months and 4 to 6 months after revascularisation with comorbid diabetes and ulceration, respectively. The relative amounts of FN-fibrin complexes up to 1600 kDa and FN monomer were significantly higher, within intervals of 4 to 24 months and 4 to 6 months after revascularisation, respectively. Moreover, the relative amounts of 750 to 1600 kDa FN-fibrin complexes within 13 to 24 months after revascularisation were higher in comparison with those in the group without restenosis. In conclusion, high levels of EDA-FN and FN-fibrin complexes could have potential diagnostic value in the management of PAD patients after revascularisation, predicting restenosis risk.

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Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition

Abstract: Preclinical studies of antioxidant-based therapies for diabetic wound healing have yielded promising results. Redox-based therapeutics constitute a novel approach for the treatment of wounds in diabetes patients that deserve further investigation. Antioxid. Redox Signal. 27, 823-838.

Cited by 164 publications

References 193 publications

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Modulation of vascular endothelial growth factor and mitogen‐activated protein kinase‐related pathway involved in extracorporeal shockwave therapy accelerate diabetic wound healing

Time‐dependent changes in extra‐domain A‐fibronectin concentration and relative amounts of fibronectin‐fibrin complexes in plasma of patients with peripheral arterial disease after endovascular revascularisation

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