Gelatinase Activities in Wounds of Healing-Impaired Mice Versus Wounds of Non-Healing-Impaired Mice

Neely, Alice N.; Clendening, Chris E.; Gardner, Jason D.; Greenhalgh, David G.

doi:10.1097/00004630-200021050-00001

Cited by 34 publications

(23 citation statements)

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“…3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers.…”

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confidence: 99%

Impaired Biomechanical Properties of Diabetic Skin

Bermudez

Herdrich

et al. 2011

The American Journal of Pathology

106

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Diabetic skin is known to have deficient wound healing properties, but little is known of its intrinsic biomechanical properties. We hypothesize that diabetic skin possesses inferior biomechanical properties at baseline, rendering it more prone to injury. Skin from diabetic and nondiabetic mice and humans underwent biomechanical testing. Real-time PCR was performed for genes integral to collagen synthesis and degradation. MMP-2 and MMP-9, and TIMP-1 protein levels were assessed by ELISA and zymography. Collagen I and III content was assessed using Western blot analysis. At baseline, both murine and human diabetic skin was biomechanically inferior compared to nondiabetic skin, with decreased maximum stress and decreased modulus (P < 0.001 and < 0.05, respectively). Surprisingly, the expression of genes involved in collagen synthesis were significantly up-regulated, and genes involved in collagen degradation were significantly down-regulated in murine diabetic skin (P < 0.01). In addition, MMP-2 and MMP-9/TIMP-1 protein ratios were significantly lower in murine diabetic skin (P < 0.05). Collagen I levels and I:III ratios were lower in diabetic skin (P < 0.05). These findings suggest that the predisposition of diabetics to wounds may be the result of impaired tissue integrity at baseline, and are due, in part, to a defect in the regulation of collagen protein synthesis at the post-transcriptional level. Diabetes is associated with increased morbidity and mortality, 1 as well as impaired wound healing. 2 Diabetesrelated admissions accounted for 22% of all hospital inpatient days in 2007, and diabetic foot ulcers account for 20% of all hospital admissions in diabetic patients, which are the leading cause of lower extremity amputations. 2 Improvements made in diabetic wound management and prevention clearly have the potential to affect a large number of patients and decrease diabetic-related health care expenditures.More than 100 factors have been identified that contribute to the impairment in diabetic wound healing. 3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers. 9 Diabetes is characterized by significantly increased cross linking and nonenzymatic glycation of collagen, as well as elevated levels of advanced glycation end products (AGEs). 10,11 Blockade of the receptor for advanced glycation end products (RAGEs) can restore the wound healing properties of diabetic (Db/Db) mice. 12 Hyperglycemic animals have been shown to have significantly higher concentrations of glycated collagen and higher levels of collagenase activity. 9,13 Furthermore...

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confidence: 99%

Impaired Biomechanical Properties of Diabetic Skin

Bermudez

Herdrich

et al. 2011

The American Journal of Pathology

106

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“…43) Emerging evidence indicates that the mechanisms responsible for diabetic foot or skin ulcers may include at least four aspects, blood capillary pathological changes, impaired fibroblast proliferation, extracellular matrix formation and remolding disorders, and peripheral nerve abnormality. [44][45][46] For these four pathogenic changes, hyperglycemia seems the major cause. 7) However, this is not supported by our present study since only control blood glucose level in diabetic rats by injecting longacting insulin could not promote the diabetic ulcer healing processes compared with vehicle control group.…”

Section: Discussionmentioning

confidence: 99%

Combined Use of Acid Fibroblast Growth Factor, Granulocyte Colony-stimulating Factor and Zinc Sulphate Accelerates Diabetic Ulcer Healing

Lin¹,

Xu²,

Xiao³

et al. 2009

JOURNAL OF HEALTH SCIENCE

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Our previous studies demonstrated that topic application of recombinant human acid fibroblast growth factor (aFGF) significantly, but still not completely, improved in diabetic ulcer healing. To obtain a maximal therapy for diabetic ulcer healing, a combined protocol containing aFGF, anti-oxidative reagent zinc (Zn) and stem cell stimulator granulocyte colony-stimulating factor (G-CSF), i.e.: aFGF/G-CSF/zinc sulphate (ZnSO 4 ), was explored in the present study. Diabetes was induced by a single dose of streptozotocin (STZ, 55 mg/kg) in Sprague Dawley rats, and full thickness skin wound was made in diabetic rats at 2 months after diabetes onset. Diabetic ulcer rats were treated with aFGF, G-CSF, ZnSO 4 , aFGF/G-CSF/ZnSO 4 or vehicle control, respectively and 3, 6, 9, 12, 15, 18, 21 and 28 days later, therapeutic effects were evaluated by calculating ulcer area. On day 7, 14, 21 after treatment, rats were sacrificed to collect 2 pieces of dorsal skin from 3 different sites (wound center, edge and healed area) to perform histopathological examination. Results showed that treatment with aFGF/G-CSF/ZnSO 4 significantly enhanced ulcer healing compared with single drug treatment groups at different time points. Healing times for 100% of the wound in the aFGF/G-CSF/ZnSO 4 group was 20.00 ± 1.15 days, and significantly shorter than those in single treatment groups (p < 0.05). Histopathological and immunohistochemical analysis disclosed significant increases in capillary density, proliferating cells, the expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and the ratios of TIMP-1 to matrix metalloproteinase 1 (MMP-1) in aFGF/G-CSF/ZnSO 4 group as compared to other single treatments. Collectively, the combinative protocol of aFGF/G-CSF/ZnSO 4 significantly enhanced the therapeutic effect on diabetic ulcer wound, probably through the promotion of fibroblast proliferation and differentiation, enhancement of blood vessel regeneration, and up-regulation of TIMP-1 and down-regulation of MMP-1 expression in diabetic ulcer healing process.

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“…Além disso, a doença vascular periférica e neuropatia também influenciam negativamente a reparação tecidual (Lerman et al, 2003 (Neely et al, 2000;Bullen et al, 1995).…”

Section: A Cicatrização No Diabetes Mellitusunclassified

“…Os fibroblastos também secretam metaloproteinases (MMPs), que são de extrema importância na migração celular e remodelação tecidual durante o processo de cicatrização. Aparentemente, MMPs apresentam-se elevadas em feridas experimentais de ratos diabéticos e em fluidos recolhidos de feridas crônicas (Neely et al, 2000;Bullen et al, 1995).…”

Section: Growth Factor) Vegf (Vascular Endothelial Growth Factor) E unclassified

Terapia com laser em baixa intensidade na prevenção dos efeitos causados pela elevada concentração de glicose na proliferação e migração de fibroblastos

Ramalho¹

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Diabetic complications, including wound healing deficiency, are usually associated to chronic hyperglycemia, which leads to oxidative stress and aleatory protein glycation. The aim of this study was to evaluate the effects of high glucose concentrations (HGC) on proliferation, migration and death of cultured fibroblasts, as well as the potential effect of low intensity laser therapy (LILT) (660 and 780 nm; 40mW; 2, 5, 10 and 30J/cm 2 ) preventing these effects. HGC reduced cell proliferation in about 40%, cell migration in about 50% and increased cell death in 30%. Daily irradiation at 660nm and 10J/cm 2 was efficient preventing the effects on cell proliferation and migration. HGC also increased the production of reactive oxygen species, an effect totally prevented by LILT. The results suggest that LILT favors cell proliferation and migration, processes very important for healing, possibly through an anti-oxidant effect.KEY WORDS: Diabetes Mellitus, wound healing, LILT. Organization). Está associado a uma insuficiência da insulina, que pode ser causada tanto pela baixa produção de insulina pelo pâncreas, como pela falta de resposta dos tecidos periféricos a este hormônio, resultando num aumento no nível sanguíneo de glicose (hiperglicemia) (Neville et al., 1995;Robbins et al., 1989). Os níveis sanguíneos normais de glicose situam-se entre 70 e 120mg/dl; em indivíduos diabéticos, estes níveis encontram-se frequentemente entre 200 e 400 mg/dl. O DM é geralmente dividido em dois grupos: insulina-dependente (DMID) outipo I e não insulina-dependente (DMNID), ou tipo II. O DMID é caracterizado por uma deficiência acentuada na produção de insulina, geralmente desde a infância (Neville et al., 1995;Robbins et al., 1989). Os indivíduos geralmente apresentam hiperglicemia intensa e cetoacidose, necessitando de injeções de insulina exógena para sobreviver. O DMNID é mais freqüente em adultos e pessoas obesas e está associado a uma baixa responsividade à insulina. Embora a hiperglicemia esteja presente, a cetoacidose raramente se desenvolve (Neville et al., 1995;Robbins et al., 1989).O DM é uma doença importante quando se consideram as inúmeras complicações dele decorrentes e o seu impacto econômico na sociedade. A causa mais comum de hospitalização de indivíduos diabéticos provém de feridas crônicas, de difícil cicatrização e com recorrência de infecções (Frykberg, 1999).Uma das principais complicações é a doença vascular periférica, devido à microangiopatia, que pode resultar num acometimento isquêmico dos membros. A isquemia predispõe o indivíduo a infecções graves, como por exemplo, a gangrena, que pode gerar uma necessidade de amputação do membro. A cada ano, 20.000 amputações de membros inferiores são realizadas nos EUA devido a complicações gangrenosas do DM (Neville et al., 1995). Os mecanismos envolvidos nesta 12 complicação, no entanto, não estão completamente elucidados (Greenhalgh, 2003). Além da microangiopatia, outras complicações como neuropatia, retinopatia e falência de órgãos, como por exemplo, os ...

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Gelatinase Activities in Wounds of Healing-Impaired Mice Versus Wounds of Non-Healing-Impaired Mice

Cited by 34 publications

References 0 publications

Impaired Biomechanical Properties of Diabetic Skin

Impaired Biomechanical Properties of Diabetic Skin

Combined Use of Acid Fibroblast Growth Factor, Granulocyte Colony-stimulating Factor and Zinc Sulphate Accelerates Diabetic Ulcer Healing

Terapia com laser em baixa intensidade na prevenção dos efeitos causados pela elevada concentração de glicose na proliferação e migração de fibroblastos

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