Large and Sustained Induction of Chemokines during Impaired Wound Healing in the Genetically Diabetic Mouse: Prolonged Persistence of Neutrophils and Macrophages during the Late Phase of Repair

Wetzler, Christian; Kämpfer, Heiko; Stallmeyer, Birgit; Pfeilschifter, Josef; Frank, Stefan

doi:10.1046/j.1523-1747.2000.00029.x

Cited by 486 publications

(474 citation statements)

References 43 publications

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“…Because early wounding is characterized by a release of pro-inflammatory mediators (6,18), this finding was consistent with the general inducibility of COX-2 by these mediators (21). Moreover, COX-2 expression also remained dramatically increased during late repair and thus paralleled the sustained presence of inflammatory cytokines in these wounds (10,11) as an additional marker of inflammatory conditions. Nevertheless, it is noteworthy that the spatial distribution of the COX isoenzymes was consistent with the localization of COX-1 (wound margin) and COX-2 (macrophages) in normal healing (22).…”

Section: Discussionsupporting

confidence: 75%

“…In this study, we investigated the role of COX isoenzymes in diabetes-impaired wound healing in ob/ob and db/db mice. Both mouse models are characterized by severe type 2 diabetes (12) and suffer from disturbed wound-healing conditions (10,11,17). Nonwounded skin of C57BL/6J wildtype mice as well as skin of ob/ob and db/db mice was characterized by a strongly expressed COX-1 (7,200 Ϯ 1,002 PhosphoImager counts/20 g RNA), whereas COX-2 expression (371 Ϯ 52 PhosphoImager counts/20 g RNA) was nearly absent (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Wound Inflammation in Diabeticob/obMice

et al. 2005

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This study focused on the regulation of prostaglandin (PG) production in diabetes-impaired wound tissue. Cyclooxygenase (COX)-1 and -2 expression and activity were severely dysregulated in chronic wounds of diabetic ob/ob mice. Those wounds were characterized by a reduced expression of COX-1 and the presence of strongly elevated levels of COX-2 when compared with conditions observed in healthy animals. Resolution of the diabetic and impaired wound-healing phenotype by systemic administration of leptin into ob/ob mice increased COX-1 expression in wound margin keratinocytes and decreased COX-2 expression in inner wound areas to levels found in wild-type animals. Notably, improved wound healing was characterized by a marked increase in PGE 2 /PGD 2 biosynthesis that colocalized with induced COX-1 in new tissue at the margin of the wound. COX-2 expression did not significantly contribute to PGE 2 /PGD 2 production in impaired wound tissue. Accordingly, only late wound tissue from SC-560 -treated (selective COX-1 inhibitor) but not celecoxibtreated (selective COX-2 inhibitor) ob/ob mice exhibited a severe loss in PGE 2 , PGD 2 , and prostacyclin at the wound site, and this change was associated with reduced keratinocyte numbers in the neo-epithelia. These data constitute strong evidence that a dysregulation of COX-1-coupled prostaglandin contributes to diabetes-impaired wound healing. Diabetes 54: 1543-1551, 2005

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Section: Discussionsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Wound Inflammation in Diabeticob/obMice

et al. 2005

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“…Because of their early arrival at the wound site and phagocytosis of bacteria and removal of tissue debris, neutrophils are considered to have a role confined to host defence [37]. It is recognised that inflammatory cells are essential for normal wound healing; neutrophil-deficient mice demonstrate impaired wound healing [38].…”

Section: Discussionmentioning

confidence: 99%

A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor

et al. 2009

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Aims/hypothesis Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration. Methods Drum implants were placed subcutaneously into thighs of diabetic and non-diabetic control baboons. After 2 and 4 weeks the skin incision sites were removed for measurement of breaking strength and epithelial thickness.Drum implants were removed for analysis of granulation tissue and inflammatory cells, CTGF and tissue inhibitor of matrix metalloproteinase (TIMP-1). Degradation of added CTGF by wound fluid was also examined. Results Healed incision site skin was stiffer (less elastic) in diabetic baboons and epithelial remodelling was slower compared with controls. Granulation tissue from diabetic baboons was reduced at 2 and 4 weeks, with increased vessel lumen areas at 4 weeks. Macrophages were reduced while neutrophils persisted in diabetic tissue. In diabetic wound tissue at 4 weeks there was less CTGF induced, as shown by immunohistochemistry, compared with controls. In contrast, Electronic supplementary material The online version of this article

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“…9,13 Furthermore, diabetic (Db/Db) mice have also been shown to have a prolonged inflammatory phase with sustained expression of the inflammatory cytokines macrophage chemoattractant protein 1 (MPC-1) and macrophage inflammatory protein 2 (MIC-2). 14 The biomechanical properties of diabetic skin are another critical aspect of wound-healing physiology. Diabetic, hyperglycemic rats were found to have inferior biomechanical properties than euglycemic rats after injury.…”

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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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Large and Sustained Induction of Chemokines during Impaired Wound Healing in the Genetically Diabetic Mouse: Prolonged Persistence of Neutrophils and Macrophages during the Late Phase of Repair

Cited by 486 publications

References 43 publications

Wound Inflammation in Diabeticob/obMice

Wound Inflammation in Diabeticob/obMice

A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor

Impaired Biomechanical Properties of Diabetic Skin

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