Streptozotocin diabetes: prolonged inflammatory response with delay of granuroma formation

Inoue, Nozomu; Nishikata, Shoji; Kawamura, Masaaki; Furuya, E; Takita, Hiroko; Nishikaze, O

doi:10.2492/jsir1981.4.4_563

Cited by 3 publications

(6 citation statements)

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“…Within 1 h of wounding, nondiabetic mice displayed an apparent, but not significant, induction of ␣-SMA mRNA (P ϭ 0.25), while upregulation of ␣-SMA transcripts was absent in diabetic mice. These data are consistent with the hypothesis that attenuation of the inflammatory response in diabetic wounds (33,34), possibly decreasing the content of proinflammatory cytokines, may contribute to the blunted induction of TF and angiogenesis. Somatic TF gene transfer induces expression of TF transcripts in wounds of diabetic mice.…”

Section: Resultssupporting

confidence: 91%

“…Several studies (33,34) have noted blunted induction of inflammatory cytokines after wounding in diabetes. This is surprising, since sustained activation of the proinflammatory transcription factor NF-B is a characteristic feature of peripheral blood mononuclear cells derived from patients with diabetes (51).…”

Section: Discussionmentioning

confidence: 98%

“…Previous reports (33,34) have shown that the inflammatory phase of wound repair is delayed/diminished in diabetes. The results reported herein indicate that early induction of TF in wounds is an essential component of the host response and is also attenuated in a murine model of diabetes.…”

Section: Discussionmentioning

confidence: 98%

“…Thus, such wounds in diabetic mice might provide an ideal setting to determine whether local induction of TF might be linked to the subsequent proliferative and angiogenic response. Furthermore, the inflammatory response, characterized by cytokine expression and recruitment of immunocompetent inflammatory cells (32) and critical for initiating wound healing, has been shown to be impaired in diabetes (33,34). We reasoned that reduced expression of inflammatory cytokines after cutaneous wounding of diabetic animals might result in reduced cytokine-dependent induction of TF (8,9,(35)(36)(37).…”

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confidence: 95%

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Tissue Factor as a Link Between Wounding and Tissue Repair

et al. 2005

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The initial phase of wound repair involves inflammation, induction of tissue factor (TF), formation of a fibrin matrix, and growth of new smooth muscle actin (alpha-SMA)-positive vessels. In diabetes, TF induction in response to cutaneous wounding, which ordinarily precedes increased expression of vascular endothelial growth factor (VEGF) and alpha-SMA transcription, is diminished, though not to a degree causing excessive local bleeding. Enhanced TF expression in wounds of diabetic mice caused by somatic TF gene transfer increased VEGF transcription and translation and, subsequently, enhanced formation of new blood vessels and elevated blood flow. Furthermore, increased levels of TF in wounds of diabetic mice enhanced wound healing; the time to achieve 50% wound closure was reduced from 5.5 days in untreated diabetic mice to 4.1 days in animals undergoing TF gene transfer (this was not statistically different from wound closure in nondiabetic mice). Thus, cutaneous wounds in diabetic mice display a relative deficiency of TF compared with nondiabetic controls, and this contributes to delayed wound repair. These data establish TF expression as an important link between the early inflammatory response to cutaneous wounding and reparative processes.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 95%

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Tissue Factor as a Link Between Wounding and Tissue Repair

et al. 2005

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“…These findings may have direct implications for inflammatory processes that characterize certain complications of diabetes and renal failure, for example, such as atherosclerosis, impaired wound healing, aggressive and inflammatory periodontal disease, and dialysis-related amyloidosis (DRA) (6,(35)(36).…”

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confidence: 99%

N ε-(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression

Kislinger

Huber

et al. 1999

Journal of Biological Chemistry

845

695

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Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N ⑀ -(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-B and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.Receptor for AGE 1 (RAGE), a member of the immunoglobulin superfamily, was first described as a cell surface interaction site for advanced glycation end products (AGEs), products of glycation and oxidation of proteins and lipids (1-2). AGEs are a heterogeneous class of compounds, whose accumulation in disorders such as diabetes, renal failure, Alzheimer's disease, and, indeed, natural aging, albeit to a lesser degree, has suggested their potential contribution to the pathogenesis of complications that typify these conditions (3-7). Our previous studies demonstrated that both in vitro and in vivo derived heterogeneous AGEs ligate cell surface RAGE on endothelium (ECs), mononuclear phagocytes (MPs), vascular smooth muscle (VSMC), and neurons to activate cell signaling pathways such as ERK1/ERK2 kinases and NF-B (8 -9), thereby redirecting cellular function in a manner linked to expression of inflammatory and prothrombotic genes important in the pathogenesis of chronic disorders as apparently diverse as diabetic macrovascular disease and amyloidosis (10 -20).Our recent studies suggested that interruption of the interaction of AGEs with RAGE in vivo, by administration of soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerotic lesion development and complexity in diabetic rodents (19 -20). In the latter studies, analysis of plasma demonstrated evidence of an sRAGE⅐AGE complex; immunoprecipitation of plasma obtained from diabetic sRAGEtreated mice with anti-RAGE IgG yielded species immunoreactive with both anti-RAGE IgG or affinity purified anti-AGE IgG, suggesting that sRAGE might bind up AGEs and limit their interaction with and activation of cell surface RAGE. The beneficial effects of sRAGE were independent of alterations in other risk factors, such as hyperglycemia and hyperlipidemia, implicating a role for AGE-RAGE interaction in the development of vascular dysfunction in diabetes (20).These past studies, however, did not elucidate ...

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The pro‐inflammatory environment in recalcitrant diabetic foot wounds

Acosta

Barco

Vera

et al. 2008

International Wound Journal

163

146

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Lower extremity ulceration is one of the serious and long-term diabetic complications rendering a significant social burden in terms of amputation and quality-of-life reduction. Diabetic patients experience a substantial wound-healing deficit. These lesions are featured by an exaggerated and prolonged inflammatory reaction with a significant impairment in local bacterial invasion control. Experimental and clinical evidences document the deleterious consequences of the wound's pro-inflammatory phenotype for the repair process. From a biochemical standpoint, hyperinflammation favours wound matrix degradation, thus, amplifying a pre-existing granulation tissue productive cells' invasiveness and recruitment deficit. Tumour necrosis factor perpetuates homing of inflammatory cells, triggers pro-apoptotic genes and impairs reepithelialisation. Advanced glycation end-products act in concert with inflammatory mediators and commit fibroblasts and vascular cells to apoptosis, contributing to granulation tissue demise. Therapeutic approaches aimed to downregulate hyperinflammation and/or attenuate glucolipotoxicity may assist in diabetic wound healing by dismantling downstream effectors. These medical interventions are demanded to reduce amputations in an expanding diabetic population.

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Streptozotocin diabetes: prolonged inflammatory response with delay of granuroma formation

Cited by 3 publications

References 0 publications

Tissue Factor as a Link Between Wounding and Tissue Repair

Tissue Factor as a Link Between Wounding and Tissue Repair

N ε-(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression

The pro‐inflammatory environment in recalcitrant diabetic foot wounds

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