The proliferative capacity of neonatal skin fibroblasts is reduced after exposure to venous ulcer wound fluid: A potential mechanism for senescence in venous ulcers

Mendez, Martha; Raffetto, Joseph D.; Phillips, Tania J.; Menzoı́an, James O.; Park, Hee-Young

doi:10.1016/s0741-5214(99)70113-8

Cited by 122 publications

(95 citation statements)

References 26 publications

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“…Similarly, an increase in fibroblast senescence appears to predominate in the venous ulcers and skin tissue of diabetic mice (37). Consistent with these findings, it was reported that a number of senescence-like features (e.g., the increased expression of SA-␤-gal, decreased production of cyclin D1, phosphorylated RB, and growth factors, and increased level of p21) can be recapitulated by exposing normal fibroblasts in culture to wound fluids derived from chronic nonhealing wounds (36,47). It is noteworthy that the most common features of these chronic wound microenvironments include markedly increased ROS levels, an active species that attacks DNA, causing the accumulation of lipofuscin (a molecule that cannot be degraded by cells) and DNA damage-induced cell cycle arrest (7)(8)(9), the decreased expression and secretion of growth factors [epidermal growth factor (EGF), platelet derived growth factor (PDGF) and insulin like growth factor I (IGF-I)], decreased keratinocyte migration, increased tissue proteases, and microbial contamination (1,12).…”

supporting

confidence: 62%

Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes

Bitar

Abdel‐Halim

Al-Mulla

2013

American Journal of Physiology-Endocrinology and Metabolism

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A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescenceassociated ␤-galactosidase activity and phospho-␥-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound.

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supporting

confidence: 62%

Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes

Bitar

Abdel‐Halim

Al-Mulla

2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Indeed SIPS has already been shown to exist in many pathophysiological conditions. For instance, HDFs excised from gastric veinous ulcers display several features of senescence: reduced proliferative capacity, enlarged size, SA ␤-gal activity, overexpression of fibronectin [18,19]. HDFs cultured from distal lower extremities in patients with veinous insufficiencies also display cellular characteristics of senescence [20] as well as arteries subjected to balloon angioplasty [21], tissue surrounding liver carcinomas [22] and benign prostatic hyperplasia [23].…”

Section: Discussionmentioning

confidence: 99%

UVB-induced premature senescence of human diploid skin fibroblasts

Chainiaux

Magalhães

Eliaers

et al. 2002

The International Journal of Biochemistry & Cell Biology

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In this work, we show that repeated stresses with UVB (290-320 nm) induce stress-induced premature senescence (SIPS) of skin human diploid fibroblasts (HDFs). HDFs at early cumulative population doublings were exposed three or five times to increasing subcytotoxic doses of UVB with one stress per day. After 2 days of recovery, several biomarkers of replicative senescence were established. First, there was an increase in the proportion of cells positive for senescence-associated ␤-galactosidase activity. Second, there was a loss of replicative potential as assessed by a very low level of [ 3 H]-thymidine incorporation. Third, the steady-state level of the mRNA of three senescence-associated genes, i.e. fibronectin, osteonectin and SM22, was increased in HDFs at 72 h after three and five exposures to UVB. In conclusion, these results suggest that it is possible to induce SIPS in HDFs after repeated exposures to subcytotoxic doses of UVB. This model could be used to test whether HDFs in UVB-induced premature senescence are able to promote epithelial cell growth and tumorigenesis in skin, as shown recently with HDFs in H 2 O 2 -induced premature senescence.

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“…An early study with immunostaining detected TNF-a at the venous ulcer bed along with undegraded fibrin (Claudy et al, 1991). Subsequently, six studies (Mendez et al, 1999;Murphy et al, 2002;Cowin et al, 2006;Wallace et al, 2006;Jull et al, 2007;Charles et al, 2009) showed a correlation between TNF-a and the non-healing state of venous ulcers. Two studies revealed higher levels of TNF-a in non-healing ulcers compared with healing ulcers (Murphy et al, 2002;Charles et al, 2009).…”

Section: Cytokines/growth Factorsmentioning

confidence: 99%

Does Inflammation Have a Role in the Pathogenesis of Venous Ulcers?: A Critical Review of the Evidence

Liu

Margolis

Isseroff

2011

Journal of Investigative Dermatology

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Chronic venous disease, a disorder involving venous return from the legs, is a growing epidemic in the developed world. Numerous studies have been conducted in the past two decades in an attempt to elucidate its underlying pathophysiology. Many theories have been proposed to address the profound inflammatory dysregulation, with the majority focusing on fibrin trap, inflammatory trap, cytokines, growth factors, and matrix metalloproteinases. Although many of these theories have obtained great momentum, much of the data are contradictory. Moreover, many treatments built on these theories have claimed overwhelming success despite insufficient evidence. At the same time, there are few reviews that critically analyze and evaluate these data. Therefore, in this paper, we will provide summaries of the background data and evolution of these theories and examine their supporting evidence.

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The proliferative capacity of neonatal skin fibroblasts is reduced after exposure to venous ulcer wound fluid: A potential mechanism for senescence in venous ulcers

Cited by 122 publications

References 26 publications

Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes

Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes

UVB-induced premature senescence of human diploid skin fibroblasts

Does Inflammation Have a Role in the Pathogenesis of Venous Ulcers?: A Critical Review of the Evidence

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