Oxygen in wound healing: More than a nutrient

Davidson, John D.; Mustoe, Thomas A.

doi:10.1046/j.1524-475x.2001.00175.x

Cited by 30 publications

(20 citation statements)

References 49 publications

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“…This capability of fibroblasts is unusual, at least among mesenchymally derived cells, and appears to be important in normal development, wound healing, and fibrosis as well as in the vascular changes that characterize hypoxic pulmonary hypertension (1)(2)(3). With regard to pulmonary artery adventitial fibroblasts, we have shown that among the resident vascular wall cells they exhibit the earliest and most dramatic responses to hypoxic exposure in vivo (4).…”

mentioning

confidence: 82%

Extracellular ATP Is an Autocrine/Paracrine Regulator of Hypoxia-induced Adventitial Fibroblast Growth

Gerasimovskaya¹,

Ahmad²,

White³

et al. 2002

Journal of Biological Chemistry

117

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, and pyridoxalphosphate-6-azophenyl-2,-4-disulfonic acid (100 M) as well as apyrase (5 units/ml) attenuated hypoxia-and ATP-induced and DNA synthesis, indicating activation and a functional role of purinoceptors under hypoxic conditions. ATP-induced DNA synthesis was augmented by hypoxia in an additive fashion, whereas ATP and hypoxia synergistically increased growth factor-induced DNA synthesis, again suggesting that ATP and hypoxia utilize similar signaling pathways to induce proliferation. Indeed, we found that ATP (100 M) and hypoxia (3% O 2 ) induced expression and activation of Egr-1 transcription factor, and both stimuli acted, in part, through a G␣ i /ERK1/2-dependent signaling pathway. Suramin, Cibacron blue 3GA, and apyrase attenuated hypoxia-induced ERK1/2 activation and Egr-1 expression. We conclude that hypoxia induces ATP release from endothelial cells and fibroblasts and that the activation of P2 purinoceptors is involved in the regulation of DNA synthesis by fibroblasts under hypoxic conditions. Hypoxia has been shown to act as a direct proliferative stimulus for fibroblasts in a variety of organs. This capability of fibroblasts is unusual, at least among mesenchymally derived cells, and appears to be important in normal development, wound healing, and fibrosis as well as in the vascular changes that characterize hypoxic pulmonary hypertension (1-3). With regard to pulmonary artery adventitial fibroblasts, we have shown that among the resident vascular wall cells they exhibit the earliest and most dramatic responses to hypoxic exposure in vivo (4). In tissue culture we have also demonstrated that hypoxia in the absence of exogenous mitogens induces proliferation of pulmonary artery fibroblasts as well as some subpopulations of aortic adventitial fibroblasts. This response is due in large part to G␣ i/o -mediated activation of a complex network of mitogen-activated protein kinases, whose specific contributions to hypoxia-induced proliferation differ from those of serum-induced growth signals (5). It remains unclear, however, whether either activation or augmentation of the hypoxiainduced growth response is due at least in part to autocrine/ paracrine responses to factors secreted by fibroblasts during hypoxia, which act through G-protein-coupled pathways.One factor that could contribute to such an autocrine loop is ATP. Purines and pyrimidines (mainly ATP, ADP, adenosine, and UTP) have widespread and specific extracellular signaling actions in the regulation of a variety of functions in many tissues and appear to have key roles in development, proliferation, differentiation, and release of hormones, neurotransmitters, and cytokines (6 -10). It is also becoming evident that alterations in the physiology of purinergic signaling may result in the development of a variety of pathologies including disorders of the immune system, neurodegenerative, and vascular diseases (7). Extracellular ATP can, in fact, stimulate the growth and proliferation of vascular smooth muscle cells (SMC), 1 and this response...

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mentioning

confidence: 82%

Extracellular ATP Is an Autocrine/Paracrine Regulator of Hypoxia-induced Adventitial Fibroblast Growth

Gerasimovskaya¹,

Ahmad²,

White³

et al. 2002

Journal of Biological Chemistry

117

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“…However, severe hypoxia in diabetic wounds often fails to directly trigger effective angiogenesis because of significant cell death under such conditions. In fact, hyperbaric oxygen treatment is beneficial for wound healing in diabetic foot ulcers [216], presumably by rescuing cells in wounded tissues from hypoxia-induced death. Rather interestingly, only intermittent hyperbaric treatment is beneficial, whereas continuous hyperbaric treatment is toxic and prevents wound healing [216].…”

Section: Hypoxia and Pathological Angiogenesismentioning

confidence: 99%

“…In fact, hyperbaric oxygen treatment is beneficial for wound healing in diabetic foot ulcers [216], presumably by rescuing cells in wounded tissues from hypoxia-induced death. Rather interestingly, only intermittent hyperbaric treatment is beneficial, whereas continuous hyperbaric treatment is toxic and prevents wound healing [216]. A likely cause to the toxicity may be the generation of reactive oxygen species, but down-regulation of HIF-a levels under hyperoxia may also diminish the expression of angiogenic factors.…”

Section: Hypoxia and Pathological Angiogenesismentioning

confidence: 99%

Mechanisms of adaptive angiogenesis to tissue hypoxia

2008

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Angiogenesis is mostly an adaptive response to tissue hypoxia, which occurs under a wide variety of situations ranging from embryonic development to tumor growth. In general, angiogenesis is dependent on the accumulation of hypoxia inducible factors (HIFs), which are heterodimeric transcription factors of alpha and beta subunits. Under normoxia, HIF heterodimers are not abundantly present due to oxygen dependent hydroxylation, polyubiquitination, and proteasomal degradation of alpha subunits. Under hypoxia, however, alpha subunits are stabilized and form heterodimers with HIF-1beta which is not subject to oxygen dependent regulation. The accumulation of HIFs under hypoxia allows them to activate the expression of many angiogenic genes and therefore initiates the angiogenic process. In recent years, however, it has become clear that various other mechanisms also participate in fine tuning angiogenesis. In this review, I discuss the relationship between hypoxia and angiogenesis under five topics: (1) regulation of HIF-alpha abundance and activity by oxygen tension and other conditions including oxygen independent mechanisms; (2) hypoxia-regulated expression of angiogenic molecules by HIFs and other transcription factors; (3) responses of vascular cells to hypoxia; (4) angiogenic phenotypes due to altered HIF signaling in mice; and (5) role of the HIF pathway in pathological angiogenesis. Studies discussed under these topics clearly indicate that while mechanisms of oxygen-regulated HIF-alpha stability provide exciting opportunities for the development of angiogenesis or anti-angiogenesis therapies, it is also highly important to consider various other mechanisms for the optimization of these procedures.

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“…(7) There is no doubt that other mechanisms are also involved, including nerve transmission control, algeassic substance reduction and control of the inflammatory response and associated irritative substance release, but as a simple and easily demonstrated effect, enhanced superficial blood flow was shown following LLLT in injured sumo wrestlers. With the enhancement of superficial blood flow, there will narturally be an increase in the oxygen tension values, and the importance of the role of oxygen in initiating and sustaining wound healing has recently become even more apparent than before, (8,9) and the oxygen gradient into injured areas, along which reparative cells migrate, has been measured. (10) …”

Section: Discussionmentioning

confidence: 99%

Effects of Diode Laser Irradiation on Superficial Blood Flow in College Sumo Wrestlers: A Preliminary Study

et al. 2005

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Sumo wrestling is a very powerful and competitive contact sport played by extremely fit and highly trained competitors. Due to the extremely competitive nature of the sport and the required training, injuries are common both during training and the actual competition. Long-term lay-up of the competitor has to be avoided in order to maintain the level of muscle tone and mental concentration generated by the grueling training, so postinjury recovery time is kept to a minimum. A noninvasive therapy is therefore required, and the recent interest in the successful application of low level laser therapy (LLLT) in pain attenuation for a large number of pain types suggested that it might offer a new tool for sumo-related injuries. The current trial, with ten sports university sumo wrestlers, examined the effect of LLLT on injuries of the knee (five subjects) and foot (five subjects), using laser speckle flowmetry to assess the possible increase in superficial blood flow which has been associated with both pain attenuation and accelerated wound healing. An 830 nm 60 mW GaAlAs diode LLLT system was applied on one point for 5 min (approximately 15 J/cm 2 ), and laser speckle flowmetry was performed before, during, immediately after, at 30 min and 60 min after irradiation. Decreased blood flow was seen intrairradiation, but an increase, significant in 7 of the 10 subjects was seen immediately postirradiation. This was maintained at significantly elevated levels in 4 subjects, while the remaining six decreased slightly, but in all ten subjects elevated levels of superficial blood flow were seen at one hour postirradiation, compared with preirradiation. LLLT is noninvasive, easy to apply, well tolerated and adverse side effect free. It is suggested that, following further trials to elucidate dosimetry and possible wavelength specificity, LLLT may well offer an exciting new tool to the sports clinician treating injured sumo wrestlers.

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Oxygen in wound healing: More than a nutrient

Cited by 30 publications

References 49 publications

Extracellular ATP Is an Autocrine/Paracrine Regulator of Hypoxia-induced Adventitial Fibroblast Growth

Extracellular ATP Is an Autocrine/Paracrine Regulator of Hypoxia-induced Adventitial Fibroblast Growth

Mechanisms of adaptive angiogenesis to tissue hypoxia

Effects of Diode Laser Irradiation on Superficial Blood Flow in College Sumo Wrestlers: A Preliminary Study

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