Early Wound Healing Exhibits Cytokine Surge Without Evidence of Hypoxia

Haroon, Zishan A.; Raleigh, James A.; Greenberg, Charles S.; Dewhirst, Mark W.

doi:10.1097/00000658-200001000-00020

Cited by 108 publications

(78 citation statements)

References 49 publications

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“…However, it has been suggested that dual pathways are involved in the induction of HIF-1 within the wound bed. Pro-inflammatory mediators stimulate early expression, whereas, wound hypoxia becomes the major stimulus at later time points (20,22,23). The induction of HIF-1α expression at the wound site in the current study is related to the early inflammatory response and, in the excisional wound, animals correlated with a strong inflammatory response.…”

Section: Discussionmentioning

confidence: 46%

Burn Injury-Induced Alterations in Wound Inflammation and Healing Are Associated with Suppressed Hypoxia Inducible Factor-1α Expression

Schwacha

Nickel

Daniel

2008

Mol Med

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A major complication associated with burn injury is delayed wound healing. While healing of the burn injury site is essential, healing of distal injury sites caused by surgical interventions and other processes also is important. The impact of burn injury on healing of these distal wound sites is not understood clearly. To study this, mice were subjected to major burn injury or a sham procedure. Immediately following, excisional wounds were made on the dorsal surface caudal to the burn site and wound closure was monitored over a 7-d period by planimetry. In a second series of experiments, plasma and excisional wounds were collected for in vitro analysis of cyto-and chemokine levels, L-arginine metabolism, and hypoxia-inducible factor (HIF)-1α expression. At 1-7 d post-injury, a significant inflammatory response was evident in both groups, but the healing process was delayed in the burninjured mice. At 3 d post-injury, wound levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and keratinocyte-derived chemokine were suppressed in the burn group. This difference in the wound inflammatory response was independent of changes in L-arginine metabolism (nitrate levels, inducible nitric oxide synthase expression, arginase activity), but correlated with a marked reduction in HIF-1α protein levels. In conclusion, these findings suggest that HIF-1α and the inflammatory response play a significant role in wound healing, and reduced levels of HIF-1α contribute to the impaired healing response post-burn.

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Section: Discussionmentioning

confidence: 46%

Burn Injury-Induced Alterations in Wound Inflammation and Healing Are Associated with Suppressed Hypoxia Inducible Factor-1α Expression

Schwacha

Nickel

Daniel

2008

Mol Med

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“…There is a normal tissue corollary to this, based on wound healing. In a rat dermal skin wound model, hypoxia was not involved in the initiation of angiogenesis; rather, it was associated with the period of wound involution after reepithelialization 14 . In an analogous fashion, HIF1 upregulation and increases in VEGF in response to tumour hypoxia may be important in vascular remodelling during continued tumour growth 128 .…”

Section: Hypoxia and Angiogenesismentioning

confidence: 99%

“…Examples of relatively hypoxic normal tissues include pericentral vein cells in the liver 12 , portions of the retina (in the dark) 13 , spinous layer of the epidermis 14 , the thymus 6,15 , renal tubular epithelium 16 , myocardium (particularly during exercise) 17 and subregions of the bone marrow that are enriched for stem cells 18 . Hypoxia has diverse roles in the function of these normal tissues.…”

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

Self Cite

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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“…This led some to suggest that hypoxia (and other stress factors such as pH and glucose availability) might be essential for promoting angiogenesis and other repair mechanisms in wound healing (58). However, Haroon et al (59) used PIMO labeling to show that hypoxia was largely absent on day 1 after punch biopsy wounds had been created in rats. Macrophages expressing various proangiogenic cytokines were found in these early, nonhypoxic lesions.…”

Section: Woundsmentioning

confidence: 99%

Hypoxia Regulates Macrophage Functions in Inflammation

Murdoch

Muthana

Lewis

2005

The Journal of Immunology

418

329

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The presence of areas of hypoxia is a prominent feature of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of joints with rheumatoid arthritis, healing wounds, and sites of bacterial infection. These areas form when the blood supply is occluded and/or unable to keep pace with the growth and/or infiltration of inflammatory cells in a given area. Macrophages are present in all tissues of the body where they normally assist in guarding against invading pathogens and regulate normal cell turnover and tissue remodeling. However, they are also known to accumulate in large numbers in such ischemic/hypoxic sites. Recent studies show that macrophages then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. In the present study, we outline and compare the phenotypic responses of macrophages to hypoxia in different diseased states and the implications of these for their progression and treatment.

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Early Wound Healing Exhibits Cytokine Surge Without Evidence of Hypoxia

Cited by 108 publications

References 49 publications

Burn Injury-Induced Alterations in Wound Inflammation and Healing Are Associated with Suppressed Hypoxia Inducible Factor-1α Expression

Burn Injury-Induced Alterations in Wound Inflammation and Healing Are Associated with Suppressed Hypoxia Inducible Factor-1α Expression

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Hypoxia Regulates Macrophage Functions in Inflammation

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