Apoptosis is Differentially Regulated by Burn Severity and Dermal Location

McNamara, Andrew R.; Zamba, K. D.; Sokolich, Julio; Jaskille, Amín D.; Light, Timothy D.; Griffin, Michelle; Meyerholz, David K.

doi:10.1016/j.jss.2009.01.038

Cited by 11 publications

(11 citation statements)

References 20 publications

(30 reference statements)

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“…While prior investigators have proposed that apoptosis plays a significant role in burn injury progression, our results indicate that apoptosis does not play a role in the death of keratinocytes, interstitial cells, and vascular endothelial cells in the zone of ischemia at early (1–4 hours) postburn time points. Rather, apoptosis is a later phenomenon at 24 hours and is responsible for cell death at the furthest reach of burn injury progression.…”

Section: Discussioncontrasting

confidence: 89%

“…We employed immunohistochemical detection of HMGB1 and CC3a to probe for evidence of necrosis and apoptosis, respectively, of various dermal elements in a murine hot comb burn model . Only one subsequent study has employed HMBG1 in vivo to assess necrosis in burn wounds . The present study represents a substantial expansion of our earlier work and, to our knowledge, represents the first study to apply morphometric analysis of the spatiotemporal degrees of necrosis and apoptosis in the zone of ischemia of burn wounds.…”

mentioning

confidence: 95%

“…Elucidation of the relative roles of cellular apoptosis and necrosis in progression of the zone of ischemia from viable to non‐viable is central to an understanding of burn injury progression. Despite its importance, the differential spatiotemporal degrees and rates of necrosis and apoptosis in burn injury progression are not well characterized . Such knowledge will both inform efforts to delineate the molecular mechanism of burn injury progression and provide objective end points by which to track the evolution of burn wounds and to evaluate potential therapeutic interventions in both experimental models and patients.…”

mentioning

confidence: 99%

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Spatiotemporal progression of cell death in the zone of ischemia surrounding burns

Lanier

McClain

Lin

et al. 2011

Wound Repair Regeneration

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Burns are dynamic injuries, characterized by progressive death of surrounding tissue over time. Though central to an understanding of burn injury progression, the spatiotemporal degrees and rates of cellular necrosis and apoptosis in the zone of ischemia surrounding burns are not well characterized. Using a validated porcine hot comb model, we probed periburn tissue at 1, 4, and 24 hours after injury for high mobility group box 1 (HMGB1) as a marker of necrosis and activated cleaved caspase 3 (CC3a) as a marker of apoptosis, followed by spatiotemporal morphometric analysis. We found that necrosis was the most prominent mechanism of cell death in burn injury progression, with significant progression between 1 and 4 hours post-burn. Apoptosis appeared not to play a role in early burn injury progression, but was observed in cells at the interface of necrotic and viable tissue at 24 hours post-burn. Our findings imply that intervention within the first 4 hours following injury is likely necessary to limit burn injury progression. Additionally, based on HMGB1 staining patterns, we define distinct early, intermediate and late pathological signs of cell necrosis that may facilitate delineation of causal mechanistic relationships of burn injury progression in vivo.

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Section: Discussioncontrasting

confidence: 89%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Spatiotemporal progression of cell death in the zone of ischemia surrounding burns

Lanier

McClain

Lin

et al. 2011

Wound Repair Regeneration

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“…Of all species, the skin of the pig is the most similar to human skin, 18 and previous studies reported establishments of various burn injury models in pigs. 19–24 Having analyzed these models and, more importantly, our previous establishment of a diabetic pig wound model, 15 we needed a pig burn model that recapitulates the characteristics of human burn wounds and, more importantly, is ideal for evaluating new therapeutic candidates. As shown in Figure 1a , triplicate burn wounds created on both sides (middle rows) of the pig underwent a clear expansion especially from 48 to 96 hours following the injury under our experimental conditions (1.5 cm × 1.5 cm 115 °C brass block for 30 seconds) and the expansion slowed down afterward (day 5).…”

Section: Resultsmentioning

confidence: 99%

Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs

Bhatia

O’Brien

Chen

et al. 2016

Molecular Therapy - Methods & Clinical Development

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Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90α is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5–treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing.

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“…It is possible that thrombomodulin-HMGB1 antagonism as demonstrated in murine skin exposed to short wavelength microbicidal UVC (254 nm), a UV exposure known to be associated with necrotizing effects, may be mechanistically different from UVB-induced apoptotic sunburn in human skin [64]. Indeed, HMGB1 extranuclear staining has been employed as an immunohistochemical marker of necrotic skin injury in the context of thermally induced third degree burns [75,76].…”

Section: Hmgb1 In Cutaneous Photodamagementioning

confidence: 99%

HMGB1-Directed Drug Discovery Targeting Cutaneous Inflammatory Dysregulation

Lamore

Cabello

Wondrak

2010

CDM

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Extracellular cytokine function of the non-histone nuclear protein high-mobility group box 1 (HMGB1) has recently been recognized as an important drug target for novel anti-inflammatory therapeutics. Accumulating evidence supports the mechanistic involvement of the alarmin HMGB1 in skin response to microbial infection and ultraviolet-induced solar damage. Moreover, HMGB1 modulation of inflammatory signaling and tissue remodeling is now emerging as a causative factor in wound repair, autoimmune dysregulation, and skin carcinogenesis, representing cutaneous pathologies that affect large patient populations with unmet therapeutic needs. Recent structure-based drug discovery efforts have aimed at increasing the number of small molecule- and biologics-based prototype therapeutics targeting HMGB1. Small molecule drugs that may provide therapeutic benefit through HMGB1-directed mechanisms involve HMGB1 inhibitory ligands, Toll-like receptor antagonists, RAGE antagonists, alpha7 nicotinic acetylcholine receptor agonists, G2A antagonists, serine protease inhibitors, and alpha-dicarbonyl-based soft electrophiles. Using some of these agents, pharmacological modulation of HMGB1-associated cutaneous pathology has been achieved with an acceptable toxicity profile, and preclinical proof-of-concept experimentation has demonstrated feasibility of developing HMGB1-modulators into novel systemic and topical therapeutics that target cutaneous inflammatory dysregulation.

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Apoptosis is Differentially Regulated by Burn Severity and Dermal Location

Cited by 11 publications

References 20 publications

Spatiotemporal progression of cell death in the zone of ischemia surrounding burns

Spatiotemporal progression of cell death in the zone of ischemia surrounding burns

Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs

HMGB1-Directed Drug Discovery Targeting Cutaneous Inflammatory Dysregulation

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