Sunburn

General characteristics of sunburn

Sunburn is a characteristic consequence of Ultraviolet Radiation (UVR) exposure, whereby the epidermis (top layer of the skin) is showing an immediate (acute) and delayed reaction of redness (erythema), hardening of the skin and in some severe instances blister formation. Burning of the skin is a result of thermal injury to skin and is classified in various gradients of severity.  Sunburn can occur to each skintype, and the severity is dependent on the length and intensity to UV-exposure. Sunburn is a process which is generally regarded as reversible to a normal state of the skin. However, it is now universally believed and scientifically supported that sunburn causes damage to skin cells, which may lead to an increased risk of skin cancer at later stages, a process known as photocarcinogenesis.

Minimal erythema dose (MED)

To determine each individual‘s propensity to sunburn, a universal scale has been used: Minimal Erythema Dose (MED). The MED is the threshold value of each individual’s skin exposed to sun (UV intensity) or an artificial light source that may produce sunburn. Another way to measure melanin’s activation under ambient or laboratory conditions is expressed as the Minimal Melanogenic Dose (MMD), the lowest dose required to develop a visible suntan.  Both MED and MMD are being tested with UV exposure, after which the skin reaction is being recorded mostly 24 hours after the UV irradiation. The minimal dose required to bring out visible reddening of the skin is defined as the MED of the individual. Immediate redness following radiation is attributed to heat, and is not defined as MED. However, the MMD is determined a few days after exposure, and is defined as the minimal exposure to produce an even and visible “tan”. The time required to measure the MMD follows the time it takes to induce the process of melanogenesis, pigment formation of the skin.

Severity

Sunburn may cause variable severity depending on skin type, length and intensity of exposure. Following sunburn injury, the skin undergoes three phases: physical damage, biochemical response and rejection of necrotic tissue. Usually only superficial layers of the skin are affected, and seldom are the deeper layers of the skin involved.

A common classification used in the discipline of emergency care and traumatology defines the skin layers involved in severe burns (most often chemical or physical):

Grade 1: superficial layers involved (epidermis)
Grade 2: deeper layer involved (dermis)
Grade 3: all and deepest layers involved (pandermis)

First-degree skin burns are visible as red, painful, and swollen skin. The burnt skin whitens (blanches) when touched lightly but does not tend to show blister formation. Second-degree burns are red, painful, swollen and show blister formation that may ooze a clear fluid (exudates). The burnt skin may show blanching when touched. Third-degree burns are not painful because the nerves and deeper layers have been destroyed. The skin often becomes leathery and may show as white, black, or bright red. The burned area does not blanch when touched, and hairs can easily be pulled from their roots without pain. No blisters develop.

Biology’s own mechanism to repair and mitigate sunburn attracts the last decennia much attention. Recently, scientific focus has been on biological pathways given the importance of programmed cell death (apoptosis) in eliminating irreparably damaged cells. The balance between survival of the UVR-damaged skin cells and factors leading to premature death of the cells determines the final cell fate. There is growing evidence suggesting that the deregulation of this balance by chronic UVR stress results in the development of skin malignancy, i.e. tumor formation. A greater understanding of the mechanisms that induce and prevent UVR-induced apoptosis will contribute to the understanding of mechanisms relevant to the integrity of the genome (cell’s information).

Biological protection

Various factors play a role in the skin protection from sunburn injury. Genomic stability and the presence of chromophores are some of the important metrics to assess one’s risk to irreversible damage from accumulated skin exposure following UVR. Rates of repair of DNA damage can differ significantly in individuals. Epidemiological data indicate that ultraviolet (UV)-induced skin cancers, including melanomas and basal and squamous cell carcinomas, occur more frequently in individuals with fair skin than in those with dark skin. Various factors determine the risk of carcinogenesis of the skin, however melanin seems to play an important role in protecting the skin against UV radiation, and the levels of one’s melanin correlate inversely with amounts of DNA damage induced by UV in human skin of different ethnic origin.

Introduction

The characteristic features of sunburn are a transient erythema following UVR exposure at doses around or above the minimum erythema dose (MED) of the individual. The MED is seen as a deterministic radiation effect, or part of non-stochastic effects:  those effects in which the severity varies with the radiation dose and for which a threshold value exists. Atmospheric radiation and UV exposure are extensively described by the International Commission on Radiological Protection.

It is possible to identify sun burn cells (SBC), being characterized as keratinocytes biologically and morphologically as cells undergoing apoptosis, programmed cell death. There is increased evidence that the formation of SBC can be seen a self-protective biological mechanism to eliminate cells which are at the highest risk of malignant transformation. Further examination of intracellular DNA damage may reveal the extent of repair mechanism in time. The tumor suppressor gene p53 has a control function in the process of cell repair and apoptosis. However, extra-nuclear events also contribute to SBC formation, such as the activation of death receptors including CD95/Fas and tumor necrosis factor (TNF). Oxidative stress also appears to be involved, probably via mitochondrial pathways, resulting in the release of cytochrome C.

Evidence of the extent of cellular damage is provided in a multitude of animal experiments, where after 24 after UVB irradiation, cells with condensed nuclei can be found in the suprabasal layers as compared with untreated control samples in which no pyknotic nuclei are present. Immunolocalisation of active caspase-3 cleavage could be observed in UVB treated skin equivalents and could be found in the suprabasal layer at 24 hours after UVB (100 mJ/cm2).

Signaling pathways

Apoptosis is mediated by a number of receptors and ligands. To initiate the pathway of apoptosis TNF-related apoptosis-inducing ligand receptors (TRAIL-R1 and R2) and respective ligands – fibroblast-associated Fas-L and TRAIL play a role by initiating a key enzyme caspase-8. TRAIL is shown to promote apoptosis of human primary melanocytes in recent studies published. A next step in the cascade consists of activation of caspase-3, which cleaves, for instance, the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), leading to DNA fragmentation and apoptotic cell death.

Mitochondrial function is pivotal to ultimately complete the apoptotic cascade. The mitochondrial network, which can be initiated by various stress signals (such as anticancer drugs and irradiation) triggers the release of cytochrome c from mitochondria. In the cytoplasm, cytochrome c, through binding to APAF-1, leads to activation of caspase 9, which in turn contributes to the stimulation of caspase 3,5 and 6.

It is shown that the keratinocye growth factor (KGF) protects human keratinocytes by electrophilic and oxidative properties while reducing the cell death induced by UV irradiation. Cytoprotection of keratinocytes by KGF is not a result of direct anti-apoptotic effect but requires de novo protein synthesis, as seen in vitro. The clinically relevant findings of KGF protected keratinocytes seem to hold for in organ-cultured human scalp hair follicles from xenobiotic toxicity of agents. In vivo studies in mice demonstrate that injection of KGF into murine back skin markedly reduce cell death in the epidermis after UVB irradiation. This apoptosis seen seems to be dependent on the fibroblast growth factor (FGF) receptor signaling because it was abrogated in transgenic mice expressing a dominant-negative FGF receptor mutant in keratinocytes. In summary, it seems that KGF plays a pivotal part in the protection of keratinocytes from chemical and physical insults.

The mechanisms underlying the protection of melanocytes are found in the functions of the stem cell factor (SCF), a physiologic melanocyte growth factor that activates both the phosphatidyl-inositol-3 kinase (PI3K) and the extracellular regulated kinase (ERK). In vitro studies have shown that SCF prevented both death and non-death receptor-induced apoptosis, mainly through the activation of the PI3K pathway. Much work needs to be completed to better understand the process by which melanocytes acquire their resistance to apoptosis. 

References

• Braun, S & Krampert, M (2006). "Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents." Journal of Cell Science. Vol 119, pp4841-4849.
• International Commission on Radiological Protection (2007). "ICRP Publication 103: Recommendarions of the ICRP". Annals of the ICRP Vol 37 (2-4).
• Melia & Bulman, J (1995). "Sunburn and tanning in a British population." Public Health. Vol 17, pp 223-229.
• Ravage, B (2005). Burn Unit: Saving Lives After the Flames. De Capo Press.
• Xu, R, X, Sun, X & Weeks, B S (2004). Burns, regenerative medicine and therapy.  Karger AG, Switzerland.