Chapter 057. Photosensitivity and Other Reactions to Light (Part 2) pps

Photosensitivity and Other Reactions to Light Part 2 Molecular Targets for UVR-Induced Skin Effects Epidermal DNA, predominantly in keratinocytes and in Langerhans cells LCs, which ar

Chapter 057 Photosensitivity and Other Reactions to Light

(Part 2)

Molecular Targets for UVR-Induced Skin Effects

Epidermal DNA, predominantly in keratinocytes and in Langerhans cells (LCs), which are dendritic antigen-presenting cells, absorbs UV-B and undergoes structural changes including the formation of cyclobutane dimers and 6,4-photoproducts These structural changes are potentially mutagenic and can be repaired by mechanisms that result in their recognition and excision and the reestablishment of normal base sequences The efficient repair of these structural aberrations is crucial, since individuals with defective DNA repair are at high risk for the development of cutaneous cancer For example, patients with xeroderma pigmentosum (XP), an autosomal recessive disorder, are characterized by variably deficient repair of UV-induced photoproducts, and their skin phenotype often

manifests the dry, leathery appearance of prematurely photoaged skin as well as basal cell and squamous cell carcinomas and melanoma in the first two decades of life Studies in mice using knockout gene technology have verified the importance

of functional genes regulating these repair pathways in preventing the development of UV-induced cancer Furthermore, incorporation of a bacterial DNA repair enzyme, T4N5 endonuclease, into liposomes in a product applied to skin of patients with XP selectively removes cyclobutane pyrimidine dimers and reduces the degree of solar damage and skin cancer DNA damage in LCs may contribute to the known immunosuppressive effects of UV-B (see "Immunologic Effects," below)

Cutaneous Optics and Chromophores

Chromophores are endogenous or exogenous chemical components that can absorb physical energy Endogenous chromophores are of two types: (1) chemicals that are normal components of skin, including nucleic acids, proteins, lipids, and 7-dehydrocholesterol, the precursor of vitamin D; and (2) chemicals, such as porphyrins, synthesized elsewhere in the body that circulate in the bloodstream and diffuse into the skin Normally, only trace amounts of porphyrins are present in the skin, but in selected diseases known as the porphyrias (Chap 352), increased amounts are released into the circulation from the bone marrow and the liver and are transported to the skin, where they absorb incident energy both in the Soret band, around 400 nm (short visible), and to a lesser extent in the

red portion of the visible spectrum (580–660 nm) This results in the generation of reactive oxygen species that can mediate structural damage to the skin, manifest as erythema, edema, urticaria, or blister formation

Acute Effects of Sun Exposure

The acute effects of skin exposure to sunlight include sunburn and vitamin

D synthesis Molecular targets for UVR in addition to DNA include molecular oxygen leading to the generation of reactive oxygen species (ROS), cell membranes, and urocanic acid

Sunburn

This painful skin condition is caused predominantly by UV-B Generally speaking, an individual's ability to tolerate sunlight is inversely proportional to the degree of melanin pigmentation Melanin, a complex tyrosine polymer, is synthesized in specialized epidermal dendritic cells known as melanocytes and is

packaged into melanosomes that are transferred via dendritic process into

keratinocytes, thereby providing photoprotection and simultaneously darkening

the skin Sun-induced melanogenesis is a consequence of increased tyrosinase activity in melanocytes that in turn is a consequence of a human gene, the

melanocortin1 receptor (MCIR), that accounts for the wide variation in human skin and hair color Human MCIR encodes a 317-amino-acid G-coupled receptor

(melanocortin receptor) that binds α-melanocyte-stimulating hormone This leads

to increased intracellular cyclic AMP and protein kinase A, followed by increased transcription of microphthalmia transcription factor (MITF) that regulates

melanogenesis MCIR mutations account for population differences in skin color,

ability to tan, and cancer susceptibility The Fitzpatrick classification of human skin is a function of the efficiency of the epidermal-melanin unit and can usually

be ascertained by asking an individual two questions: (1) Do you burn after sun exposure? and (2) Do you tan after sun exposure? The answers to these questions permit division of the population into six skin types varying from type I (always burn, never tan) to type VI (never burn, always tan) (Table 57-1)

Table 57-1 Skin Type and Sunburn Sensitivity (Fitzpatrick Classification)

Type Description

I Always burn, never tan

II Always burn, sometimes tan

III Sometimes burn, sometimes tan

IV Sometimes burn, always tan

V Never burn, sometimes tan

VI Never burn, always tan

Sunburn is due to vasodilatation of dermal blood vessels There is a lag in time between skin exposure to sunlight and the development of visible redness (usually 4–12 h), suggesting that an epidermal chromophore causes delayed production and/or release of vasoactive mediator(s), or cytokines, that diffuse to the dermal vasculature to evoke vasodilatation

The action spectrum for sunburn erythema includes the UV-B and UV-A Photons in the B are at least 1000-fold more efficient than photons in the

UV-A in evoking the response However, UV-UV-A may contribute to sunburn erythema

at midday when much more UV-A than UV-B is present in the solar spectrum UV-induced activation of nuclear factor-κB (NF-κB)-dependent gene transactivation can augment release of several proinflammatory cytokines including interleukin (IL) 1B, 1L-6, IL-8, vascular endothelial growth factor, prostaglandin E2, and tumor necrosis factor α Local accumulation of these cytokines occurs in sunburned skin, providing chemotactic factors that attract neutrophils and macrophages It is of interest that nonsteroidal anti-inflammatory

drugs (NSAIDs) can reduce sunburn erythema, perhaps by blocking I-κB kinase 2, the enzyme essential for nuclear translocation of cytosolic NF-κB