Chapter 057. Photosensitivity and Other Reactions to Light (Part 2) pps
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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 UV-B are at least 1000-fold more efficient than photons in the UV-
A in evoking the response. However, 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 E
2
, 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.
