DD 03-10-14 08-09am UV Light and Skin Repair - Box Flashcards
UV Radiation - Effects on the Skin
Damage to DNA, RNA, Lipids, Proteins Both Pro-inflammatory & Immunosuppressive Induction of Innate defenses Induction of apoptosis Vitamin D synthesis
UV radiation & Vitamin D production
UVR induces the non-enzymatic synthesis of cholecalciferol (VitD3) and ergocalciferol (VitD2)
In liver & kidney, both are converted to systemically active form (Di-hydroxy VitD3)
Vitamin D from other sources
VitD3 & VitD2 are contained in dietary supplements
- But, there is controversy regarding VitD & cancer protection, and the need for UV-induced VitD
DNA damage by UVR
Thymine dimer (cyclobutane pyrimidine dimer) : UVB Pyrimidine-6-4 pyrimidone : UVB Hydroxyguanosine : UVA & singlet oxygen
Outcomes of DNA Damage
Repair of damage
Apoptosis (p53-induced –> peeling in sunburn)
Gene mutation (carcinogenesis – initiation, transformation, progression)
Important mediators released by UVR – Primary Cytokines (primary responders to UV)
IL-1a, TNFalpha
Important mediators released by UVR – Secondary Cytokines
IL-6, -8, -10
GM-CSF
Important mediators released by UVR – Lipid Mediators
PAF, PGE2, LTB4
Important mediators released by UVR – Growth Factors & Tumor Progression Factors
MSH, ET-1, VEGF, MIA
Important mediators released by UVR – Mast Cell Mediators
Histamine
Proinflammatory effects of UVR – Mediators
Primary & Secondary cytokines and Lipid Mediators
Proinflammatory effects of UVR – Effects
- Erythema
- Sunburn cells
- Potentiation of other types of cutaneous inflammation (adhesion molecule induction, cytokine/chemokine release)
Immunosuppressive effects of UVR - Effects
- Decreased Langerhans cells (migration out of epidermis)
- Induction of inhibitory cytokines (IL-10, Th2 cytokines)
- Suppressor cells (Treg, NKT cells) tolerance
UVR Immunosuppression cascade
UVR induces keratinocyte release of PAF & Cis-UCA
IL-10 is produced when…
- Cis-UCA activates mast cells or B cells
- PAF induces PGE2, which activates B cells
IL-10 blocks IL-12 production by DCs
T cells CANNOT be activated to form cytotoxic cells, but NKT & Treg induce tolerance
Melanin & UVR Immunosuppression
Melanin screens out a lot of the effects of UVR, but Immunosuppression is NOT inhibited by high melanin content (dark skin color)
–> potentiates induction of Non-melanoma skin cancer (NMSC)
Skin defenses against UVR
DNA repair
Apoptosis of cells w/DNA damage
Defenses against ROS
Melanin
Xerderma Pigmentosum
Family of disease with genetic defects in DNA Repair
–> premature skin aging & fatal UVR-induced skin cancers
DNA Repair Enzyme involved in Nucleotide Excision repair
Excision of mutated strand of DNA <– DNA Ligase
DNA Repair Enzyme for DNA damage recognition
XPC
Repair Enzymes for Unwinding of DNA helix
XPA, XPB, XPD
DNA Repair Enzymes for Incisions & Release of nucleotides
XPB, XPD, XPF, XPG
DNA Repair Enzymes for Gap Filling & Ligation
PCNA, DNA Polymerase, RPA
Activation of DNA Repair Enzymes
By UVR activation of p53
Enzymes for Defense against Reactive Oxygens in the Epidermis
Peroxidases & Catalases
Superoxide dismutase
Glutathione reductase
Thioredoxin reductase
Melanocytes & Melanin production
- In basal layer
- Pheomelanin –> Eumelanin –> Mature melanin (as move outward from ER)
- Tyrosinase is the rate-limiting step
Genes that control pigmentation
Tyrosinase = Rate limiting, Oculocutaneous Albinism (OCA)
TRP-1 & -2 (Tyrosinase-related) = Eumelanin
Pink = transport (membrane protein)
Silver = matrix protein
MC1-R Tyr, Tyrp-1 & -2, ASP = Eumelanin vs. Pheomelanin
Pigment control – SLC24A5
= K-dependent Na/Ca ion exchanger
- Explains 225-38% of European / African differences in pigmentation
Pigment control –SLC45A2
= aka MATP (Membrane Associated Transporter Protein)
= Marker for Caucasians
= Important in melanoma / nevi-formation
Results of Mutations in Genes Controlling Pigmentation
Humans & Mice: Oculocutaneous Albinism
Mice: Agouti (expression of agouti-signaling protein)
Oculocutaneous Albinism- Types & Enzyme involved
OCA I: Tyrosinase
OCA II: Pink
OCA III: Tyrp 1
OCA IV: MATP
Racial Differences in Pigmentation
- Difference melanosomal structure, distribution, & synthesis of melanin
- Differences in MC1R, ASP, SLC transporters
- Potential differences in signaling pathways that contol MITF: MSH, WNT, SCF/Kit
Melanosome & skin color
Not the number of melanocytes but rather, the deposition of melanosomes & the type of pigment produced by them
Europeans – deposited in membrane-bound clusters
Asians – produce more melanin, but looks like Europeans in depositions (clusters)
Africans – larger, more mature melanosomes deposited individually throughout cell
Photocarcinogenesis Cascade
UV Exposure –> DNA damage –> Mutations –> Multistage Carcinogenesis (Initiation, Promotion, Transformation)
UV-Induced Skin Cancers
Melanoma
Non-Melanoma Skin Cancer = Basal & Squamous Cell Carcinomas
Photodermatoses – Types
Idiopathic (probably immunologic)
DNA repair defects
Chemical photosensitivity
Photoaggravated
Photodermatoses – Idiopathic/immunologic
Solar urticaria, PMLE, actinic prurigo
Photodermatoses – DNA repair defects
Xeroderma pigmentosum
Photodermatoses – Chemical photosensitivity
Drug-induced
Porphyria (purpling, blisters, necrosis)
Photodermatoses – Photoaggravated
Psoriasis
Atopic Dermatitis
The Paradox of UV phototherapy
For treatment of
- Extensive psoriasis
- Atopic dermatitis
- Cutaneous T cell lymphoma
- Mastocytosis
- Repigmentation of vitiligo
SPF refers to…
only refers to UVB rating
SPF & Other sunblocks
Best sunscreens have both UVB & UVA protection
- Parsol 1789, avobenzome
- Neutrogena Helioplex
- Nex gen: Mexoryl
Unlike FDA says, sunscreen w/ SPF>15 is needed, esp. for photosensitive pts, skiers, pts w/cancer risk
