PBL 3 – J ACK AND HIS S POTS FQ – E FFECT OF UV EXPOSURE ON THE S KIN Rick Allen

S KIN INTERACTION WITH UV Chromophore – molecule with differing light absorbance capability Skin chromophores = DNA, urocanic acid, aromatic amino acids Chromophores take photon. Use energy to form new molecule (photoproduct), often covalent bonds w. neighbouring molecules. Vit D production Properties of UVR

M OLECULAR L EVEL D AMAGE Absorbed energy to covalent bonds C  T or CC  TT are UVB signature mutations Not speedily fixed, stays as a lesion. The four-membered ring ring is called a cyclobutane pyrimidine dimer (CPD) or (6-4)

M ACROSCOPIC LEVEL DAMAGE Sunburn Inflammation signs based on exposure dose, not duration (few hours) Afferent nerves release neuropeptides  itch, pain, inflammation, immunomodulation. UVR causes melanocytes, keratinocytes and endothelial cells to release neutrophins and hormones  vasodilation, mast cell degranulation, and other cytokine release attracting inflam. mediators. Mast cell products ~1hr, neutrophil and T cell at 3hrs w. max at 48hrs Mitochondrial damage, keratinocyte and fibroblast enzymes  ROS  activation and death.

M ACROSCOPIC D AMAGE Skin aging ROS  cell surface receptor activation  AP-1 activation  ↓ collagen production. UV  nuclear factor  MMP-1 (collagenase) Neutrophils  MMP – 8 (collagenase) Half dead collagen accumulates, ↓ integrity, ↓ elasticticity and inhibits new collagen.

I MMUNOSUPPRESSION CPD are made within APC (Langerhan’s)  ↓ antigen- presenting capacity. Damage persists for days, unable to repair, migrate to lymph node. ROS may be involved. UVB internalises some cell surface receptors Membrane lipids oxidised  will bind to PAF receptors  cytokine synthesis (IL – 10) UVB hits keratinocytes  IL-10 and TNF-α IL-10 from Th2 suppresses Th1 cytokines, promotes Th2 activation over Th1 and causes Th1 anergy This induces T suppressor cells which shut down activated T cells. NK T cells observed with reg. powers.

A DAPTIVE R ESPONSES Hyperplasia of dermis and stratum corneum. UVR triggered, protective Antioxidant defences Tanning DNA photodamage/repair  melanogenesis Tyrosinase activivty ↑ w. UV exposure UV damage ↑ cell surface receptors for keratinocyte-derived melanogenic factors UVA  immediate skin darkening UVB  ↑ activity and # of melanocytes Melanocyte dendrites elongate and branch.

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Q UESTIONS Describe how DNA is damaged/mutated by UV rays. Explain the mechanism behind photodamage resulting in premature aging.