Ultraviolet light B (UVB) exposure is a particularly common form of skin injury, which is associated with increased synthesis of eicosanoids. The mechanisms of enhanced synthesis are poorly understood. Recent data obtained in our lab indicate that endogenous release of histamine in human skin explants mediates 60% of the increased prostaglandin synthesis in the early period (up to 8 hours) after UV exposure. Studies of epidermal cultures indicate that UV-induced potentiation of histamine-stimulated prostaglandin synthesis involves an increase in the cellular capacity for prostaglandin synthesis, an increase in sensitivity to histamine and calcium influx. We propose to test the hypothesis that peroxidative injury by UV light increases release of esterified fatty acids through the action of phospholipases A2 and C with consequent activation of protein kinase C. Preliminary data clearly suggest that protein kinase C activation has occurred in UV-injured keratinocytes. In addition, we propose that the normal calcium compartmentalization present in skin is disrupted in UV injury, increasing the availability of calcium to potentiate agonist-induced prostaglandin release. The agonist histamine, which we know stimulates prostaglandin synthesis, and which preliminary data show is synthesized by keratinocytes in UV injury, will be used to dissect these mechanisms. The long-term objective of these studies is to provide the necessary foundation to develop therapy for UVB-induced skin injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Modified Research Career Development Award (K04)
Project #
1K04AR001849-01
Application #
3071413
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Gresham, A; Masferrer, J; Chen, X et al. (1996) Increased synthesis of high-molecular-weight cPLA2 mediates early UV-induced PGE2 in human skin. Am J Physiol 270:C1037-50
Sudbeck, B D; Parks, W C; Welgus, H G et al. (1994) Collagen-stimulated induction of keratinocyte collagenase is mediated via tyrosine kinase and protein kinase C activities. J Biol Chem 269:30022-9
Miller, C C; Hale, P; Pentland, A P (1994) Ultraviolet B injury increases prostaglandin synthesis through a tyrosine kinase-dependent pathway. Evidence for UVB-induced epidermal growth factor receptor activation. J Biol Chem 269:3529-33
Kang-Rotondo, C H; Miller, C C; Morrison, A R et al. (1993) Enhanced keratinocyte prostaglandin synthesis after UV injury is due to increased phospholipase activity. Am J Physiol 264:C396-401
Hruza, L L; Pentland, A P (1993) Mechanisms of UV-induced inflammation. J Invest Dermatol 100:35S-41S
Pentland, A P; Morrison, A R; Jacobs, S C et al. (1992) Tocopherol analogs suppress arachidonic acid metabolism via phospholipase inhibition. J Biol Chem 267:15578-84
Pentland, A P; Jacobs, S C (1991) Bradykinin-induced prostaglandin synthesis is enhanced in keratinocytes and fibroblasts by UV injury. Am J Physiol 261:R543-7