The Role of Ultraviolet Irradiation and Heparin-Binding Epidermal Growth Factor-Like Growth Factor in the Pathogenesis of Pterygium

Abstract

Ultraviolet (UV) light is one of the major factors implicated in the pathogenesis of pterygium. The mechanism by which UV light induces this disease remains elusive. The aim of this study was to evaluate the effects of UVB irradiation on the expression of growth factors in cultured pterygium epithelial cells and to demonstrate their distribution within pterygium. We cultured pterygial epithelial cells from pterygium explants and these cells were exposed to 20 mJ/cm 2 of UVB. Total RNA was extracted at 0, 6, and 12 hours after irradiation. 32 P-labeled cDNA was synthesized and analyzed using microarray technology to determine the differential expression of 268 growth factor and cytokine related genes. Semiquantitative reverse transcriptase-polymerase chain reaction was used to corroborate this data. Conditioned media derived from cells exposed to UVB irradiation was analyzed for protein expression by enzyme-linked immunosorbent assay. Immunohistochemistry was used to evaluate the distribution of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in pterygium tissue. Analysis of the hybridization signals revealed that the genes encoding HB-EGF, fibroblast growth factor 3, and cytotoxic trail ligand receptor were consistently elevated at 6 and 12 hours after UVB treatment. HB-EGF mRNA was elevated 6.8-fold at 6 hours after irradiation and was augmented in culture supernatants after the same treatment. Furthermore, HB-EGF reactivity was identified in the epithelium and vasculature of pterygium by immunohistochemistry. HB-EGF was present in normal limbal epithelium, although it was not induced in cultured limbal epithelial cells by UV irradiation. HB-EGF is a potent mitogen, localized in pterygium tissue, and significantly induced by UVB in pterygium-derived epithelial cells. We postulate that this growth factor is a major driving force in the development of pterygia and a means by which UV irradiation causes the pathogenesis of pterygium. (Am J Pathol 2003, 162:567-574) Pterygia are characterized by the encroachment of a wing of altered vascular tissue over the cornea. It is a disorder of epithelial hyperplasia and accompanied fibrovascular growth thought to originate at the corneal-conjunctival junction, where it is proposed that altered limbal stem cells migrate centripetally to encroach on the central cornea.

Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

“…Using a pterygium-derived epithelial cell culture model, we demonstrated the partial involvement of the EGFR in transmitting an extracellular UVB signal that resulted in the activation of an intracellular signal transduction pathway. Interestingly, the same molecules and pathways were not activated by UVB in normal conjunctival or limbal 8 epithelial cells and this observation is currently under investigation in our laboratory.…”

“…6 Recently, we have identified UVB as an environmental agent likely to be responsible for initiating molecular events that lead to the formation of pterygia. 7,8 From our hypothesis, 9 we postulate that UVB radiation activates cells at or near the limbus. This activation may cause 1) phenotypic alterations in a distinct population of epithelial cells, 2) production of proinflammatory and angiogenic cytokines 7 and growth factors, 8 and 3) increased invasiveness due to enhanced production of matrix metalloproteinases (MMPs) over and above their natural tissue inhibitors (TIMPs).…”

“…7,8 From our hypothesis, 9 we postulate that UVB radiation activates cells at or near the limbus. This activation may cause 1) phenotypic alterations in a distinct population of epithelial cells, 2) production of proinflammatory and angiogenic cytokines 7 and growth factors, 8 and 3) increased invasiveness due to enhanced production of matrix metalloproteinases (MMPs) over and above their natural tissue inhibitors (TIMPs). 6,9 -12 To date, we 6,9 -12 and others [13][14][15][16][17] have accumulated data from in vitro culture and in vivo tissue-based studies that resemble investigations performed in human UVexposed skin.…”

“…32 It is highly likely that stimulation of such receptors by UV contributes to the activation of MAPK pathways. Furthermore, targeting the EGFR in our model is relevant because this receptor 33,34 and at least one of its ligands heparin-binding epidermal growth factor-like growth factor (HB-EGF) 8,35 has been identified in pterygia. Using a pterygium-derived epithelial cell culture model, we demonstrated the partial involvement of the EGFR in transmitting an extracellular UVB signal that resulted in the activation of an intracellular signal transduction pathway.…”

Genetic polymorphism of hOGG1 and risk of pterygium in Chinese

“…Among these risk factors, UV exposure has been documented to have strong correlation with pterygium, but the mechanism by which UV light induces pterygium remains elusive. Nolan et al 15 demonstrated that heparin-binding epidermal growth factor-like growth factor, a potent mitogen, was localized in pterygium tissue, and was significantly induced by UVB in pterygium-derived epithelial cells. Lu et al 16 has proposed photo-damage in pterygium from the point of view of lipid peroxidation.…”