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Lars Bellner, Timothy Fox, Katherine Gotlinger, Michael Dunn, Tatyana Milman, Gerald Zaidman, Michal Schwartzman; Dysregulated Heme Oxygenase-Ferritin System in Pterygium Pathogenesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3898.
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Pterygium is an ocular surface disease of humans attributed to chronic ultraviolet-B exposure. It involves invasive centripetal growth with associated inflammation and neovascularisation. Cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 monooxygenases (CYP) derived eicosanoids have been implicated in ocular surface inflammation and neovascularization. These eicosanoids are subjected to regulation by enzymes such as heme oxygenases (HO) and Ferritin.
Quantitative PCR and LC-MS/MS based lipidomics were performed on pterygium from patients undergoing surgical removal of pterygium. Control tissues consisted of donor corneal grafts. In addition, LC-MS/MS based lipidomics was performed on tears collected from patients prior to surgery.
mRNA of HO-2, the constitutive HO isoform, was upregulated by 40% in pterygium as compared to control tissue, while the mRNA level of the inducible form, HO-1, was downregulated by more than 50%. Ferritin light and heavy chain mRNA expression levels were 60% and 30% lower in pterygium as compared to control. CYP4B1 mRNA levels were 2-fold higher in pterygium compared to control. Lipidomic analysis indicated a doubling in the level of COX-derived PGE2 and TxB2 in pterygium as compared to control. Among LOX-derived metabolites, the anti-inflammatory 15-HETE levels were significantly reduced in pterygium (79.3±48.11 pg/mg protein) as compared to control (586.2±213.5 pg/mg protein), whereas pro-inflammatory LOX and CYP4B1-derived 12-HETE levels were 10-fold higher in pterygium (2768±832.3 pg/mg protein) compared to control (231.4±87.35 pg/mg protein). PGE2 and the HETEs were also present in tears from patients with pterygium, but were not detected in tears from healthy volunteers.
We believe a dysfunctional HO-Ferritin system leads to increased mRNA levels of CYP4B1 and increased production of the LOX- and COX-derived proinflammatory lipid mediators, thus contributing to the pathogenesis of pterygium. Moreover, the lower expression levels of ferritin have the potential of increasing intracellular iron levels, contributing to oxidative stress and could be a major cause of the iron-deposition often observed along the leading edge of the pterygium, Stocker’s line.
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