Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

Abstract

Background: Deficiency of the nucleotide excision repair protein xeroderma pigmentosum type A (XPA) is characterized by photosensitivity. Results: XPA-deficient cells and mice generate increased platelet-activating factor (PAF), oxidized glycerophosphocholines, and skin inflammation following ultraviolet B radiation with the skin inflammation blocked by PAF antagonists. Conclusion: PAF-R signaling mediates photosensitivity seen in XPA deficiency. Significance: These studies provide important insights into the mechanisms of photosensitivity.

Chemotherapeutic Agents Subvert Tumor Immunity by Generating Agonists of Platelet-Activating Factor

“…1c). Similar to our previously published findings examining PAF-R biochemical activity generated in human epithelial tumor cells or human skin in response to the pro-oxidative stressor UVB (20,24,36), preincubation of melanoma cells with antioxidants vitamin C or N-acetylcysteine (NAC) blocked this PAF agonistic activity (Fig. 1d).…”

“…Mass spectrometry was performed on cell lines and perfusion samples using the AB Sciex (Foster City, CA) triple quadrupole QTRAP® 5500 mass spectrometer, equipped with a CTC-PAL autosampler and a Shimadzu HPLC as previously described (24). Please see on-line Supplemental Methods for details of instrument settings and characterization of the various species monitored.…”

“…Pro-oxidative stressors including aromatic hydrocarbons found in jet fuel, cigarette smoke, and ultraviolet B radiation (UVB) (14–18) generate ROS that can act directly on glycerophosphocholines (GPC) to produce oxidized GPC (Ox-GPC) which are potent PAF-receptor (PAF-R) agonists (18–21). Structural studies using mass spectrometry have identified more than a dozen Ox-GPC, including native PAF itself (20–24). There is evidence for hundreds of these biologically active compounds (22–25) that have by-passed the tightly controlled enzymatic process of PAF production (26,27).…”

Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts

“…Platelet activating factor (PAF) -like lipids that were identified as important signaling photoproducts can promote TNF alpha synthesis upon UV exposure [56]. We also detected PL-oxidation products that were identified as iso-prostanoids [57] (PEIPC) and were reported as EP2 receptor ligands [58].…”

Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids

“…UVB light also generated az-PAF (Zhang et al, 2005). Furthermore, UVB irradiation of fibroblast from mice deficient in xeroderma pigmentosum type A DNA repair gene led to 2-fold higher levels butanoyl-PAF, OV-PAF, and glutaryl-PAF (Yao et al, 2012). Exposure of dark adapted rats to physiological light for even as little as 4 hours increased retinal concentration of OV-PC and glutaryl-PC, AZ-PC, and ON-PC about 2-fold compared to rats without this light exposure (Sun et al, 2006).…”