A study on prostaglandin F2α in photodermatoses

Summary Prostaglandin F₂ (PGF₂) as a possible mediator was studied. Its plasma content was determined by radioimmunoassay. Changes in the DNA synthesis were followed by autoradiography. In active polymorphous light eruption (PLE) and porphyria cutanea tarda (PCT) a remarkable increase (over 300 pg/ml) in plasma content occurred, especially in cases involving large skin areas. Values returned to normal in remission. PGF₂ administered i.d., significantly increased the DNA synthesis of the epidermal cells 48 h after injection similar to the effect of three minimal erythema dosis UV-irradiation. This was more pronounced in PLE patients than in controls. These findings suggest some role of PGF₂ in producing the inflammatory and perhaps proliferative components of the skin symptoms in PLE. PGF₂ — in parallel to literary data concerning PGE — seems to be a mediator of UV-induced changes in DNA synthesis of the epidermal cells. Offprint requests to: Irene Horkay, MD (address see above)     

UV-Induced changes in urinary polyamine excretion in the mouse

Summary Exposure of hairless mice to the light of a germicidal lamp (254 nm) under conditions which are known to induce epidermal DNA synthesis, cell proliferation, and polyamine metabolism produced a marked increase of polyamine excretion in the urine which lasted for many days. The increase was about the same for free and acetylated polyamines. Although the ratio of N¹-acetylspermidine/N⁸-acetylspermidine increased somewhat in the urine of animals exposed to UV, the increase was not significant enough to be useful as a marker of enhanced cell proliferation. A single topical dose of -difluoromethylornithine, a selective inhibitor of ornithine decarboxylase, prevented the UV-induced increase of polyamine excretion in agreement with its effect on UV-induced epidermal polyamine turnover.     

295nm紫外线晶状体损伤实验研究

本实验来用295nm紫外线光源辐射活体大白鼠,30天、60天、90天后散瞳裂隙灯检查并行晶状体蛋白含量分析,结果发现急性辐射30天时,晶状体无明显改变;辐射60天时晶状体皮质出现点状混浊,辐射90天时晶状体皮质大片混浊,核呈棕色变。可溶性晶状体蛋白下降同这些形状学改变基本平行。作者以为,295mn紫外线辐射的急性迭加性损伤易于导致白内障改变,从而为高原地区白内障研究提供一动物模型。     

Experimental elastosis induced by chronic ultraviolet exposure

Summary The effect of long-term ultraviolet irradiation on the connective tissue of the skin was investigated in 25 naked (Ng/-) mice which received a total daily radiant dose of 40±2 J/cm² for a period of 8.5 months. The produced alterations were very similar to those found in actinic elastosis of humans, as assessed by histologic and electron-microscopic criteria.Presented at the 6th Annual Meeting of the Society of Cutaneous Ultrastructure Research, Barcelona, Spain, June 7–9, 1979     

Topical indomethacin protects from UVB and UVA irradiation

Conclusions Indomethacin is known to decrease the UVB (290–310 nm) induced erythema when applied topically in regular intervals after irradiation [2,5,6], probably via inhibition of prostaglandin synthesis. The absorption spectrum of an IM solution (Fig. 1) suggests that this drug may also exert a high filter capacity in the UVB and UVA range, when applied as a topical suncreen before exposure to UV light. The present study demonstrates that a 2.5% solution of IM indeed protects from UVB induced erythema, and these results are in accordance with those of Lim et al., recently published in abstracted form (1983). The present study demonstrates that topically aplied IM exerts a photoprotective effect also at the cellular level since it prevents UV induced keratinocyte cell death (formation of sunburn cells).Topical application of 2.5% IM decreases the induction of PUVA erythema and inhibits the development of immediate pigment darkening, which demonstrates a potent photoprotective effect also in the UVA range.The photoprotective mechanism of IM when applied prior to irradiation seems to be a filter effect (as to be expected from the absorption spectrum) rather than a biochemical action such as inhibition of prostaglandin synthesis, although the latter explanation cannot be excluded completely from the present results. Preliminary data, however, indicate that sunburn cells do occur in skin irradiated with erythemogenic doses of UVB light and treated with topical IM after exposure, which prevents erythema formation. Before IM can be widely used, it is necessary to evaluate optimal concentration and vehicles and in particular percutaneous absorption and possible systemic toxicity. The UVB screening potency of topical IM seems to be similar to other sunscreens (e.g. para-aminobenzoic acid/PABA), but IM offers a much higher protection against UVA light. This may be important in the treatment of certain photodermatoses and also in the prevention of elastotic skin damage by sunlight.     

UV irradiation causes multiple cellular changes in cultured human retinal pigment epithelium cells

Background The retinal pigment epithelium maybe causally involved in the development and progression of age-related macula degeneration; however, the mechanisms leading to the development of age-related macula degeneration remain largely unknown. The purpose of this study was to examine cellular changes in the retinal pigment epithelium induced by direct irradiation with UV light in culture.Methods Retinal pigment epithelium cells from post-mortem human retinas were used to obtain dissociated cultures with cells retaining the ability to differentiate in vitro. These cells were cultured over several days to weeks. The UV radiation (UV-A and UV-B) occurred under sterile conditions with a 100 HBO/mercury bulb attached to a dissecting microscope, delivering co-axial illumination. The time dependence of irradiation effects was analysed using morphometric, immunohistochemical, functional and apoptosis-detecting techniques.Results Vital and proliferating retinal pigment epithelium cell cultures could be prepared consistently. The cells showed tissue-specific morphologies in vitro for several days to weeks. Pigment epithelium-derived factor was detected in these cells using immunocytochemistry and Western blots. The UV irradiation but not white light resulted in measurable alterations of cell shape and size. The irradiated cells showed partial swelling and shrinkage reminiscent of progressing apoptotic degeneration. TUNEL staining revealed that apoptosis was induced by UV light, but not detectably by white light. The phagocytosis of fluorescent micro-particles diminished after irradiation. These effects were dependent on the duration of irradiation.Conclusions Cultures of retinal pigment epithelium are suitable and sensitive models to study cell damage and may contribute to unravelling the pathogenetic mechanisms of retinal degeneration.     

Gene Expression Profiling of Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a rare recessive disorder that is characterized by extreme sensitivity to UV light. UV light exposure results in the formation of DNA damage such as cyclobutane dimers and (6-4) photoproducts. Nucleotide excision repair (NER) orchestrates the removal of cyclobutane dimers and (6-4) photoproducts as well as some forms of bulky chemical DNA adducts. The disease XP is comprised of 7 complementation groups (XP-A to XP-G), which represent functional deficiencies in seven different genes, all of which are believed to be involved in NER. The main clinical feature of XP is various forms of skin cancers; however, neurological degeneration is present in XPA, XPB, XPD and XPG complementation groups. The relationship between NER and other types of DNA repair processes is now becoming evident but the exact relationships between the different complementation groups remains to be precisely determined.Using gene expression analysis we have identified similarities and differences after UV light exposure between the complementation groups XP-A, XP-C, XP-D, XP-E, XP-F, XP-G and an unaffected control. The results reveal that there is a graded change in gene expression patterns between the mildest, most similar to the control response (XP-E) and the severest form (XP-A) of the disease, with the exception of XP-D. Distinct differences between the complementation groups with neurological symptoms (XP-A, XP-D and XP-G) and without (XP-C, XP-E and XP-F) were also identified. Therefore, this analysis has revealed distinct gene expression profiles for the XP complementation groups and the first step towards understanding the neurological symptoms of XP.     

Pathways involved in proliferating,senescent and immortalized keratinocyte cell death mediated by two different TRAIL preparations

Properly regulated keratinocyte cell death is fundamentally important to maintain structural integrity and homeostatic function of epidermis. Moreover, from an oncological perspective, therapeutic approaches selectively targeting apoptosis of malignant cell types while sparing normal keratinocytes in surrounding skin is desirable. Apo2Ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has been observed to preferentially induce cytopathic effects on transformed/malignant cell types compared with their non-neoplastic counterparts. In this report, two different biologically active preparations of Apo2L/TRAIL, a non-tagged version, NT-Apo2L/TRAIL, and a leucine zipper fusion protein, LZ-Apo2L/TRAIL, were examined for their ability to trigger apoptosis in normal human keratinocytes, and in an immortalized cell line (HaCaT cells). Differences between these preparations were observed, including: NT-Apo2L/TRAIL induced less keratinocyte apoptosis compared with LZ-Apo2L/TRAIL; NT-Apo2L/TRAIL also induced less apoptosis of HaCaT cells compared with LZ-Apo2L/TRAIL; LZ-Apo2L/TRAIL but not NT-Apo2L/TRAIL induced cytotoxic effects when keratinocytes became growth arrested due to undergoing spontaneous replicative senescence--a biological state previously observed to be resistant to UV-light-induced apoptosis. Similarities between preparations included: an enhanced ability for both Apo2L/TRAIL preparations to kill a greater relative percentage of HaCaT cells compared with keratinocytes; enhanced cytotoxicity towards keratinocytes that had their NF-B activity inhibited; a dependence of both Apo2L/TRAIL preparations on FADD and caspase activation; triggering of the same caspase cascades including caspase 8 and 3; and an ability to induce apoptosis even when HaCaT cells and keratinocytes were transduced to overexpress either Bcl-2 or Bcl-x(L) (survival factors that reduce susceptibility to UV-light-induced apoptosis). These results indicate that while both preparations of Apo2L/TRAIL possess biological activity, there are important differences as regards their ability to induce apoptosis in normal and immortalized keratinocytes. Moreover, the death receptor pathway triggered by LZ-Apo2L/TRAIL can overcome the apoptotic resistance normally observed in response to UV-light mediated by Bcl-2/Bcl-x(L), as well as by the state of cellular senescence. Unraveling the molecular basis for these differential biological effects may reveal a new strategic role for these death receptor/ligands linked to apoptosis in maintaining the dynamic balance of keratinocyte proliferation, differentiation, and cell death necessary to achieve a homeostatic thickness and function of normal skin. In addition, it may be possible to utilize these Apo2L/TRAIL preparations for the treatment of various sun-induced skin cancers as they can differentially trigger apoptosis of transformed keratinocytes, or keratinocytes with abnormal NF-kappaB signaling, while sparing adjacent normal keratinocytes.     

再生障碍性贫血患者DNA损伤修复活性检测

用盐酸氮芥和紫外线作为ＤＮＡ损伤修复诱导剂，对２４例再生障碍性贫血（再障）骨髓单个核细胞及３３例再障外周血单个核细胞的ＤＮＡ损伤修复活性进行了检测。发现再障患者的脱氧核糖核酸损伤修复活性明显低于正常（Ｐ＜０．０５），其低下与患者贫血程度、骨髓增生状况无关，临床治疗也不易纠正。提示患者ＤＮＡ修复活性低下可能在再障的发生中起重要作用。