中波高能紫外光诱导豚鼠皮肤色素沉着改变的实验研究
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摘要
目的通过研究中波高能紫外光对豚鼠皮肤色素沉着的诱导作用,希望能够对其治疗白癜风的作用机制、剂量选择及安全性有初步了解,为其更好的应用于临床而提供一定的参考。
方法以正常健康棕黄色豚鼠皮肤为实验模型,经背部脱毛处理后,取4个相邻近的区域依次作为对照组和低、中、高剂量组。根据最小红斑量(MED值)并参考预实验结果将照射起始剂量分别定为0、90 mJ/cm2、180 mJ/cm2、270 mJ/cm2(即0、1MED、2MED、3MED),首次照射后未发生红斑者下次照射剂量增加10-20%；发生红斑但下次照射前可恢复者维持原剂量；出现有症状的红斑、脱屑,则暂停照射致皮损缓解,且下次照射剂量减少10-20%。每周照射两次,共照射6周,每周对实验动物照射部位进行观察、拍摄,按时记录照射区皮肤色素沉着情况。全部实验结束后处死动物,分别取各组皮肤标本进行组织病理染色和免疫组织化学分析。实验分别采用肉眼评估、黑素细胞染色(Imokawa法)以及黑素颗粒染色(Masson-Fontana法)方法,研究中波高能紫外光所致色素沉着作用；应用免疫组织化学染色法对不同照射剂量组豚鼠皮肤中的一氧化氮合酶(NOS)进行检测,间接观察黑素调节因子一氧化氮(NO)的变化情况；应用组织病理常规染色方法(HE染色)观察表皮经中波高能紫外光照射后的组织学改变
结果全部豚鼠均完成实验,少数豚鼠照射部位皮肤在照射初期出现红斑、脱屑等不良反应,减少剂量或暂停照射后均缓解。随着实验的进行,豚鼠照射部位皮肤逐渐对中波高能紫外光产生耐受,不良反应未再出现。各照射组均出现不同程度的色素沉着,除中、高剂量组色素沉着评分结果无显著性差异外,其余各组的色素沉着评分、平均黑素数量以及多巴阳性黑素细胞数之间的差异均具有统计学意义(P<0.05),且中剂量组结果优于高剂量组；对照组无明显改变。免疫织化学染色示iNOS的表达亦呈剂量依赖式递增,各组间的差异具有统计学意义(P<0.05)。HE染色结果显示各照射组表皮增生呈剂量依赖式递增,与紫外线照射正常皮肤所致的组织形态学改变相符。未观察到各剂量组中波高能紫外光照射引起的色素脱失及表皮细胞的异形性改变。
结论中波高能紫外光可诱导豚鼠皮肤色素沉着,而且这种效应具有一定的剂量依赖性,但并非剂量越高越好。选择接近或略高于最小红斑量(MED)剂量作为初始剂量进行照射,可有效减少累积剂量,在取得满意疗效的同时又可降低紫外线治疗的潜在致癌风险。
OBJECTIVE To study the experimental hyperpigmentation induced by targeted UVB phototherapy on the skin of brownish guinea pigs and provide experimental evidence for treating vitiligo with targeted UVB phototherapy.
METHODS Ten brownish guinea pigs were enrolled as the experimental model in this 6-week study. After their back hair removal treatment,four isolated areas were selected on each guinea pigs as control group, low increment dose group, moderate increment dose group and high increment dose group. According to the minimum erythema dose (MED) and the pre-test results of the targeted UVB,we set the initial dose irradiation of each tested group as 90 mJ/cm、180 mJ/cm、270 mJ/cm, while nothing is treated on the control group. Each tested group was treated with different dosages of targeted UVB for twice a week, and the subsequent dose was determined as follows:the dose was increased by 10-20% in every session until the development of erythema was noted. When erythema occurs before the next time of irradiation, the dose of the next session was to maintain the original dose. If symptomatic erythema(burning,pain) or even blistering developed, the treament was suspended until remission, and then the dose of the next session was diminished by 10-20%. Efficatcy was evaluated at the end of the experiment by Masson-Fontana staining, Imokawa's staining and immunohistochemistry to stain NOS.
RESULTS All the guinea pigs had completed the study. At the early part of treatment, a small number of guinea pigs had transient erythema and slight desquamating,which can be controled by decreasing the dosage or being suspended the treatment for severy days. Experimental hyperpigmentation was observed and analyzed in each tested group, the differences among the 4 group were statistically significant (P<0.05),except the difference between moderate increment dose group and high increment dose group in pigmentation score. Of course, there was no significant change in all the untreated areas(the contol group). The differences among the 4 groups were proved to be of statistical significances (P<0.05) by Masson-Fontana staining and Imokawa's staining, However, moderate increment dose group were better than high increment dose group. In addition, the expression of iNOS is upregulated by UVB irradiation and the differences between the 4 groups was considered significant (P<0.05).
CONCLUSION Targeted UVB phototherapy can induce experimental hyperpigmentation on the skin of brownish guinea pigs in a dose-dependent manner. Selecting a close to or slightly higher than the minimal erythema dose (MED) irradiation can effectively reduce the cumulative dose and the potential risk of cancer with a satisfactory effect.
方法以正常健康棕黄色豚鼠皮肤为实验模型,经背部脱毛处理后,取4个相邻近的区域依次作为对照组和低、中、高剂量组。根据最小红斑量(MED值)并参考预实验结果将照射起始剂量分别定为0、90 mJ/cm2、180 mJ/cm2、270 mJ/cm2(即0、1MED、2MED、3MED),首次照射后未发生红斑者下次照射剂量增加10-20%；发生红斑但下次照射前可恢复者维持原剂量；出现有症状的红斑、脱屑,则暂停照射致皮损缓解,且下次照射剂量减少10-20%。每周照射两次,共照射6周,每周对实验动物照射部位进行观察、拍摄,按时记录照射区皮肤色素沉着情况。全部实验结束后处死动物,分别取各组皮肤标本进行组织病理染色和免疫组织化学分析。实验分别采用肉眼评估、黑素细胞染色(Imokawa法)以及黑素颗粒染色(Masson-Fontana法)方法,研究中波高能紫外光所致色素沉着作用；应用免疫组织化学染色法对不同照射剂量组豚鼠皮肤中的一氧化氮合酶(NOS)进行检测,间接观察黑素调节因子一氧化氮(NO)的变化情况；应用组织病理常规染色方法(HE染色)观察表皮经中波高能紫外光照射后的组织学改变
结果全部豚鼠均完成实验,少数豚鼠照射部位皮肤在照射初期出现红斑、脱屑等不良反应,减少剂量或暂停照射后均缓解。随着实验的进行,豚鼠照射部位皮肤逐渐对中波高能紫外光产生耐受,不良反应未再出现。各照射组均出现不同程度的色素沉着,除中、高剂量组色素沉着评分结果无显著性差异外,其余各组的色素沉着评分、平均黑素数量以及多巴阳性黑素细胞数之间的差异均具有统计学意义(P<0.05),且中剂量组结果优于高剂量组；对照组无明显改变。免疫织化学染色示iNOS的表达亦呈剂量依赖式递增,各组间的差异具有统计学意义(P<0.05)。HE染色结果显示各照射组表皮增生呈剂量依赖式递增,与紫外线照射正常皮肤所致的组织形态学改变相符。未观察到各剂量组中波高能紫外光照射引起的色素脱失及表皮细胞的异形性改变。
结论中波高能紫外光可诱导豚鼠皮肤色素沉着,而且这种效应具有一定的剂量依赖性,但并非剂量越高越好。选择接近或略高于最小红斑量(MED)剂量作为初始剂量进行照射,可有效减少累积剂量,在取得满意疗效的同时又可降低紫外线治疗的潜在致癌风险。
OBJECTIVE To study the experimental hyperpigmentation induced by targeted UVB phototherapy on the skin of brownish guinea pigs and provide experimental evidence for treating vitiligo with targeted UVB phototherapy.
METHODS Ten brownish guinea pigs were enrolled as the experimental model in this 6-week study. After their back hair removal treatment,four isolated areas were selected on each guinea pigs as control group, low increment dose group, moderate increment dose group and high increment dose group. According to the minimum erythema dose (MED) and the pre-test results of the targeted UVB,we set the initial dose irradiation of each tested group as 90 mJ/cm、180 mJ/cm、270 mJ/cm, while nothing is treated on the control group. Each tested group was treated with different dosages of targeted UVB for twice a week, and the subsequent dose was determined as follows:the dose was increased by 10-20% in every session until the development of erythema was noted. When erythema occurs before the next time of irradiation, the dose of the next session was to maintain the original dose. If symptomatic erythema(burning,pain) or even blistering developed, the treament was suspended until remission, and then the dose of the next session was diminished by 10-20%. Efficatcy was evaluated at the end of the experiment by Masson-Fontana staining, Imokawa's staining and immunohistochemistry to stain NOS.
RESULTS All the guinea pigs had completed the study. At the early part of treatment, a small number of guinea pigs had transient erythema and slight desquamating,which can be controled by decreasing the dosage or being suspended the treatment for severy days. Experimental hyperpigmentation was observed and analyzed in each tested group, the differences among the 4 group were statistically significant (P<0.05),except the difference between moderate increment dose group and high increment dose group in pigmentation score. Of course, there was no significant change in all the untreated areas(the contol group). The differences among the 4 groups were proved to be of statistical significances (P<0.05) by Masson-Fontana staining and Imokawa's staining, However, moderate increment dose group were better than high increment dose group. In addition, the expression of iNOS is upregulated by UVB irradiation and the differences between the 4 groups was considered significant (P<0.05).
CONCLUSION Targeted UVB phototherapy can induce experimental hyperpigmentation on the skin of brownish guinea pigs in a dose-dependent manner. Selecting a close to or slightly higher than the minimal erythema dose (MED) irradiation can effectively reduce the cumulative dose and the potential risk of cancer with a satisfactory effect.
引文
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3.中国中西医结合学会皮肤性病专业委员会色素病学组,白癜风临床分型及疗效标准(2003年修订稿)[J].中华皮肤科杂志,2004,37(7)：440.
4. Westerhof W, Nieuweboer Krobotova L. Treatment of vitiligo with UVB radiation vs topical psoralen plus UVA[J]. Arch Dermatol,1997,133(12):1525-1528.
5. Scherschun L, Kim JJ, Lin HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo [J]. J Am Acad Dermatol,2001 Jun,44(6); 999-1003.
6.冯舸.中波高能紫外线照射治疗白癜风临床疗效观察[J].中国皮肤性病学杂志,2008,22(8)：474-475.
7. Menchini G, Tsoureli-Nikita E, Hercogova J. Narrow-band UV-B micro-phototherapy:a new treatment for vitiligo[J]. J Eur Acad Dermatol Venereol,2003; 17:171-177.
8. Welsh 0, Herz-Ruelas ME, Gomez M, et al. Therapeutic evaluation of UVB-targeted phototherapy in vitiligo that affects less than 10% of the body surface area[J].Int J Dermato,2009,48(5):529-534.
9. Lotti T, Buggiani G, Troiano M, et al. Targeted and combination treatments for vitiligo. Comparative evaluation of different current modalities in 458 subjects[J]. Dermatol Ther 2008; 21:S20-S26.
10.胡佳,杨莉佳,曹蕾.高能中波紫外线治疗寻常型白癜风的临床疗效观察[J].中华皮肤科杂志.2011,44(1)：58-59.
11. Hadi SM, Spencer JM, Lebwohl M. The use of the 308-nm excimer laser for the treatment of vitiligo[J]. Dermatol Surg,2004,30(7):983-986.
12.郭静,项蕾红,郑志忠,等.单频准分子激光治疗白癜风的临床研究[J].中华皮肤科杂志,2006,39(1)：32-34.
13.董秀芹,刘涛,肖洁平,等.中波高能紫外线照射治疗白癜风疗效观察[J].中国美容医学.2010,19(8)：1173-1176.
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2. Westerhof W, d.IschiaM. Vitiligo puzzle:the pieces fall in place[J]. Pigment Cell Res,2007,20(5):345-359.
3.中国中西医结合学会皮肤性病专业委员会色素病学组,白癜风临床分型及疗效标准(2003年修订稿)[J].中华皮肤科杂志,2004,37(7)：440.
4. Westerhof W, Nieuweboer Krobotova L. Treatment of vitiligo with UVB radiation vs topical psoralen plus UVA[J]. Arch Dermatol,1997,133(12):1525-1528.
5. Scherschun L, Kim JJ, Lin HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo [J]. J Am Acad Dermatol,2001 Jun,44(6); 999-1003.
6.冯舸.中波高能紫外线照射治疗白癜风临床疗效观察[J].中国皮肤性病学杂志,2008,22(8)：474-475.
7. Menchini G, Tsoureli-Nikita E, Hercogova J. Narrow-band UV-B micro-phototherapy:a new treatment for vitiligo[J]. J Eur Acad Dermatol Venereol,2003; 17:171-177.
8. Welsh 0, Herz-Ruelas ME, Gomez M, et al. Therapeutic evaluation of UVB-targeted phototherapy in vitiligo that affects less than 10% of the body surface area[J].Int J Dermato,2009,48(5):529-534.
9. Lotti T, Buggiani G, Troiano M, et al. Targeted and combination treatments for vitiligo. Comparative evaluation of different current modalities in 458 subjects[J]. Dermatol Ther 2008; 21:S20-S26.
10.胡佳,杨莉佳,曹蕾.高能中波紫外线治疗寻常型白癜风的临床疗效观察[J].中华皮肤科杂志.2011,44(1)：58-59.
11. Hadi SM, Spencer JM, Lebwohl M. The use of the 308-nm excimer laser for the treatment of vitiligo[J]. Dermatol Surg,2004,30(7):983-986.
12.郭静,项蕾红,郑志忠,等.单频准分子激光治疗白癜风的临床研究[J].中华皮肤科杂志,2006,39(1)：32-34.
13.董秀芹,刘涛,肖洁平,等.中波高能紫外线照射治疗白癜风疗效观察[J].中国美容医学.2010,19(8)：1173-1176.
14.丁晓岚,徐前喜,孙青苗,等.高能紫外光治疗白癜风的临床观察[J].临床皮肤科杂志.2010,39(11)：729-731.
15.沈丹蓓,孙建方.白癜风相关研究领域中常用的动物模型[J].国外医学皮肤性病学分册.2004,30(4)：226-228.
16.刘玮.皮肤晒黑的发生机制[J].学信息导报.2005,20(3)：13.
17. Romero-Grail let C, Aberdam E, Biagoli N, et al. Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes[J]. J Biol Chem,1996,271(45): 28052-28056.
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