HIF-1α、VEGF和MVD与银屑病的相关性研究
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摘要
目的:银屑病(psoriasis,PS)是一种常见的慢性复发性炎症性皮肤病。表皮增生和真皮乳头层内血管新生是PS的主要病理学特点。遗传因素和环境刺激是其发病的两大因素。最初的炎症刺激原因不明确,但血管新生对于中性粒细胞和淋巴细胞的浸润是必不可少的。其中微血管生成异常与PS的发生、持续存在及复发有密切关系,在银屑病的发病机制中起重要作用[1]。在促进血管生成的各种调节因子中血管内皮生长因子(vascular endothelial growth factor, VEGF)是主要的刺激因子,它能特异性引起血管内皮细胞分裂增殖、通透性增加,促进内皮细胞、单核细胞迁移,诱导血管生成及炎细胞浸润[2]。VEGF的上调是PS病理生理学早期和重要的一步,而影响VEGF的各种因子成为目前PS研究的热点。低氧诱导因子-1(hypoxia-inducible factor-1, HIF-1)是细胞在缺氧条件下产生的具有转录活性的核蛋白,可以使细胞适应低氧环境。在PS中细胞增殖增加了氧的消耗,表皮肥厚导致了氧供应的障碍。HIF-1α可很好反应机体缺氧情况,它可促使VEGF的转录激活,从而诱导PS的血管生成。其很可能参与了PS的发病过程。目前HIF-1α在皮肤中的研究仍处于起步阶段。
为了解PS中HIF-1α与VEGF的表达及与血管生成的关系,我们利用免疫组化的方法检测了HIF-1α与VEGF蛋白在PS患者及不同病期皮损中的表达,并用CD34标记血管内皮细胞,计数微血管密度(microvessel density, MVD)值,从而探讨它们在PS血管生成中的作用。
方法: PS患者皮损标本来源于2004年10月~2007年3月河北医科大学第四医院皮肤科门诊患者,共计32例。所有患者均经临床和组织病理确认为银屑病。其中男14例,女18例,年龄7~68岁,平均27.5岁。包括进展期22例,静止期10例。所有患者均无其他系统疾病,且近3个月内未曾接受任何治疗。取患者皮损组织用于常规病理分析,并用免疫组化法分别检测皮损中HIF-1α,VEGF,CD34蛋白的表达水平。选取河北医科大学第四医院外科20例外伤患者的健康皮肤作为正常对照,且年龄、性别及取材部位与实验组患者相匹配。
组织病理采用石蜡切片HE染色观察;免疫组化采用SP法。免疫组化实验结果采用SPSS15.0统计软件中的Mann-whitney U检验、t检验及Spearman等级相关分析。以P<0.05作为显著性界限。
结果:
1 HIF-1α表达主要位于表皮角质形成细胞与真皮浅层毛细血管内皮细胞及其周围部分炎细胞胞浆。在32例PS中,表皮层阳性表达共25例,其中强阳性7例,阳性、弱阳性各9例,阴性7例。正常对照组20例中,阴性14例,弱阳性5例,阳性1例,无强阳性表达,且表达主要在基底层;真皮层强阳性1例,阳性6例,弱阳性15例,阴性10例,而20例正常对照组均为阴性表达。结果显示,HIF-1α在银屑病中阳性表达均比正常对照组增高,差异有非常显著性(P<0.01),且在PS进行期的表达高于静止期,差异有统计学意义(P<0.05)。在不同性别、年龄及病程之间均无显著性差异(P>0.05)。
2 VEGF表达主要位于表皮全层的角质形成细胞,真皮浅层血管内皮细胞及其周围部分炎细胞胞浆。在32例PS中,表皮层阳性表达共26例,其中强阳性5例,阳性9例,弱阳性12例,阴性6例;真皮层表达强阳性2例,阳性8例,弱阳性15例,阴性7例。而对照组20例中,在基底层与棘层仅1例阳性表达,8例弱阳性表达,真皮血管内皮细胞及炎细胞均无表达。结果显示,VEGF在PS中的表达高于对照组,差异有非常显著性(P<0.01)。进行期的表达高于静止期,差异有统计学意义(P<0.05),在不同性别、年龄及病程之间均无显著性差异(P>0.05)。
3 CD34表达位于真皮浅层小血管内皮细胞胞浆。PS患者MVD值高于对照组,差异有非常显著性(P<0.01);且进行期皮损MVD值高于静止期,差异有显著性(P<0.05)。
4 HIF-1α和VEGF在PS患者同一皮损中的表达相关系数rs=0.791,有显著性差异(P<0.01)。两者呈正相关。
5我们以表皮层HIF-1α明确表达阳性的25例标本为阳性组,与另一组7例HIF-1α明确表达阴性的标本为阴性组进行比较。HIF-1α阳性组MVD值高于HIF-1α阴性组,两者比较,差异有显著性(P<0.05)。
结论:根据实验结果得出以下结论
1 HIF-1α在银屑病主要表达于表皮细胞、真皮浅层毛细血管内皮细胞及其周围部分炎细胞胞浆,并明显高于对照组,且进行期皮损明显高于静止期。提示银屑病存在缺氧与缺氧适应性反应;同时HIF-1α与银屑病的疾病进展有关。
2 VEGF在银屑病表达主要位于表皮细胞、真皮浅层血管内皮细胞及其周围部分炎细胞胞浆,并明显高于对照组,且进行期高于静止期。提示VEGF在银屑病血管生成中起重要作用,并与其疾病进展有关。
3银屑病患者组MVD值明显高于对照组,且进行期高于静止期,表明银屑病的微血管生成较健康皮肤增高,提示MVD可作为判断病情的指标之一。
4 HIF-1α与VEGF呈正相关,提示银屑病患者由于角质形成细胞与血管内皮细胞缺氧诱导了HIF-1α活化,并通过其上调VEGF而共同参与了血管的生成。
5银屑病中HIF-1α阳性组MVD值明显高于HIF-1α阴性组,HIF-1α与MVD呈正相关,也提示HIF-1α与微血管生成相关。
6 HIF-1α、VEGF与性别、年龄和病程之间均无相关性。
Objective: Psoriasis (PS) is a chronic replapsing inflammatory dermatosis. Epidermal hyperplasia and angiogenesis in papillary dermis constitute the major pathology characteristics of psoriasis. Pathogenetic factors involve genetic factor and environmental stimuli. Although the first stimulus of inflammation is unknown origin, angiogenesis is indispensable for infiltration of neutrophils and lymphocytes. And angiogenesis is obviously related to pathogenesis, lasting and relapse of PS. In most angiogenic factors, vascular endothelial growth factor (VEGF) is main stimulating factor, which can cause vascular endothelial cell proliferate, enhance the permeability of the microvesles and promote the migrating of the endothelial cell and mononuclear cell to the lesion. Some evidences suggested that VEGF upregulation is an early and important step in the pathophysiology of psoriasis. At present, various factors that influence VEGF have being the investigative focus of psoriasis. Hypoxia-inducible factors-1 (HIF-1) is a transcription active neucleoprotein that forms in the hypoxia condition and can adapt cells the hypoxia environmemt. In psoriasis, the cell proliferation could increase oxygen cost and the epidermal thickening could lead to impaired oxygen supply, and HIF-1αcan perfectly respond to anaerobic condition of organism. VEGF can contribute to angiogenesis of psoriasis, while VEGF can be activated by HIF-1α. Now it is the beginning that HIF-1αhas been studied in dermatosis.
In order to research HIF-1αexpression and the relations beween HIF-1αand the angiogenesis in psoriasis, we detected HIF-1αand VEGF proteins in psoriasis with the method of immunohistochemistry, and used CD34 to mark vascular endothelial cells and counted microvessel density (MVD).
Methods: 32 patients with psoriasis diagnosed by clinic and histopathology were collected from the dermatology department of the Forth Affiliated Hospital of Heibei University from October, 2004 to March, 2007. The expressions of HIF-1α, VEGF and CD34 in these patients were detected by immunohistochemical method. 30 healthy skin specimens from the surgery department were taken as controls. There were no significant differences in sex, age and locus of biopsy between controls and patients.
Paraffin section was used by HE staining in histophathology and by histostain-SP methed in immunohistochemistry. The data was analyzed by SPSS 15.0 Mann-Whitney U rank test, t-test and Spearman rank correlation analysis.
Results:
1 The expression of HIF-1α: HIF-1αwas distributed mainly in the cytoplasm of epidermal keratinocytes and capillary endothelial cells and a small amount of perivascular inflammatory cells in the dermal papilla. And showed 25of 32 cases with psoriasis were positive, including 7 strong positive, 9 positive, 9 weakly positive and 7 negative. In the normal controls, it was found that 14 cases were negative, 5 weakly positive, 1 positive, and expressed mainly in the basal layer. In the dermis there were 1 strong positive, 6 positive, 15 weakly positive and 10 negative of 32 cases with PS, while all the cases of controls were negative. The results showed there were statistically significant differences beween PS and controls (P<0.01). Expression of HIF-1αin active stage was higher than in stable stage (P <0.05) and there was no significant difference among the gender, age and duration of the disease (P> 0.05).
2 The expression of VEGF: VEGF was mainly located in the cytoplasm of keratinocytes, the vascular endothelial cells and inflammatory cells of dermal paplla. In epidermis, VEGF expression were found in 26 cases with PS , including 5 strongly positive, 9 positive, 12 weakly positive and 6 negative .and in the dermis 2 strong positive, 8 positive, 15 weakly positive, 7 negative. But in the controls, VEGF were only expressed positively or weak positively in the basal layer of epidermis and no in the vascular endothelial cells and inflammatory cells of dermis. The results indicated that VEGF expression in the patients with PS was higher than in the controls (P <0.01) and in the active stage higher than in the stable stage (P <0.05), showing significant difference. But there was no significant difference among gender, age and duration of the disease (P> 0.05).
3 The expression of CD34: The CD34 was mainly stained in the vascular endothelial cells of dermis. Compared the value of the MVD between the two groups, it is indicated the MVD value was higher in the PS patients than in the controls and in active stage than stable stage, showing the significantly difference (P<0.05).
4 There was a positive correlation between the expression of HIF-1αand VEGF in psoriasis (P<0.05). The coefficient correlation rs= 0.791.
5 MVD is a quantitative indicator of angiogenesis. It was resulted that the mean value of MVD was higher in the patients with HIF-1αexpression than in the patients without HIF-1αexpression, showing statistically significant differences (P<0.05).
Conclusions:
1 The HIF-1αexpression in psoriatic skin is higher than controls. It is suggested that hypoxia and hypoxia reaction occured in psoriasis with increased oxygen consumption and impaired oxygen supply duing to cell proliferation and epidermal thickening. The HIF-1αexpression in the active stage was higher than in the stable stage, hinting that HIF-1αmight be related to the progression of the disease.
2 The VEGF expression in patients is higher than in controls and in the active stage higher than in the stable stage of psoriasis, which hint that it take part in angiogenesis of psoriasis and might be related to the progression of it .
3 MVD was significantly higher in the patients with PS than that in controls and in the active stage higher than in the stable stage of PS, suggesting that angiogenesis in psoriasis significantly higher than in controls and it can be used as an indicator of the condition of the disease.
4 There was a positive correlation between HIF-1αand VEGF in psoriasis, suggesting that hypoxia may activate HIF-1αand HIF-1αactivates VEGF, which contribute to angiogenesis.
5 The mean of MVD with HIF-1αexpression is higher than that without HIF-1αexpression, suggesting that HIF-1αrelated to angiogenesis.
为了解PS中HIF-1α与VEGF的表达及与血管生成的关系,我们利用免疫组化的方法检测了HIF-1α与VEGF蛋白在PS患者及不同病期皮损中的表达,并用CD34标记血管内皮细胞,计数微血管密度(microvessel density, MVD)值,从而探讨它们在PS血管生成中的作用。
方法: PS患者皮损标本来源于2004年10月~2007年3月河北医科大学第四医院皮肤科门诊患者,共计32例。所有患者均经临床和组织病理确认为银屑病。其中男14例,女18例,年龄7~68岁,平均27.5岁。包括进展期22例,静止期10例。所有患者均无其他系统疾病,且近3个月内未曾接受任何治疗。取患者皮损组织用于常规病理分析,并用免疫组化法分别检测皮损中HIF-1α,VEGF,CD34蛋白的表达水平。选取河北医科大学第四医院外科20例外伤患者的健康皮肤作为正常对照,且年龄、性别及取材部位与实验组患者相匹配。
组织病理采用石蜡切片HE染色观察;免疫组化采用SP法。免疫组化实验结果采用SPSS15.0统计软件中的Mann-whitney U检验、t检验及Spearman等级相关分析。以P<0.05作为显著性界限。
结果:
1 HIF-1α表达主要位于表皮角质形成细胞与真皮浅层毛细血管内皮细胞及其周围部分炎细胞胞浆。在32例PS中,表皮层阳性表达共25例,其中强阳性7例,阳性、弱阳性各9例,阴性7例。正常对照组20例中,阴性14例,弱阳性5例,阳性1例,无强阳性表达,且表达主要在基底层;真皮层强阳性1例,阳性6例,弱阳性15例,阴性10例,而20例正常对照组均为阴性表达。结果显示,HIF-1α在银屑病中阳性表达均比正常对照组增高,差异有非常显著性(P<0.01),且在PS进行期的表达高于静止期,差异有统计学意义(P<0.05)。在不同性别、年龄及病程之间均无显著性差异(P>0.05)。
2 VEGF表达主要位于表皮全层的角质形成细胞,真皮浅层血管内皮细胞及其周围部分炎细胞胞浆。在32例PS中,表皮层阳性表达共26例,其中强阳性5例,阳性9例,弱阳性12例,阴性6例;真皮层表达强阳性2例,阳性8例,弱阳性15例,阴性7例。而对照组20例中,在基底层与棘层仅1例阳性表达,8例弱阳性表达,真皮血管内皮细胞及炎细胞均无表达。结果显示,VEGF在PS中的表达高于对照组,差异有非常显著性(P<0.01)。进行期的表达高于静止期,差异有统计学意义(P<0.05),在不同性别、年龄及病程之间均无显著性差异(P>0.05)。
3 CD34表达位于真皮浅层小血管内皮细胞胞浆。PS患者MVD值高于对照组,差异有非常显著性(P<0.01);且进行期皮损MVD值高于静止期,差异有显著性(P<0.05)。
4 HIF-1α和VEGF在PS患者同一皮损中的表达相关系数rs=0.791,有显著性差异(P<0.01)。两者呈正相关。
5我们以表皮层HIF-1α明确表达阳性的25例标本为阳性组,与另一组7例HIF-1α明确表达阴性的标本为阴性组进行比较。HIF-1α阳性组MVD值高于HIF-1α阴性组,两者比较,差异有显著性(P<0.05)。
结论:根据实验结果得出以下结论
1 HIF-1α在银屑病主要表达于表皮细胞、真皮浅层毛细血管内皮细胞及其周围部分炎细胞胞浆,并明显高于对照组,且进行期皮损明显高于静止期。提示银屑病存在缺氧与缺氧适应性反应;同时HIF-1α与银屑病的疾病进展有关。
2 VEGF在银屑病表达主要位于表皮细胞、真皮浅层血管内皮细胞及其周围部分炎细胞胞浆,并明显高于对照组,且进行期高于静止期。提示VEGF在银屑病血管生成中起重要作用,并与其疾病进展有关。
3银屑病患者组MVD值明显高于对照组,且进行期高于静止期,表明银屑病的微血管生成较健康皮肤增高,提示MVD可作为判断病情的指标之一。
4 HIF-1α与VEGF呈正相关,提示银屑病患者由于角质形成细胞与血管内皮细胞缺氧诱导了HIF-1α活化,并通过其上调VEGF而共同参与了血管的生成。
5银屑病中HIF-1α阳性组MVD值明显高于HIF-1α阴性组,HIF-1α与MVD呈正相关,也提示HIF-1α与微血管生成相关。
6 HIF-1α、VEGF与性别、年龄和病程之间均无相关性。
Objective: Psoriasis (PS) is a chronic replapsing inflammatory dermatosis. Epidermal hyperplasia and angiogenesis in papillary dermis constitute the major pathology characteristics of psoriasis. Pathogenetic factors involve genetic factor and environmental stimuli. Although the first stimulus of inflammation is unknown origin, angiogenesis is indispensable for infiltration of neutrophils and lymphocytes. And angiogenesis is obviously related to pathogenesis, lasting and relapse of PS. In most angiogenic factors, vascular endothelial growth factor (VEGF) is main stimulating factor, which can cause vascular endothelial cell proliferate, enhance the permeability of the microvesles and promote the migrating of the endothelial cell and mononuclear cell to the lesion. Some evidences suggested that VEGF upregulation is an early and important step in the pathophysiology of psoriasis. At present, various factors that influence VEGF have being the investigative focus of psoriasis. Hypoxia-inducible factors-1 (HIF-1) is a transcription active neucleoprotein that forms in the hypoxia condition and can adapt cells the hypoxia environmemt. In psoriasis, the cell proliferation could increase oxygen cost and the epidermal thickening could lead to impaired oxygen supply, and HIF-1αcan perfectly respond to anaerobic condition of organism. VEGF can contribute to angiogenesis of psoriasis, while VEGF can be activated by HIF-1α. Now it is the beginning that HIF-1αhas been studied in dermatosis.
In order to research HIF-1αexpression and the relations beween HIF-1αand the angiogenesis in psoriasis, we detected HIF-1αand VEGF proteins in psoriasis with the method of immunohistochemistry, and used CD34 to mark vascular endothelial cells and counted microvessel density (MVD).
Methods: 32 patients with psoriasis diagnosed by clinic and histopathology were collected from the dermatology department of the Forth Affiliated Hospital of Heibei University from October, 2004 to March, 2007. The expressions of HIF-1α, VEGF and CD34 in these patients were detected by immunohistochemical method. 30 healthy skin specimens from the surgery department were taken as controls. There were no significant differences in sex, age and locus of biopsy between controls and patients.
Paraffin section was used by HE staining in histophathology and by histostain-SP methed in immunohistochemistry. The data was analyzed by SPSS 15.0 Mann-Whitney U rank test, t-test and Spearman rank correlation analysis.
Results:
1 The expression of HIF-1α: HIF-1αwas distributed mainly in the cytoplasm of epidermal keratinocytes and capillary endothelial cells and a small amount of perivascular inflammatory cells in the dermal papilla. And showed 25of 32 cases with psoriasis were positive, including 7 strong positive, 9 positive, 9 weakly positive and 7 negative. In the normal controls, it was found that 14 cases were negative, 5 weakly positive, 1 positive, and expressed mainly in the basal layer. In the dermis there were 1 strong positive, 6 positive, 15 weakly positive and 10 negative of 32 cases with PS, while all the cases of controls were negative. The results showed there were statistically significant differences beween PS and controls (P<0.01). Expression of HIF-1αin active stage was higher than in stable stage (P <0.05) and there was no significant difference among the gender, age and duration of the disease (P> 0.05).
2 The expression of VEGF: VEGF was mainly located in the cytoplasm of keratinocytes, the vascular endothelial cells and inflammatory cells of dermal paplla. In epidermis, VEGF expression were found in 26 cases with PS , including 5 strongly positive, 9 positive, 12 weakly positive and 6 negative .and in the dermis 2 strong positive, 8 positive, 15 weakly positive, 7 negative. But in the controls, VEGF were only expressed positively or weak positively in the basal layer of epidermis and no in the vascular endothelial cells and inflammatory cells of dermis. The results indicated that VEGF expression in the patients with PS was higher than in the controls (P <0.01) and in the active stage higher than in the stable stage (P <0.05), showing significant difference. But there was no significant difference among gender, age and duration of the disease (P> 0.05).
3 The expression of CD34: The CD34 was mainly stained in the vascular endothelial cells of dermis. Compared the value of the MVD between the two groups, it is indicated the MVD value was higher in the PS patients than in the controls and in active stage than stable stage, showing the significantly difference (P<0.05).
4 There was a positive correlation between the expression of HIF-1αand VEGF in psoriasis (P<0.05). The coefficient correlation rs= 0.791.
5 MVD is a quantitative indicator of angiogenesis. It was resulted that the mean value of MVD was higher in the patients with HIF-1αexpression than in the patients without HIF-1αexpression, showing statistically significant differences (P<0.05).
Conclusions:
1 The HIF-1αexpression in psoriatic skin is higher than controls. It is suggested that hypoxia and hypoxia reaction occured in psoriasis with increased oxygen consumption and impaired oxygen supply duing to cell proliferation and epidermal thickening. The HIF-1αexpression in the active stage was higher than in the stable stage, hinting that HIF-1αmight be related to the progression of the disease.
2 The VEGF expression in patients is higher than in controls and in the active stage higher than in the stable stage of psoriasis, which hint that it take part in angiogenesis of psoriasis and might be related to the progression of it .
3 MVD was significantly higher in the patients with PS than that in controls and in the active stage higher than in the stable stage of PS, suggesting that angiogenesis in psoriasis significantly higher than in controls and it can be used as an indicator of the condition of the disease.
4 There was a positive correlation between HIF-1αand VEGF in psoriasis, suggesting that hypoxia may activate HIF-1αand HIF-1αactivates VEGF, which contribute to angiogenesis.
5 The mean of MVD with HIF-1αexpression is higher than that without HIF-1αexpression, suggesting that HIF-1αrelated to angiogenesis.
引文
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11 Crews S T. Control of cell Lineage-specific development and transcription by bHLH-PAS. Protines Genes Dev, 1998, 12(5):607~620
12 Jewell UR, Kvietikova I, Scheid A, et al. Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J, 2001, 15, 1312
13 IvanM, KaelinWG. The von-Hippel-Lindau tumor supp ressor protein. CurrOpin Genet Dev, 2001, 11(1):27~34
14 Semanza GL. Hypoxia-inducible factor-1: oxygen homeostasis and disease pathophysiology. Trends Mol Med, 2001, 7:345~350
15 Kwon YW, Kwon KS, Moon HE. Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. J Invest Dermatol, 2004, 123(1):152~158
16 Simonetti O, Lucarini G, Goteri G. VEGF is likely a keyfactor in the link between inflammation and angiogenesis in psoriasis: results of an immunohistochemical study. Int J Immunopathol Pharmacol, 2006, 19(4):751~760
17 Yun Z, Maecker HL, Johnson RS. Inhibition of PPAR gamma 2 gene expression by the HIF212regulated gene DEC1/ Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell, 2002, 2(3):331~341
18 Tovar-Castillo LE, Cancino-Díaz JC, García-Vázquez F. Under-expression of VHL and over-expression of HDAC-1, HIF-1αlpha, LL-37, and IAP-2 in affected skin biopsies of patients with psoriasis. Int J Dermatol, 2007, 46(3):239~246
19 Fajas L, Landsberg RL, Huss-Garcia Y, et al. E-Fs regulate adipocyte differentiation. Dev Cell, 2002, 3(1) :39~49
20 Hareld F, Dvorak, Lawrence F, et al. Vascular permeability factor, microvascular hypermeability, and angiogenesis. Am J Pathology, 1995, (146):10~19
21 Dvorak HF, BrownLF, Detmar M, et al. Vascular permeability factor vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol, 1995, 146(3):1029~1039
22 Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med, 1994, 180:1141~1146
23 Xia YP, Li B, Hylton D, et al. Rudge GS Transgenic delivery of VEGF to mouse skin leads to an inflammatorycondition resembling human psoriasis. Blood, 2003, 102:161~168
24 张锡宝, 罗权, 吴志华等. 血管内皮生长因子及其受体在银屑病发病中的作用及意义。中华皮肤科杂志, 2005, 38:140~142
25 朱凡, 郑敏, 鲍彰. 银屑病患者皮损中血管内皮生长因子受体的表达与血管增生的关系. 中华皮肤科杂志, 2003, 36(7):365~367
26 Resar JR, Roguin A, Voner J, et al. Hypoxia-inducible factor-1polymorphism and coronary collaterals in patients with is chemic heart disease. Chest, 2005, 128(2):787~791
27 Chavez JC, LaManna JC. Activation of hypoxia-induced factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1. J Neurosci, 2002, 22:8922~8931
28 任宏, 孙光. HIF-1与肿瘤血管新生及其表达的基因调控.国外医学泌尿系统分册, 2005, 25(2):180~183
29 Jones A, Fujiyama C, et al. Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines. Clin Cancer Res, 2001, 7(5):1263~1272
30 Liu LX, Lu H. Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor-1. Biochem Biophys Res Commun, 2002, 291(4):908~914
31 Strieth S, Hartschuh W, Pilz L, et al. Angiogenic switchoccurs late in squamous cell carcinomas of human skin. Br J Cancer, 2000, 82:591~600
32 Sochorova R, Svecova D, Sinka L, et al. Increased endothelemia as an indirect marker of changes in the blood vessel endothelium in psoriasis.世界核心医学期刊文摘.皮肤病学, 2005, 1(2):52
33 Fieger CB, Sassetti CM, Rosen SD. Endogly-can, a member of the CD34 family, functions as an L-selectin ligand through modification with tyrosine sulfation sialy lewis. J Biol Chem, 2003, 278(30):27390~27398
34 金力, 陈凯, 王萍等. CD34 在寻常型银屑病中医辨证分型皮损中的表达. 中华皮肤性病学杂志, 2006, 20(5): 273~275
35 任德莲, 李晓辉, 朱晓华等. 银屑病皮损区肥大细胞分布和血管内皮细胞 CD34 表达的研究. 临床皮肤科杂志, 2004, 33(8):468~470
1 Pili R, Donehower RC. Is HIF-1 alpha a valid therapeutic target. J Natl Cancer Inst, 2003, 95(7):498~499
2 Choi KS, Bae MK, Jeong JW, et al. Hypoxia-induced angiogenesis during carcinogenesis. J Biochem MolBiol, 2003, 36(1):120~127
3 Gregg L. Semenza HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med, 2002, 8 (4):S62~S67
4 Mazure NM, Brahimi Horn MC, Pouyssegur J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Curr Pharm Des, 2003, 9(7):531~541
5 Semenza GL. HIF-1 and tumor progression: pathophysiology and thera-peutics. Trends Mol Med, 2002, 8(4 Suppl):S62~S67
6 Linden T, Katschinski DM, Eckhardt K, et al. The antimycotic ci clopirox olamine induces HIF-1alpha stability, VEGF expression, and angiogenesis. FASEB J, 2003, 17 (6):761~763
7 Vincent KA, Feron O, Kelly RA. Harnessing the response to tissue hypoxia: HIF-1 alpha and therapeutic angiogenesis. Trends Cardiovasc Med, 2002, 12(8):362~367
8 Jewell UR, Kvietikova I, Scheid A, et al. Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J, 2001, 15, 1312
9 IvanM, KaelinWG. The von-Hippel-Lindau tumor supp ressor protein. CurrOpin Genet Dev, 2001, 11 (1):27~34
10 Rosenberger C, Solovan C, Rosenberger AD, et al. Upregulation of Hypoxia-Inducible Factors in Normal and psoriatic Skin. J Invest Dermatol, 2007, 127(10):2445~2452
11 Heather ER, Michelle P, Wayne MN. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res, 2000, 60:4010
12 赵丽, 刘林, 马长路. HIF-1α在皮肤鳞状细胞癌和基底细胞癌中的表达及其与血管生成的关系. 肿瘤基础与临床, 2006, 19(2):365~367
13 Sun B, Zhang D, Zhang S, et al. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett, 2007, 249(2):188~197
14 Michaylira CZ, Nakagawa H. Hypoxic microenvironment as a cradle for melanoma development and progression. Cancer Biol Tner, 2006, (5):476~479
15 Koga K, Nabeshima K, Nishimura N. Microvessel density and HIF-1alpha expression correlate with malignant potential in fibrohistiocytic tumors. Eur J Dermatol, 2005,15(6):465~469
16 Giatromanolaki A, Arvanitidou V, Hatzimichael A. The HIF-2alpha/VEGF pathway activation in cutaneous capillary haemangiomas. Pathology, 2005, 37(2):149~151
17 Kwon YW, Kwon KS, Moon HE. Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. J Invest Dermatol, 2004, 123(1):152~158
18 Simonetti O, Lucarini G, Goteri G. VEGF is likely a key factor in the link between inflammation and angiogenesis in psoriasis: results of an immunohistochemical study. Int J Immunopathol Pharmacol, 2006, 19(4):751~760
19 Tovar-Castillo LE, Cancino-Díaz JC, García-Vázquez F. Under-expression of VHL and over-expression of HDAC-1, HIF-1αlpha, LL-37, and IAP-2 in affected skin biopsies of patients with psoriasis. Int J Dermatol, 2007, 46(3):239~246
20 Hong KH, Yoo SA, Kang SS, et al. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts. Clin Exp Immunol, 2006, 146(2):362~370
21 Distler K. Hypoxia and angiogenesis in rheumatic diseases. Z Rheumatol, 2003, 62(Suppl 2):II43~45
22 KonttinenYT,MackiewiczZ,PovilenaiteD.Disease-associated increased HIF-1, alphavbeta3 integrin, and Flt-1 do not suffice to compensate the damage-inducing loss of blood vessels in inflammatory myopathies. Rheumatol Int, 2004, 24(6):333~339
23 Elson DA, Ryan HE, Snow JW, et al. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res, 2000, 60(21):6189~6195
24 Scheid A, Wenger RH, Sch?ffer L, et al. Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3. FASEB J, 2002, 16(3):411~413
25 Zhang Q, Wu Y, Chau CH, et al. Crosstalk of hypoxia-mediated signaling pathways in upregulating plasminogen activator inhibitor-1 expression in keloid fibroblasts. J Cell Physiol, 2004, 199(1):89~97
26 Viemann D, Schmidt M, Tenbrock K, et al. The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol, 2007, 178(5):3198~3207
27 Fajas L, Landsberg RL, Huss2Garcia Y, et al. E-Fs regulate adipocyte differentiation [J]. Dev Cell, 2002, 3(1):39~49
28 Arrais-Silva WW, Paffaro VA Jr, Yamada AT, et al. Expression of hypoxia-inducible factor-1alpha in the cutaneous lesions of BALB/c mice infected with Leishmania amazonensis. Exp Mol Pathol, 2005 Feb,78(1):49~54
29 Rezvani HR, Dedieu S, North S. Hypoxia-inducible factor-1alpha, a key factor in the keratinocyte response toUVB exposure. J Biol Chem, 2007, 282(22):16413~16422
30 Gu M, Singh RP, Dhanalakshmi S, et al. Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice. Cancer Res, 2007, 67(7):3483~3491
31 Martin-Oliva D, Aguilar-Quesada R, O'valle F, et al. Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res, 2006, 66(11):5744~5756
32 Grimm A, Dimmler A, Stange S, et al. Expression of HIF-1 alpha in irradiated tissue is altered by topical negative-pressure therapy. Strahlenther Onkol, 2007, 183(3):144~149
2 Senger DR, van de Water L, Brown LF, et al. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev,1993,12:303~324
3 Christian Rosenberger C, Solovan C, Rosenberger AD, et al. Upregulation of Hypoxia-Inducible Factors in Normal and psoriatic Skin. Journal of Investigative Dermatology, 2007, 127(10):2445~2452
4 Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-induced factor. Annu Rew Cell Dev Biol, 1999,15:551~578
5 王刚, 张开明. 银屑病. 人民卫生出版社, 197~200
6 赵辩.临床皮肤病学.第三版.南京:江苏科技出版社, 2001,759~772
7 Creamer D, Allen M, Jagger R, et al. Mediation of Systemic vascular hypermeability in severe psoriasis by circulating vascular endothelial growth factor. Arch Dermatol, 2002, 138:791~796
8 Stadler W, Wilding G. Angiogenesis inhibitors in genitourinary cancers. Crit Rev Oncol Hematol, 2003, 46Suppl:41~47
9 Siemeister G, Schirner M, Weindel K, et al. Martiny-Baron G. Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie22 pathway. Cancer Res, 1999, 59(13):3185~3191
10 Lammering G. Anti-epidermal growth factor receptor strategies to enhance radiation action. Curr Med Chem Anti-Canc Agents, 2003, 3(5):327~333
11 Crews S T. Control of cell Lineage-specific development and transcription by bHLH-PAS. Protines Genes Dev, 1998, 12(5):607~620
12 Jewell UR, Kvietikova I, Scheid A, et al. Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J, 2001, 15, 1312
13 IvanM, KaelinWG. The von-Hippel-Lindau tumor supp ressor protein. CurrOpin Genet Dev, 2001, 11(1):27~34
14 Semanza GL. Hypoxia-inducible factor-1: oxygen homeostasis and disease pathophysiology. Trends Mol Med, 2001, 7:345~350
15 Kwon YW, Kwon KS, Moon HE. Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. J Invest Dermatol, 2004, 123(1):152~158
16 Simonetti O, Lucarini G, Goteri G. VEGF is likely a keyfactor in the link between inflammation and angiogenesis in psoriasis: results of an immunohistochemical study. Int J Immunopathol Pharmacol, 2006, 19(4):751~760
17 Yun Z, Maecker HL, Johnson RS. Inhibition of PPAR gamma 2 gene expression by the HIF212regulated gene DEC1/ Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell, 2002, 2(3):331~341
18 Tovar-Castillo LE, Cancino-Díaz JC, García-Vázquez F. Under-expression of VHL and over-expression of HDAC-1, HIF-1αlpha, LL-37, and IAP-2 in affected skin biopsies of patients with psoriasis. Int J Dermatol, 2007, 46(3):239~246
19 Fajas L, Landsberg RL, Huss-Garcia Y, et al. E-Fs regulate adipocyte differentiation. Dev Cell, 2002, 3(1) :39~49
20 Hareld F, Dvorak, Lawrence F, et al. Vascular permeability factor, microvascular hypermeability, and angiogenesis. Am J Pathology, 1995, (146):10~19
21 Dvorak HF, BrownLF, Detmar M, et al. Vascular permeability factor vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol, 1995, 146(3):1029~1039
22 Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med, 1994, 180:1141~1146
23 Xia YP, Li B, Hylton D, et al. Rudge GS Transgenic delivery of VEGF to mouse skin leads to an inflammatorycondition resembling human psoriasis. Blood, 2003, 102:161~168
24 张锡宝, 罗权, 吴志华等. 血管内皮生长因子及其受体在银屑病发病中的作用及意义。中华皮肤科杂志, 2005, 38:140~142
25 朱凡, 郑敏, 鲍彰. 银屑病患者皮损中血管内皮生长因子受体的表达与血管增生的关系. 中华皮肤科杂志, 2003, 36(7):365~367
26 Resar JR, Roguin A, Voner J, et al. Hypoxia-inducible factor-1polymorphism and coronary collaterals in patients with is chemic heart disease. Chest, 2005, 128(2):787~791
27 Chavez JC, LaManna JC. Activation of hypoxia-induced factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1. J Neurosci, 2002, 22:8922~8931
28 任宏, 孙光. HIF-1与肿瘤血管新生及其表达的基因调控.国外医学泌尿系统分册, 2005, 25(2):180~183
29 Jones A, Fujiyama C, et al. Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines. Clin Cancer Res, 2001, 7(5):1263~1272
30 Liu LX, Lu H. Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor-1. Biochem Biophys Res Commun, 2002, 291(4):908~914
31 Strieth S, Hartschuh W, Pilz L, et al. Angiogenic switchoccurs late in squamous cell carcinomas of human skin. Br J Cancer, 2000, 82:591~600
32 Sochorova R, Svecova D, Sinka L, et al. Increased endothelemia as an indirect marker of changes in the blood vessel endothelium in psoriasis.世界核心医学期刊文摘.皮肤病学, 2005, 1(2):52
33 Fieger CB, Sassetti CM, Rosen SD. Endogly-can, a member of the CD34 family, functions as an L-selectin ligand through modification with tyrosine sulfation sialy lewis. J Biol Chem, 2003, 278(30):27390~27398
34 金力, 陈凯, 王萍等. CD34 在寻常型银屑病中医辨证分型皮损中的表达. 中华皮肤性病学杂志, 2006, 20(5): 273~275
35 任德莲, 李晓辉, 朱晓华等. 银屑病皮损区肥大细胞分布和血管内皮细胞 CD34 表达的研究. 临床皮肤科杂志, 2004, 33(8):468~470
1 Pili R, Donehower RC. Is HIF-1 alpha a valid therapeutic target. J Natl Cancer Inst, 2003, 95(7):498~499
2 Choi KS, Bae MK, Jeong JW, et al. Hypoxia-induced angiogenesis during carcinogenesis. J Biochem MolBiol, 2003, 36(1):120~127
3 Gregg L. Semenza HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med, 2002, 8 (4):S62~S67
4 Mazure NM, Brahimi Horn MC, Pouyssegur J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Curr Pharm Des, 2003, 9(7):531~541
5 Semenza GL. HIF-1 and tumor progression: pathophysiology and thera-peutics. Trends Mol Med, 2002, 8(4 Suppl):S62~S67
6 Linden T, Katschinski DM, Eckhardt K, et al. The antimycotic ci clopirox olamine induces HIF-1alpha stability, VEGF expression, and angiogenesis. FASEB J, 2003, 17 (6):761~763
7 Vincent KA, Feron O, Kelly RA. Harnessing the response to tissue hypoxia: HIF-1 alpha and therapeutic angiogenesis. Trends Cardiovasc Med, 2002, 12(8):362~367
8 Jewell UR, Kvietikova I, Scheid A, et al. Induction of HIF-1α in response to hypoxia is instantaneous. FASEB J, 2001, 15, 1312
9 IvanM, KaelinWG. The von-Hippel-Lindau tumor supp ressor protein. CurrOpin Genet Dev, 2001, 11 (1):27~34
10 Rosenberger C, Solovan C, Rosenberger AD, et al. Upregulation of Hypoxia-Inducible Factors in Normal and psoriatic Skin. J Invest Dermatol, 2007, 127(10):2445~2452
11 Heather ER, Michelle P, Wayne MN. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res, 2000, 60:4010
12 赵丽, 刘林, 马长路. HIF-1α在皮肤鳞状细胞癌和基底细胞癌中的表达及其与血管生成的关系. 肿瘤基础与临床, 2006, 19(2):365~367
13 Sun B, Zhang D, Zhang S, et al. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett, 2007, 249(2):188~197
14 Michaylira CZ, Nakagawa H. Hypoxic microenvironment as a cradle for melanoma development and progression. Cancer Biol Tner, 2006, (5):476~479
15 Koga K, Nabeshima K, Nishimura N. Microvessel density and HIF-1alpha expression correlate with malignant potential in fibrohistiocytic tumors. Eur J Dermatol, 2005,15(6):465~469
16 Giatromanolaki A, Arvanitidou V, Hatzimichael A. The HIF-2alpha/VEGF pathway activation in cutaneous capillary haemangiomas. Pathology, 2005, 37(2):149~151
17 Kwon YW, Kwon KS, Moon HE. Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. J Invest Dermatol, 2004, 123(1):152~158
18 Simonetti O, Lucarini G, Goteri G. VEGF is likely a key factor in the link between inflammation and angiogenesis in psoriasis: results of an immunohistochemical study. Int J Immunopathol Pharmacol, 2006, 19(4):751~760
19 Tovar-Castillo LE, Cancino-Díaz JC, García-Vázquez F. Under-expression of VHL and over-expression of HDAC-1, HIF-1αlpha, LL-37, and IAP-2 in affected skin biopsies of patients with psoriasis. Int J Dermatol, 2007, 46(3):239~246
20 Hong KH, Yoo SA, Kang SS, et al. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts. Clin Exp Immunol, 2006, 146(2):362~370
21 Distler K. Hypoxia and angiogenesis in rheumatic diseases. Z Rheumatol, 2003, 62(Suppl 2):II43~45
22 KonttinenYT,MackiewiczZ,PovilenaiteD.Disease-associated increased HIF-1, alphavbeta3 integrin, and Flt-1 do not suffice to compensate the damage-inducing loss of blood vessels in inflammatory myopathies. Rheumatol Int, 2004, 24(6):333~339
23 Elson DA, Ryan HE, Snow JW, et al. Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res, 2000, 60(21):6189~6195
24 Scheid A, Wenger RH, Sch?ffer L, et al. Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3. FASEB J, 2002, 16(3):411~413
25 Zhang Q, Wu Y, Chau CH, et al. Crosstalk of hypoxia-mediated signaling pathways in upregulating plasminogen activator inhibitor-1 expression in keloid fibroblasts. J Cell Physiol, 2004, 199(1):89~97
26 Viemann D, Schmidt M, Tenbrock K, et al. The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol, 2007, 178(5):3198~3207
27 Fajas L, Landsberg RL, Huss2Garcia Y, et al. E-Fs regulate adipocyte differentiation [J]. Dev Cell, 2002, 3(1):39~49
28 Arrais-Silva WW, Paffaro VA Jr, Yamada AT, et al. Expression of hypoxia-inducible factor-1alpha in the cutaneous lesions of BALB/c mice infected with Leishmania amazonensis. Exp Mol Pathol, 2005 Feb,78(1):49~54
29 Rezvani HR, Dedieu S, North S. Hypoxia-inducible factor-1alpha, a key factor in the keratinocyte response toUVB exposure. J Biol Chem, 2007, 282(22):16413~16422
30 Gu M, Singh RP, Dhanalakshmi S, et al. Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice. Cancer Res, 2007, 67(7):3483~3491
31 Martin-Oliva D, Aguilar-Quesada R, O'valle F, et al. Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res, 2006, 66(11):5744~5756
32 Grimm A, Dimmler A, Stange S, et al. Expression of HIF-1 alpha in irradiated tissue is altered by topical negative-pressure therapy. Strahlenther Onkol, 2007, 183(3):144~149