血管生成素-1、2及其受体Tie-2在寻常型银屑病皮损中的表达及意义
摘要
研究背景银屑病是一种常见的以皮肤鳞屑性红斑为主要特征的慢性炎症性皮肤病,病理表现为表皮过度增殖、真皮乳头层微血管异常增生及炎细胞浸润。患者皮损中真皮乳头层微血管扭曲扩张、通透性增加,促进了炎症反应,且出现新生血管。微血管生成异常与银屑病发生、持续存在及复发有密切关系,在银屑病发病中起重要作用。目前有关银屑病血管生成,特别是一些血管生成相关因子以及抗血管生成药物治疗银屑病的研究日益受到重视。血管生成素(angiopoietin,Ang)是新近发现的一族分泌型糖蛋白类细胞因子,主要在肿瘤细胞和内皮细胞中表达,与其酪氨酸激酶受体-2(tyrosine kinase withimmunoglobulin and epidermal growth factor homology domains,Tie-2)特异性结合,主要参与血管的成熟,维持血管的完整性及稳定性,并在血管发育、血管重建、炎症、癌症等生理及病理过程中发挥重要作用。已知的血管生成素家族成员有Ang1、2、3、4,其中Ang-1和Ang-2与血管生成关系最密切。有研究表明,Ang-1与Tie-2结合,在促进血管的成熟,维持血管的完整性及稳定性过程中起重要作用,而Ang-2与Tie-2结合参与引发血管的重新塑型和内膜去稳定的作用,在血管重塑、胚胎血管发育、癌症发生发展等过程中都发挥重要作用。
研究目的研究Ang-1、2与Tie-2在寻常型银屑病进行期皮损组织中的表达,分析其在寻常型银屑病皮损组织处与正常组织中表达水平的差异和三者之间的相关性,探讨其在促进银屑病发病过程中的作用。
研究方法利用免疫组织化学方法检测24例寻常型银屑病进行期皮损组织和12例正常皮肤组织石蜡包埋组织标本中Ang-1、2及其受体Tie-2的表达与定位。综合染色强度及阳性细胞数对其染色结果进行半定量测定,分析其在寻常型银屑病组织皮损处与正常组织中表达水平的差异;并对Ang-1、2及其受体Tie-2在皮损中的两两表达水平进行相关性分析,探讨三者之间的相互关系。
结果在银屑病皮损组织中,Ang-1主要表达于受累皮肤真皮乳头层的基质细胞的胞浆内,Ang-2主要表达于受累皮肤表皮层和真皮乳头层的内皮细胞,Tie-2主要表达于受累皮肤表皮层和高度血管化的真皮乳头层的内皮细胞和包括真皮深层的其它区域的内皮细胞;在正常皮肤组织中,Ang-1表达极弱或呈阴性表达,Ang-2呈阴性表达,Tie-2仅在真皮深层内皮细胞可见表达。Ang-1、2与Tie-2在银屑病皮损处的表达明显高于正常皮肤,其差异具有统计学意义(P＜0.05)。寻常型银屑病组织中Ang-1、2及Tie-2表达均上调,任意两者之间的表达均呈显著正相关(P＜0.05)。
结论①Ang-1在银屑病皮损处真皮乳头层的基质细胞中表达,在正常皮肤中几乎无表达;②Ang-2在银屑病皮损处表皮层和真皮乳头层的内皮细胞表达,在正常皮肤组织中无表达;③Tie-2在银屑病皮损处表达于受累皮肤表皮层和高度血管化的真皮乳头层的内皮细胞和包括真皮深层的其它区域的内皮细胞,在正常皮肤组织中仅在真皮层血管内皮细胞中表达,其在银屑病皮损中的表达显著高于正常组织;④血管生成在银屑病进展过程中起重要作用,Ang-1、2和Tie-2在银屑病皮损处的高表达与银屑病血管新生密切相关,Ang-1、2交替作用于Tie-2受体,促进银屑病皮损处血管生成。
Research Background Psoriasis is a common,chronic,inflammatory dermatosis with erythema and scaling papules,pathological characterized by hyperproliferation of the epidermis,angiogenesis and accumulation of inflammatory.Microvessels of the papillary dermis in psoriatic lesions are elongated,tortuous,and dilated,which contributes significantly to the proinflammatory response.Abnormal micrangium formation is relative to origination,persistence and recrudescence of psoriasis. Rencently psoriasis angiogenesis,especially angiogenesis factor and drugs of anti-angiogenesis of psoriasis are more and more valued.Angiopoietin(Ang) is recently recognized as a family of cytokine in secreted glycoprotein.Ang is tightly related to tumor angiogenesis and it is mainly expressed in tumor cells and the surface of vascular endothelial cell.Ang functions as ligands for tyrosinkinase with immunoglobulin-like and epidermal growth factor homology domains(Tie-2).Ang participate maturity of blood vessels,maintain integrity and stability of blood vessels, and it plays an important role in development of blood vessels,reconstruction of blood vessels,inflammation,cancer,etc.Family members of angiogenesis include Ang-1-4,of which Ang-1 and Ang-2 are most important.Binding of Ang-1 to Tie-2 receptor is thought to induce stabilization of maturing vessels;While Ang-2 and Tie-2 play an important role in the Angiogenesis,the remodeling of the vascular network and the repair of trauma.
Research objective The aim of study is to detect the expression of Ang-1、2 and Tie-2 in involved psoriasis vulgaris tissue and to observe their level of expression between involved psoriasis vulgaris tissue and normal control skin.The role of Ang-2 and Tie-2 in genesis,development and angiogenesis of psoriasis was approached.
Research Methods The expression of Ang-1、2 and Tie-2 was determined with immunohistochemistry in samples of psoriasis vulgaris tissue from 24 patients with psoriasis vulgaris and those of skin tissue from 12 healthy individuals.
Results The expression of Ang-1、2 and Tie-2 in psoriasis vulgaris tissue was significantly higher than those in the normal group(P＜0.05).There was positive correlation between the expression of Ang-1、2 and that of Tie-2(P＜0.05).
Conclusions①Ang-1 was expressed by matrix cells in the papillary dermis of involved psoriasis skin,and it was scarcely expressed in normal skin.②Ang-2 was expressed by endothelial cells in the epidermis and papillary dermis of involved psoriasis skin,and it was not expressed in normal skin.③Tie-2 was expressed by endothelial cells in the epidermis the highly vascularized papillary dermis as well as by endothelial cells in other areas including the deep dermis.The expression of Tie-2 in involved psoriasis skin was significant higher than that was in normal skin.④Angiogenesis plays an important role in progression of psoriasis.The overexpression of Ang-1、2 and Tie-2 receptor is closely correlated with the angiogenesis of psoriasis. It can induce the angiogenesis of psoriasis by Ang-1 and Ang-2 acting on Tie-2 alternatively.
研究目的研究Ang-1、2与Tie-2在寻常型银屑病进行期皮损组织中的表达,分析其在寻常型银屑病皮损组织处与正常组织中表达水平的差异和三者之间的相关性,探讨其在促进银屑病发病过程中的作用。
研究方法利用免疫组织化学方法检测24例寻常型银屑病进行期皮损组织和12例正常皮肤组织石蜡包埋组织标本中Ang-1、2及其受体Tie-2的表达与定位。综合染色强度及阳性细胞数对其染色结果进行半定量测定,分析其在寻常型银屑病组织皮损处与正常组织中表达水平的差异;并对Ang-1、2及其受体Tie-2在皮损中的两两表达水平进行相关性分析,探讨三者之间的相互关系。
结果在银屑病皮损组织中,Ang-1主要表达于受累皮肤真皮乳头层的基质细胞的胞浆内,Ang-2主要表达于受累皮肤表皮层和真皮乳头层的内皮细胞,Tie-2主要表达于受累皮肤表皮层和高度血管化的真皮乳头层的内皮细胞和包括真皮深层的其它区域的内皮细胞;在正常皮肤组织中,Ang-1表达极弱或呈阴性表达,Ang-2呈阴性表达,Tie-2仅在真皮深层内皮细胞可见表达。Ang-1、2与Tie-2在银屑病皮损处的表达明显高于正常皮肤,其差异具有统计学意义(P＜0.05)。寻常型银屑病组织中Ang-1、2及Tie-2表达均上调,任意两者之间的表达均呈显著正相关(P＜0.05)。
结论①Ang-1在银屑病皮损处真皮乳头层的基质细胞中表达,在正常皮肤中几乎无表达;②Ang-2在银屑病皮损处表皮层和真皮乳头层的内皮细胞表达,在正常皮肤组织中无表达;③Tie-2在银屑病皮损处表达于受累皮肤表皮层和高度血管化的真皮乳头层的内皮细胞和包括真皮深层的其它区域的内皮细胞,在正常皮肤组织中仅在真皮层血管内皮细胞中表达,其在银屑病皮损中的表达显著高于正常组织;④血管生成在银屑病进展过程中起重要作用,Ang-1、2和Tie-2在银屑病皮损处的高表达与银屑病血管新生密切相关,Ang-1、2交替作用于Tie-2受体,促进银屑病皮损处血管生成。
Research Background Psoriasis is a common,chronic,inflammatory dermatosis with erythema and scaling papules,pathological characterized by hyperproliferation of the epidermis,angiogenesis and accumulation of inflammatory.Microvessels of the papillary dermis in psoriatic lesions are elongated,tortuous,and dilated,which contributes significantly to the proinflammatory response.Abnormal micrangium formation is relative to origination,persistence and recrudescence of psoriasis. Rencently psoriasis angiogenesis,especially angiogenesis factor and drugs of anti-angiogenesis of psoriasis are more and more valued.Angiopoietin(Ang) is recently recognized as a family of cytokine in secreted glycoprotein.Ang is tightly related to tumor angiogenesis and it is mainly expressed in tumor cells and the surface of vascular endothelial cell.Ang functions as ligands for tyrosinkinase with immunoglobulin-like and epidermal growth factor homology domains(Tie-2).Ang participate maturity of blood vessels,maintain integrity and stability of blood vessels, and it plays an important role in development of blood vessels,reconstruction of blood vessels,inflammation,cancer,etc.Family members of angiogenesis include Ang-1-4,of which Ang-1 and Ang-2 are most important.Binding of Ang-1 to Tie-2 receptor is thought to induce stabilization of maturing vessels;While Ang-2 and Tie-2 play an important role in the Angiogenesis,the remodeling of the vascular network and the repair of trauma.
Research objective The aim of study is to detect the expression of Ang-1、2 and Tie-2 in involved psoriasis vulgaris tissue and to observe their level of expression between involved psoriasis vulgaris tissue and normal control skin.The role of Ang-2 and Tie-2 in genesis,development and angiogenesis of psoriasis was approached.
Research Methods The expression of Ang-1、2 and Tie-2 was determined with immunohistochemistry in samples of psoriasis vulgaris tissue from 24 patients with psoriasis vulgaris and those of skin tissue from 12 healthy individuals.
Results The expression of Ang-1、2 and Tie-2 in psoriasis vulgaris tissue was significantly higher than those in the normal group(P＜0.05).There was positive correlation between the expression of Ang-1、2 and that of Tie-2(P＜0.05).
Conclusions①Ang-1 was expressed by matrix cells in the papillary dermis of involved psoriasis skin,and it was scarcely expressed in normal skin.②Ang-2 was expressed by endothelial cells in the epidermis and papillary dermis of involved psoriasis skin,and it was not expressed in normal skin.③Tie-2 was expressed by endothelial cells in the epidermis the highly vascularized papillary dermis as well as by endothelial cells in other areas including the deep dermis.The expression of Tie-2 in involved psoriasis skin was significant higher than that was in normal skin.④Angiogenesis plays an important role in progression of psoriasis.The overexpression of Ang-1、2 and Tie-2 receptor is closely correlated with the angiogenesis of psoriasis. It can induce the angiogenesis of psoriasis by Ang-1 and Ang-2 acting on Tie-2 alternatively.
引文
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3. Roselyne Binetruy-Tournaire, Caroline Demangel, Bernard Malavaud, et al. Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. EMBO. 2000,19:1525-1533.
4. Arbiser JL. Angiogenesis and the skin: a primer. J Am Acad Dermatol. 1996;34(3):486-497.
5. Braverman IM, Jane Sibley. Role of the microcirculation in the treatment and pathogenesis of Psoriasis J Invest Dermatol, 1982;78:12-17.
6. Malhotra R, Sten KS, Fernandez LA, et al. Angiogenic properties of normal and psoriatic skin associate with epidermis, not dermis [see comment] Lab Invest. 1989;61(2:162-165) .
7. Goodfield M, Macdonald Hull S, Holland D, et al. Investigations of "active" edge of plaque psoriasis: vascular proliferation procedes changes in epidermal keratin. British J of Dermatology, 1994; 131:808-813.
8. Creamer D, Allen MH, Sousa A, et al. Localization of endothelial proliferation and microvascular expansion in active plaque psoriasis. Br J Dermatol. 1997;136(6):859-865.
9. Patan S. Vasculogenesis and angiogenesis. Cancer Treat Res. 2004; 117:3-32.
10. Iruela-Arispe ML, Dvorak HF. Angiogenesis: a dynamic balance of stimulators and inhibitors. Thromb Haemost. 1997;78(1):672-677.
11. Inan S, kuscu NK, Vatansever S, et al. Increased vascular surface density in ovarian endometriosis. Gynecol Endocrinol. 2003,17(2): 143-150.
12. Stefano J, Mandriota, Charles P, et al. Hypoxia-inducible angiopoietin-2 expression is mimicked by iodonium compounds and occurs in the rat brain and skin in response to systemic hypoxia and tissue is chemia [J]. Am J Pathol, 2000,156(6):506-513.
13.Gamble,JR.Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctionsrJ,].Circ Res,2000,87:603-607.
14.Li V et al.Prog Dennatol,1995;29(2):1-12.
15.Minauer Bet al.Cancer lleS,1996;56:1615-1620.
16.Huang YQ,Li JJ,Karpatkin S.Identification of a family of al-ternatively spliced mRNA species of angiopoietin21[J].Blood,2000,95:1993-1999.
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