五谷虫促进创面愈合作用及其机制的实验研究
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摘要
近年来,随着抗生素滥用情况的日益严重,由耐药菌引起的严重感染性创面逐渐增多,临床缺乏有效的治疗手段。由于此类创面愈合的病程长、并发症多,严重影响了患者的健康和生活质量,给社会带来巨大负担。中国传统中药?“五谷虫”,为丽蝇科丝光绿蝇、大头金蝇的幼虫。《本草纲目》、《本草求原》均记载:该虫性寒无毒,可搽敷外用,能治疗臁疮等外科疾病。五谷虫疗法,是近年来兴起的有效治疗耐药菌引起的严重感染创面的新型生物治疗方法,即临床上应用活体无菌丽蝇科丝光绿蝇幼虫,来治疗耐药菌感染创面,已取得满意效果,其作用机制主要包括:生物清创、抗菌和促进创面愈合。
本课题组前期研究已经证实,五谷虫对感染创面起到抗菌作用的有效成分为具有生物活性的抗菌肽类蛋白。但是目前对五谷虫促进创面愈合作用有效成分的功能学研究尚无报道,仍存在以下尚未解决的问题:
(1)目前国际上应用活体五谷虫生物清创的同时,利用活体五谷虫分泌的活性成分,控制创面的细菌感染;而我国传统医学记载五谷虫作为一种中药,经过炮制后,使用其干粉外敷,同样可以促进创面的愈合。但是尚缺乏活体五谷虫有效成分和五谷虫干粉的比较研究;(2)皮肤创面愈合病理过程复杂,涉及修复细胞的迁移、创面血管生成和局部神经再生等多个过程。关于五谷虫有效成分对上述愈合过程的影响机制尚不清楚;(3)五谷虫在中药学作为一种动物中药,其成分复杂,大多为大分子化合物,分离分析难度较大,这大大的限制了五谷虫干粉在临床上的应用,远远落后于临床上对活体五谷虫的应用。因此,对待动物药,必须在理论和方法上有所创新,研究和开发其有效成分。
为了解决以上几个问题,本课题从多种五谷虫有效成分获取方式出发,采用组织形态学、药物化学、药物分析及分子生物学方法,比较了五谷虫有效成分不同获取方式对创面愈合过程的影响,并对其有效组分进行提取、分析,寻找五谷虫对创面愈合有促进作用的有效成分,并明确其作用机制以及可能参与的信号转导通路。
本课题研究分三个部分:(1)五谷虫成分不同获取方式对创面愈合作用的比较研究;(2)活体五谷虫成分对创面愈合的促进作用及其机制研究;(3)中药
五谷虫脂肪酸组分对创面愈合的促进作用及其机制研究。?
1.五谷虫成分不同获取方式对创面愈合作用的比较研究?
本部分选用了活体五谷虫的匀浆产物和中药五谷虫干粉为研究对象,对比两种使用方法对大鼠皮肤创面愈合过程的影响,结果发现:创伤后第1和第3天五谷虫匀浆物组、五谷虫干粉组和对照组创面愈合率无显著性差异(P>0.05);创伤后第7,10和14天五谷虫匀浆物组和五谷虫干粉组的创面愈合率高于对照组(P<0.05),五谷虫匀浆物组和五谷虫干粉组创面愈合率无显著性差异(P>0.05)。组织学观察显示:在创面修复过程中,匀浆物组、干粉组与对照组相比,肉芽组织成熟,血管垂直于创面生长,胶原纤维排列整齐,瘢痕窄,成纵行条带,可见再生的皮肤附属器,再生上皮厚,爬行距离远。因此,活体五谷虫匀浆物和中药五谷虫干粉都可以减少大鼠皮肤创面的愈合时间、提高创面的愈合率和愈合质量。?
2.活体五谷虫成分对创面愈合的促进作用及其机制研究?
(1)五谷虫分泌物对血管内皮细胞增殖和迁移的影响及机制研究本实验部分以活体五谷虫的分泌物(ES)为研究对象,应用体外创面愈合模型,研究分泌物对人微血管内皮细胞系(HMEC-1)迁移和增殖的影响,以及参与的信号通路。MTT法检测ES对内皮细胞活力的影响,结果显示:虽然在10μg/ml ES下,内皮细胞活力最大,但不同浓度ES对细胞活力无明显影响(P>0.05);进一步应用体外创面愈合模型和Transwell法,结果显示:10μg/ml ES可促进内皮细胞迁移;应用Western-blot技术结果表明,ES可以诱导HMEC-1细胞发生迁移,并且时间依赖性激活AKT1,而不是ERK1/2。另外,应用PI3K抑制剂LY294002,可以部分降低ES诱导的细胞迁移,完全地抑制ES诱导的AKT1激活。因此,ES对人微血管内HMEC-1的迁移具有促进作用,而对增殖无影响;ES诱导HMEC-1的迁移作用,主要是激活PI3K/AKT1通路,而非ERK1/2 MAPK通路。
(2)五谷虫匀浆物对创面神经再生的影响
本实验部分以活体五谷虫的匀浆物作为研究对象,研究五谷虫的匀浆物对大鼠皮肤创面P物质(SP)分泌和蛋白基因产物9.5(PGP9.5)表达的影响,进而探讨五谷虫匀浆物促进创面愈合的机制及它对创面神经再生的影响。免疫组织化学结果显示:创伤后第3,7和10天,五谷虫匀浆物组SP表达的面积、平均光密度和积分光密度均高于对照组(P<0.05);创伤后第7和10天,PGP9.5表达在再生神经中,五谷虫匀浆物组表达多于对照组(P<0.05),创伤后第14天,五谷虫匀浆物组内真皮浅层仍见PGP9.5表达在再生神经中,而对照组未见表达。因此,活体五谷虫匀浆物可以促进创面SP和PGP9.5的表达,并且可能通过促进大鼠皮肤创面神经再生,进而促进创面愈合。
3.中药五谷虫脂肪酸组分对创面愈合的促进作用及其机制研究?
本部分应用药物化学提纯方法,提取五谷虫干粉中的脂肪酸成分,应用大鼠创面愈合模型,明确该脂肪酸提取物与创面愈合和血管生成之间的关系,寻找五谷虫的有效成分组。结果显示:创伤后第7天和第10天,五谷虫提取物可提高创面愈合率(P<0.05);免疫组织化学显示:创伤后第3天,五谷虫提取物可促进创面微血管密度(MVD)、血管内皮生长因子A(VEGFA)的表达(P<0.05);RT-PCR和Western-blot显示:创伤后第3天,五谷虫提取物可促进VEGFA基因和蛋白的表达(P<0.05)。应用气相色谱—质谱(GC-MS)分析,该脂肪酸提取物中共含有10种不同种类脂肪酸,且饱和脂肪酸:单不饱和脂肪酸:多不饱和脂肪酸为:20.57%:60.32%:19.11%。因此,中药五谷虫脂肪酸提取物通过促进大鼠皮肤创面血管生成,进而促进创面愈合。
In recent years, with the growing abuse of antibiotics, severe infected wounds caused by drug-resistant bacterae are on the rise lack of effective clinical treatment. This poses a significant impact on the health care system on account of its complications, the chronicity of care required and the associated cost. Traditional Chinese medicine“WuGuChong”is the larvae of Lucilia sericata, Chrysomyia megacephala or other relative Calliphoridae insects. According to traditional Chinese medicine principle and the book Compendium of Materia Medica records,“WuGuChong”is salty in taste, cold in nature and non-toxic. It is a medicine for external application to treat superficial purulent diseases such as furuncle or carbuncle. Nowadays, WuGuChong therapy, as a kind of biological therapy, has been widely used to treat various refractory wounds including diabetes foot and venous ulcers. The therapeutic action contains biological debridement, disinfection and enhancement of wound healing.
In previous study of our group, we have obtained an antibacterial peptide. However, there are still several controversial and unsettled problems: 1) in western medicine, WuGuChong therapy using living body of larvae is applied as a surgical debridement technique to treat infected wounds. While in traditional Chinese medicine, WuGuChong is extra-administration as a kind of dried drug after heat processing. There is no report on the relationship and comparative study of the above two applications; 2) the process of wound healing is complicated, referring to migration of related cells, angiogenesis and wound nerve regeneration. The effect of active components from WuGuChong on wound healing and related mechanisms is not clear. 3) based on traditional Chinese medicine documentation, WuGuChong is a animal drug, and it is difficult to analyze due to its complicated components. Therefore dried WuGuChong is limited clinically and falls behind from living body application. So for the animal drugs, new theory and methods must be innovated to develop its active components.
To solve the above problems, the present study under the guidance of integrated medicine theory is committed to clarify the effect of WuGuChong on wound healing and its related mechanisms ignoring infection. The contents of present study are as follows: 1) comparative study of different application of WuGuChong on wound healing; 2) effect of active components from living WuGuChong on wound healing and related mechanisms; 3) effect of fatty acid extracts from dried WuGuChong on wound healing and related mechanisms.
1. Comparative study of different application of WuGuChong on wound healing
In this part of study, we compared the effects of living WuGuChong homogenate products with that of dried WuGuChong on murine cutaneous wound healing in vivo. It was demonstrated that on day 1 and 3 after murine acute excision wounds creation, there was no statistical difference among homogenate group, died group and control group(P>0.05). On day 7, 10and 14, the percent wound contraction of homogenate group and died group was higher than that of control group(P < 0.05). However, the percent wound contraction in both homogenate group and died group was the same. Histological examination showed that comparing with control group, wounds of both homogenate group and dried group displayed a more accumulation of granulation tissue with a high degree of newly-formed micro-vessels and numerous inflammatory cells and fibroblast, the granulation was matured showing capillary vertically oriented, robust fusiform fibrocytes and moderate well-arranged collagen, and regenerative folliculus and sebaceous glands were detected in the fibrous connective tissue. In conclusion, both living WuGuChong homogenate and dried WuGuChong can reduce the rat skin wound healing course and improve wound healing rate and quality of healing.
2. Effect of active components from living WuGuChong on wound healing and related mechanisms
(1) WuGuChong excretions/secretions induces human microvascular endothelial cell migration through AKT1 pathway
In this part of study, we investigated if WuGuChong excretion/secretion(ES) induced cell proliferation and migration during wound healing process using microvascular endothelial cells (HMEC-1) as model. Wound healing and transwell migration assays were performed to study the effects of ES on HMEC-1 cell migration. Our data showed that ES significantly induced HMEC-1 cell migration in both wound healing and transwell assays, and time-dependently (P<0.05) activated AKT1, but not ERK1/2. Moreover LY294002 (a PI3K inhibitor) partially attenuated (P<0.05) ES-induced cell migration in wound healing assay while completely inhibited (P<0.05) ES-induced AKT1 activation. These findings demonstrate that ES directly induces HMEC-1 cell migration and this event is partially mediated by the activation of AKT1.
(2) WuGuChong homogenate is associated with neural regeneration and murine cutaneuous wound healing
In this part of study, we evaluated effects of living WuGuChong homogenate on acute skin wound healing and wound nerve regeneration. On days 7, 10, and 14 following injury, the rate of wound healing was significantly greater in the homogenate product group compared with the control group (P < 0.05), and homogenate healing was better than that seen in the control group. On days 3, 7, and 10, SP expression in cells and regenerative nerves was significantly greater in the homogenate product group compared with the control group (P < 0.05). On days 7 and 10, protein gene product 9.5 expression was detected in the regenerative nerve, and expression level was significantly greater in the homogenate product group compared with the control group (P < 0.05). It can be concluded that WuGuChong homogenate up-regulates SP and protein gene product 9.5 expressions during wound healing process, thereby promoting neural regeneration and wound healing.
3. Effect of fatty acid extracts from dried WuGuChong on wound healing and related mechanisms.
In his part of study, we aimed to investigate the effect of fatty acid extracts from dried WuGuChong on murine cutaneuous wound healing as well as angiogenesis. Results demonstrated that on day 7 and 10 after murine acute excision wounds creation, the percent wound contraction of fatty acid extracts group was higher than that of vaseline group(P<0.05). On day 3, 7 and 10 after wounds creation, the wound healing quality of fatty acid extracts group was better than that of vaseline group on terms of granulation formation and collagen organization(P<0.05). On day 3 after wounds creation, the micro vessel density and vascular endothelial growth factor expression of fatty acid extracts group were higher than that of vaseline group(P<0.05). Component analysis of the fatty acid extracts by Gas chromatography-mass spectrometry showed there were 10 kinds of fatty acids in total and the ratio of saturated fatty acid, monounsaturated fatty acid and polyunsaturated fatty acid (PUFA) was: 20.57%:60.32%:19.11%. In conclusion, fatty acid extracts from dried WuGuChong, four fifths of which are unsaturated fatty acids, can promote murine cutaneous wound healing probably resulting from the powerful angiogenic activity of the extracts.
本课题组前期研究已经证实,五谷虫对感染创面起到抗菌作用的有效成分为具有生物活性的抗菌肽类蛋白。但是目前对五谷虫促进创面愈合作用有效成分的功能学研究尚无报道,仍存在以下尚未解决的问题:
(1)目前国际上应用活体五谷虫生物清创的同时,利用活体五谷虫分泌的活性成分,控制创面的细菌感染;而我国传统医学记载五谷虫作为一种中药,经过炮制后,使用其干粉外敷,同样可以促进创面的愈合。但是尚缺乏活体五谷虫有效成分和五谷虫干粉的比较研究;(2)皮肤创面愈合病理过程复杂,涉及修复细胞的迁移、创面血管生成和局部神经再生等多个过程。关于五谷虫有效成分对上述愈合过程的影响机制尚不清楚;(3)五谷虫在中药学作为一种动物中药,其成分复杂,大多为大分子化合物,分离分析难度较大,这大大的限制了五谷虫干粉在临床上的应用,远远落后于临床上对活体五谷虫的应用。因此,对待动物药,必须在理论和方法上有所创新,研究和开发其有效成分。
为了解决以上几个问题,本课题从多种五谷虫有效成分获取方式出发,采用组织形态学、药物化学、药物分析及分子生物学方法,比较了五谷虫有效成分不同获取方式对创面愈合过程的影响,并对其有效组分进行提取、分析,寻找五谷虫对创面愈合有促进作用的有效成分,并明确其作用机制以及可能参与的信号转导通路。
本课题研究分三个部分:(1)五谷虫成分不同获取方式对创面愈合作用的比较研究;(2)活体五谷虫成分对创面愈合的促进作用及其机制研究;(3)中药
五谷虫脂肪酸组分对创面愈合的促进作用及其机制研究。?
1.五谷虫成分不同获取方式对创面愈合作用的比较研究?
本部分选用了活体五谷虫的匀浆产物和中药五谷虫干粉为研究对象,对比两种使用方法对大鼠皮肤创面愈合过程的影响,结果发现:创伤后第1和第3天五谷虫匀浆物组、五谷虫干粉组和对照组创面愈合率无显著性差异(P>0.05);创伤后第7,10和14天五谷虫匀浆物组和五谷虫干粉组的创面愈合率高于对照组(P<0.05),五谷虫匀浆物组和五谷虫干粉组创面愈合率无显著性差异(P>0.05)。组织学观察显示:在创面修复过程中,匀浆物组、干粉组与对照组相比,肉芽组织成熟,血管垂直于创面生长,胶原纤维排列整齐,瘢痕窄,成纵行条带,可见再生的皮肤附属器,再生上皮厚,爬行距离远。因此,活体五谷虫匀浆物和中药五谷虫干粉都可以减少大鼠皮肤创面的愈合时间、提高创面的愈合率和愈合质量。?
2.活体五谷虫成分对创面愈合的促进作用及其机制研究?
(1)五谷虫分泌物对血管内皮细胞增殖和迁移的影响及机制研究本实验部分以活体五谷虫的分泌物(ES)为研究对象,应用体外创面愈合模型,研究分泌物对人微血管内皮细胞系(HMEC-1)迁移和增殖的影响,以及参与的信号通路。MTT法检测ES对内皮细胞活力的影响,结果显示:虽然在10μg/ml ES下,内皮细胞活力最大,但不同浓度ES对细胞活力无明显影响(P>0.05);进一步应用体外创面愈合模型和Transwell法,结果显示:10μg/ml ES可促进内皮细胞迁移;应用Western-blot技术结果表明,ES可以诱导HMEC-1细胞发生迁移,并且时间依赖性激活AKT1,而不是ERK1/2。另外,应用PI3K抑制剂LY294002,可以部分降低ES诱导的细胞迁移,完全地抑制ES诱导的AKT1激活。因此,ES对人微血管内HMEC-1的迁移具有促进作用,而对增殖无影响;ES诱导HMEC-1的迁移作用,主要是激活PI3K/AKT1通路,而非ERK1/2 MAPK通路。
(2)五谷虫匀浆物对创面神经再生的影响
本实验部分以活体五谷虫的匀浆物作为研究对象,研究五谷虫的匀浆物对大鼠皮肤创面P物质(SP)分泌和蛋白基因产物9.5(PGP9.5)表达的影响,进而探讨五谷虫匀浆物促进创面愈合的机制及它对创面神经再生的影响。免疫组织化学结果显示:创伤后第3,7和10天,五谷虫匀浆物组SP表达的面积、平均光密度和积分光密度均高于对照组(P<0.05);创伤后第7和10天,PGP9.5表达在再生神经中,五谷虫匀浆物组表达多于对照组(P<0.05),创伤后第14天,五谷虫匀浆物组内真皮浅层仍见PGP9.5表达在再生神经中,而对照组未见表达。因此,活体五谷虫匀浆物可以促进创面SP和PGP9.5的表达,并且可能通过促进大鼠皮肤创面神经再生,进而促进创面愈合。
3.中药五谷虫脂肪酸组分对创面愈合的促进作用及其机制研究?
本部分应用药物化学提纯方法,提取五谷虫干粉中的脂肪酸成分,应用大鼠创面愈合模型,明确该脂肪酸提取物与创面愈合和血管生成之间的关系,寻找五谷虫的有效成分组。结果显示:创伤后第7天和第10天,五谷虫提取物可提高创面愈合率(P<0.05);免疫组织化学显示:创伤后第3天,五谷虫提取物可促进创面微血管密度(MVD)、血管内皮生长因子A(VEGFA)的表达(P<0.05);RT-PCR和Western-blot显示:创伤后第3天,五谷虫提取物可促进VEGFA基因和蛋白的表达(P<0.05)。应用气相色谱—质谱(GC-MS)分析,该脂肪酸提取物中共含有10种不同种类脂肪酸,且饱和脂肪酸:单不饱和脂肪酸:多不饱和脂肪酸为:20.57%:60.32%:19.11%。因此,中药五谷虫脂肪酸提取物通过促进大鼠皮肤创面血管生成,进而促进创面愈合。
In recent years, with the growing abuse of antibiotics, severe infected wounds caused by drug-resistant bacterae are on the rise lack of effective clinical treatment. This poses a significant impact on the health care system on account of its complications, the chronicity of care required and the associated cost. Traditional Chinese medicine“WuGuChong”is the larvae of Lucilia sericata, Chrysomyia megacephala or other relative Calliphoridae insects. According to traditional Chinese medicine principle and the book Compendium of Materia Medica records,“WuGuChong”is salty in taste, cold in nature and non-toxic. It is a medicine for external application to treat superficial purulent diseases such as furuncle or carbuncle. Nowadays, WuGuChong therapy, as a kind of biological therapy, has been widely used to treat various refractory wounds including diabetes foot and venous ulcers. The therapeutic action contains biological debridement, disinfection and enhancement of wound healing.
In previous study of our group, we have obtained an antibacterial peptide. However, there are still several controversial and unsettled problems: 1) in western medicine, WuGuChong therapy using living body of larvae is applied as a surgical debridement technique to treat infected wounds. While in traditional Chinese medicine, WuGuChong is extra-administration as a kind of dried drug after heat processing. There is no report on the relationship and comparative study of the above two applications; 2) the process of wound healing is complicated, referring to migration of related cells, angiogenesis and wound nerve regeneration. The effect of active components from WuGuChong on wound healing and related mechanisms is not clear. 3) based on traditional Chinese medicine documentation, WuGuChong is a animal drug, and it is difficult to analyze due to its complicated components. Therefore dried WuGuChong is limited clinically and falls behind from living body application. So for the animal drugs, new theory and methods must be innovated to develop its active components.
To solve the above problems, the present study under the guidance of integrated medicine theory is committed to clarify the effect of WuGuChong on wound healing and its related mechanisms ignoring infection. The contents of present study are as follows: 1) comparative study of different application of WuGuChong on wound healing; 2) effect of active components from living WuGuChong on wound healing and related mechanisms; 3) effect of fatty acid extracts from dried WuGuChong on wound healing and related mechanisms.
1. Comparative study of different application of WuGuChong on wound healing
In this part of study, we compared the effects of living WuGuChong homogenate products with that of dried WuGuChong on murine cutaneous wound healing in vivo. It was demonstrated that on day 1 and 3 after murine acute excision wounds creation, there was no statistical difference among homogenate group, died group and control group(P>0.05). On day 7, 10and 14, the percent wound contraction of homogenate group and died group was higher than that of control group(P < 0.05). However, the percent wound contraction in both homogenate group and died group was the same. Histological examination showed that comparing with control group, wounds of both homogenate group and dried group displayed a more accumulation of granulation tissue with a high degree of newly-formed micro-vessels and numerous inflammatory cells and fibroblast, the granulation was matured showing capillary vertically oriented, robust fusiform fibrocytes and moderate well-arranged collagen, and regenerative folliculus and sebaceous glands were detected in the fibrous connective tissue. In conclusion, both living WuGuChong homogenate and dried WuGuChong can reduce the rat skin wound healing course and improve wound healing rate and quality of healing.
2. Effect of active components from living WuGuChong on wound healing and related mechanisms
(1) WuGuChong excretions/secretions induces human microvascular endothelial cell migration through AKT1 pathway
In this part of study, we investigated if WuGuChong excretion/secretion(ES) induced cell proliferation and migration during wound healing process using microvascular endothelial cells (HMEC-1) as model. Wound healing and transwell migration assays were performed to study the effects of ES on HMEC-1 cell migration. Our data showed that ES significantly induced HMEC-1 cell migration in both wound healing and transwell assays, and time-dependently (P<0.05) activated AKT1, but not ERK1/2. Moreover LY294002 (a PI3K inhibitor) partially attenuated (P<0.05) ES-induced cell migration in wound healing assay while completely inhibited (P<0.05) ES-induced AKT1 activation. These findings demonstrate that ES directly induces HMEC-1 cell migration and this event is partially mediated by the activation of AKT1.
(2) WuGuChong homogenate is associated with neural regeneration and murine cutaneuous wound healing
In this part of study, we evaluated effects of living WuGuChong homogenate on acute skin wound healing and wound nerve regeneration. On days 7, 10, and 14 following injury, the rate of wound healing was significantly greater in the homogenate product group compared with the control group (P < 0.05), and homogenate healing was better than that seen in the control group. On days 3, 7, and 10, SP expression in cells and regenerative nerves was significantly greater in the homogenate product group compared with the control group (P < 0.05). On days 7 and 10, protein gene product 9.5 expression was detected in the regenerative nerve, and expression level was significantly greater in the homogenate product group compared with the control group (P < 0.05). It can be concluded that WuGuChong homogenate up-regulates SP and protein gene product 9.5 expressions during wound healing process, thereby promoting neural regeneration and wound healing.
3. Effect of fatty acid extracts from dried WuGuChong on wound healing and related mechanisms.
In his part of study, we aimed to investigate the effect of fatty acid extracts from dried WuGuChong on murine cutaneuous wound healing as well as angiogenesis. Results demonstrated that on day 7 and 10 after murine acute excision wounds creation, the percent wound contraction of fatty acid extracts group was higher than that of vaseline group(P<0.05). On day 3, 7 and 10 after wounds creation, the wound healing quality of fatty acid extracts group was better than that of vaseline group on terms of granulation formation and collagen organization(P<0.05). On day 3 after wounds creation, the micro vessel density and vascular endothelial growth factor expression of fatty acid extracts group were higher than that of vaseline group(P<0.05). Component analysis of the fatty acid extracts by Gas chromatography-mass spectrometry showed there were 10 kinds of fatty acids in total and the ratio of saturated fatty acid, monounsaturated fatty acid and polyunsaturated fatty acid (PUFA) was: 20.57%:60.32%:19.11%. In conclusion, fatty acid extracts from dried WuGuChong, four fifths of which are unsaturated fatty acids, can promote murine cutaneous wound healing probably resulting from the powerful angiogenic activity of the extracts.
引文
1.Graczyk TK, Knight R, Gilman RH, et al. The role of non-biting flies in the epidemiology of human infectious diseases. Microbes Infect. 2001,3(3):231-235.
2.Courtenay M, Church JC, Ryan TJ. Larva therapy in wound management. J R Soc Med. 2000; 93(2):72-4.
3.Baer WS. The treatment of chronic osteomyelitis with the maggot (larva of the blowfly). J Bone Joint Surg 1931;13-438-475.
4.李时珍.本草纲目.第二版.北京:人民卫生出版社. 2005.
5.赵其光.本草求原.广东:广东科技出版社. 2009.
6.张秉成.本草便读.上海:上海科学技术出版社. 1958.
7.黄宫秀.本草求真.上海:上海科学技术出版社. 1959.
8.中国医学科学院药物研究所等.中药志.北京:人民卫生出版社. 1979.
9.吉林医科大学第四临床学院.东北动物药.长春:吉林人民出版社. 1972.
10.邓明鲁.中国动物药.长春:吉林人民出版社. 1981.
11.Martin P. Wound healing– aiming for perfect skin regeneration. Science 1997;276:75–81.
12.Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med 1999;341:738–46.
13.王寿宇,吕德成,王江宁,等.蛆虫治疗糖尿病足溃疡的临床与实验研究.中国实用美容整形外科杂志2005,16:349-50.
14.王寿宇,张振,刁云鹏,等.活体五谷虫对压疮创面的生物清创技术研究.中华中医药学刊2010,28:741-3.
15.Wollina U, Karte K, Herold C, et al. Biosurgery in wound healing—the renaissance of maggot therapy. J Eur Acad Dermatol Venereol 2000;14:285-9.
16.Chambers L, Woodrow S, Brown AP, et al. Degradation of extracellular matrix components by defined proteinases from the greenbottle larva Lucilia sericata used for the clinical debridement of non-healing wounds. Br J Dermatol 2003;148:14-23.
17.Huberman L, Gollop N, Mumcuoglu KY, et al. Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata. Med Vet Entomol. 2007 ,21(2):127-131.
18.Bexfield A, Nigam Y, Thomas S, et al. Detection and partial characterisation of two antibacterial factors from the excretions/secretions of the medicinal maggot Lucilia sericata and their activity against methicillinresistant Staphylococcus aureus (MRSA). Microbes Infect 2004;6:1297-304.
19.Horobin AJ, Shakesheff KM, Pritchard DI. Promotion of human dermal fibroblast migration, matrix remodelling and modification of fibroblast morphology within a novel 3D model by Lucilia sericata larval secretions. J Invest Dermatol 2006;126:1410-8.
20.陈平,王明扬.皮肤病临床常用中药指南.北京:科学技术文献出版社. 2005.
21.申斗垣.外科启玄.北京:人民卫生出版社. 1955.
22.陶永富,戈隆阿弘.象形医学.昆明:云南民族出版社. 1996.
1.Baer WS: The treatment of chronic osteomyelitis with the maggot (larva of the blowfly). J Bone Joint Surg 1931,13:438-75.
2.Sherman RA: Maggot versus conservative debridement therapy for the treatment of pressure ulcer. Wound Repair Regen 2002,10:208-14.
3.Mumcuoglu KY, Ingber A, Gilead L, et al. Maggot therapy for the treatment of intractable wounds. Int J Dermatol 1999,38: 623-27.
4.Courtenay M, Church JC, Ryan TJ. Larva therapy in wound management. J R Soc Med 2000, 93:72-4.
5.Wang J, Wang S, Zhao G, et al. Treatment of infected wounds with maggot therapy after replantation. J Reconstr Microsurg 2006;22:277-80.
6.王寿宇,吕德成,王江宁,等.蛆虫治疗糖尿病足溃疡的临床与实验研究.中国实用美容整形外科杂志2005,16:349-50.
7.王寿宇,张振,刁云鹏,等.活体五谷虫对压疮创面的生物清创技术研究.中华中医药学刊2010,28:741-3.
8.Dinman S. Medical maggots. Plast Surg Nurs 2007, 27:212–4.
9.Chan DC, Fong DH, Leung JY, et al. Maggot debridement therapy in chronic wound care. Hong Kong Med J 2007, 13:382–6.
10.Kerridge A, Lappin-Scott H, Stevens JR. Antibacterial properties of larval secretions of the blowfly, Lucilia sericata. Med Vet Entomol 2005, 9:333–7.
11.Huberman L, Gollop N, Mumcuoglu KY, et al. Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata. Med Vet Entomol 2007, 21:127–31.
12.Hosgood G. Stages of wound healing and their clinical relevance. Vet Clin North Am Small Anim Pract 2006, 36:667–85.
13.Zheng ZZ, Liu ZX. Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates CD151-induced endothelial cell proliferation and cell migration. Int J Biochem Cell Biol 2007, 39:340–8.
14.Gentilini D, Busacca M, Di Francesco S, et al. PI3K/Akt and ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17beta-estradiol and growth factors. Mol Hum Reprod 2007,13:317–22.
15.Jiang Q, Zhou C, Bi Z, et al. EGF-induced cell migration is mediated by ERK and PI3K/AKT pathways in cultured human lens epithelial cells. J Ocul Pharmacol Ther 2006,22:93–102.
16.Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007,129:1261–74.
17.Somanath PR, Razorenova OV, Chen J, et al. Akt1 in endothelial cell and angiogenesis. Cell Cycle 2006,5:512–8.
18.Goren I, Muller E, Schiefelbein D, et al. Akt1 controls insulin-driven VEGF biosynthesis from keratinocytes: implications for normal and diabetes-impaired skin repair in mice. J Invest Dermatol 2009,129:529–31.
19.Mizutani K, Ito H, Iwamoto I, et al. Essential roles of ERK-mediated phosphorylation of vinexin in cell spreading, migration and anchorage-independent growth. Oncogene 2007, 26:7122–31.
20.Ray RM, Vaidya RJ, Johnson LR. MEK/ERK regulates adheres junctions and migration through Rac1. Cell Motil Cytoskeleton 2007,64:143–56.
21.Cheng B, Liu HW, Fu XB, et al. Recombinant human platelet-derived growth factor enhanced dermal wound healing by a pathway involving ERK and c-fos in diabetic rats. J Dermatol Sci 2007,45:193–201.
22.Smith AG, Powis RA, Pritchard DI, et al. Green-bottle (Lucilia sericata) larval secretions delivered from a prototype hydrogel wound dressing accelerate the closure of model wounds. Biotechnol Prog 2006,2:1690–6.
23.Horobin AJ, Shakesheff KM, Pritchard DI . Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon the migration of human dermal fibroblasts over a fibronectin-coated surface. Wound Repair Regen 2005,13:422–33.
24.Chambers L, Woodrow S, Brown AP, et al. Degradation of extracellular matrix components by defined proteinases from the greenbottle larva Lucilia sericata used for the clinical debridement of non-healing wounds. Br J Dermatol 2003;148:14-23.
25.Bexfield A, Nigam Y, Thomas S, et al. Detection and partial characterisation of two antibacterial factors from the excretions/secretions of the medicinal maggot Lucilia sericata and their activity against methicillinresistant Staphylococcus aureus (MRSA). Microbes Infect 2004;6:1297-304.
26.Eming SA, Brachvogel B, Odorisio T, et al. Regulation of angiogenesis: wound healing as a model. Prog Histochem Cytochem 2007,42:115–70.
27.Menke MN, Menke NB, Boardman CH, et al. Biologic therapeutics and molecular profiling to optimize wound healing. Gynecol Oncol 2008, 111:S87–S91.
28.Krauss G. Biochemistry of signal transduction and regulation, third edition. Wiley-VCH 2003, 187-9.
29.Chong H, Vikis HG, Guan KL. Mechanisms of regulating the Raf kinase family. Cell Signal 2003,
15:463-9.
30.Hagemann C, Blank JL. The ups and downs of MEK kinase interactions. Cell Signal 2001, 13:863-75.
1.Engin C, Demirkan F, Ayhan S, et al. Delayed effect of denervation on wound contraction in rat skin. Plast Reconstr Surg. 1996; 98(6): 1063-7.
2.Liu M, Warn JD, Fan Q, et al. Relationships between nerves and myofibroblasts during cutaneous wound healing in the developing rat. Cell Tissue Res. 1999; 297(3): 423-33.
3.Kishimoto S, Maruo M, Ohse C, et al. The regeneration of the sympathetic catecholaminergic nerve fibers in the process of burn wound healing in guinea pigs. J Invest Dermatol. 1982; 79(3): 141-6.
4.Atkins S, Smith KG, Loescher AR, et al. Scarring impedes regeneration at sites of peripheral nerve repair. Neuroreport. 2006;17(12):1245-9.
5.Imaizumi T, Akita S, Akino K, et al. Acceleration of sensory neural regeneration and wound healing with human mesenchymal stem cells in immunodeficient rats. Stem Cells. 2007; 25(11):2956-63.
6.Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001; 9(4):513-21.
7.Peters EM, Ericson ME, Hosoi J, et al. Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol. 2006; 126(9):1937-47.
8.Delgado AV, McManus AT, Chambers JP. Exogenous administration of Substance P enhances wound healing in a novel skin-injury model. Exp Biol Med. 2005; 230(4):271-80.
9.Dallos A, Kiss M, Polyánka H, et al. Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides. 2006; 40(4):251-63.
10.Rook JM, Hasan W, McCarson KE. Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. .Biochem Pharmacol. 2009; 77(11):1747-55.
11.Rook JM, Hasan W, McCarson KE. Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology 2008; 109(1):130-6.
12.Scott JR, Muangman P, Gibran NS. Making sense of hypertrophic scar: a role for nerves. Wound Repair Regen 2008; 16(4):582.
13.Thompson RJ, Doran JF, Jackson P, et al. PGP9.5-a new marker for vertebrate neurons and neuroendocrine cells. Brain Res. l983, 278: 224-8.
14.Taylor AM, Peleshok JC, Ribeiro-da-Silva A. Distribution of P2X(3)-immunoreactive fibers inhairy and glabrous skin of the rat. J Comp Neurol 2009; 514(6):555-66.
15.Furukawa M, Shimoda H, Kajiwara T, et al. Topographic study on nerve-associated lymphatic vessels in the murine craniofacial region by immunohistochemistry and electron microscopy. Biomed Res, 2008; 29(6):289-96.
16.Brewer KL, Lee JW, Downs H, et al, Dermatomal scratching after intramedullary quisqualate injection: correlation with cutaneous denervation. J Pain 2008; 9(11):999-1005.
17.Maddison B, Namazi MR, Samuel LS, et al. Unexpected diminished innervation of epidermis and dermoepidermal junction in lichen amyloidosus. Br J Dermatol. 2008;159(2):403-6.
18.Mumcuoglu KY, Ingber A, Gilead L, et al. Maggot therapy for the treatment of diabetic foot ulcers. Diabetes Care 1998,21(11):2030-31.
19.Sherman RA. Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy. Diabetes Care 2003,26(2):446-51.
20.Mumcuoglu KY, Ingber A, Gilead L, et al. Maggot therapy for the treatment of intractable wounds. Int J Dermatol. 1999;38(8):623-627.
21.Sherman RA. Maggot versus conservative debridement therapy for the treatment of pressure ulcers. Wound Repair Regen. 2002; 10(4):208-14. PMID: 12191002
22.Chan DC, Fong DH, Leung JY, et al. Maggot debridement therapy in chronic wound care. Hong Kong Med J. 2007,13(5):382-6.
23.Nuesch R, Rahm G, Rudin W, et al. Clustering of bloodstream infections during maggot debridement therapy using contaminated larvae of Protophormia terraenovae. Infection. 2002; 30(5): 306-9.
24.The Ministry of Science and Technology of the People’s Republic of China. Guidance suggestion of caring laboratory animals.2006-09-30.
25.Batchelor PE, Wills TE, Hewa AP, et al. Stimulation of axonal sprouting by trophic factors immobilized within the wound core. Brain Res. 2008; 1209:49-56.
26.Kishi K, Ohyama K, Satoh H, et al. Mutual dependence of murine fetal cutaneous regeneration and peripheral nerve regeneration. Wound Repair Regen.2006;14(1):91-9.
27.Gantus MA, Nasciutti LE, Cruz CM, et al. Modulation of extracellular matrix components by metalloproteinases and their tissue inhibitors during degeneration and regeneration of rat sural nerve. Brain Res. 2006;1122:36-46.
28.Zhang WG, Lv DC, Wang SY, et al. Effects of tacrolimus (FK506) on sciatic nerve regeneration in rats. Neural Regen Res. 2009; 4(5), 333-8.
29.Duchossoy Y, Horvat JC, Stettler O. MMP-related gelatinase activity is strongly induced in scar tissue of injured adult spinal cord and forms pathways for ingrowing neurites. Mol Cell Neurosci.2001;17(6):945-56.
30.Yu CQ, Zhang M, Matis KI, et al. Vascular endothelial growth factor mediates corneal nerve repair. Invest Ophthalmol Vis Sci. 2008;49(9):3870-8.
31.Ansel JC, Kaynard AH, Armstrong CA, et al. Skin-nervous system interactions. J Invest Dermatol. 1996;106(1):198-204.
32.Oudega M. Schwann cell and olfactory ensheathing cell implantation for repair of the contused spinal cord. Acta Physiol (Oxf). 2007; 189(2):181-9.
1.Martin P. Wound healing–aiming for perfect skin regeneration. Science 1997, 276:75-81.
2.Singer AJ, Clark RA. Cutaneous wound healing. New Engl J Med 1999, 341:738-46.
3.Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukocyte Biol 2001, 69:513-21.
4.Peters EM, Ericson ME, Hosoi J, et al. Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol 2006, 126:1937-47.
5.Carmeliet P. Angiogenesis in health and disease. Nat Med 2003, 9:653-60.
6.Bluff JE, O’Ceallaigh S, O’Kane S, et al. The microcirculation in acute murine cutaneous incisional wounds shows a spatial and temporal variation in the functionality of vessels. Wound Repair Regen 2006, 14:434-42.
7.Risau W. Mechanisms of angiogenesis. Nature 1997, 386:671-4.
8.Velazquez OC. Angiogenesis and vasculogenesis: inducing the growth of new blood vessels and wound healing by stimulation of bone marrow derived progenitor cell mobilization and homing. J Vasc Surg 2007, 45(Suppl A):39-47.
9.Sen CK, Khanna S, Babior BM, et al. Oxidant-induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J Biol Chem 2002, 277:33284-90.
10.Galiano RD, Tepper OM, Pelo CR, et al. Topical VEGF accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrowderived cells. Am J Pathol 2004,164:1935–47.
11.Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005, 437:497–504.
12.Frank S, Hubner G, Breier G, et al. Regulation of VEGF expression in cultured keratinocytes. J Biol Chem 1995, 270:12607–13.
13.Sellmayer A, Hrboticky N, Weber PC. Lipids in vascular function. Lipids 1999, 34:13-8.
14.Cardoso CR, Souza MA, Ferro EA, et al. Influence of topical administration of n-3 and n-6 essential and n-9 nonessential fatty acids on the healing of cutaneous wounds. Wound Repair Regen 2004, 12:235-43.
15.Ruthig DJ, Meckling-Gill KA. Both (n-3) and (n-6) fatty acids stimulate wound healing in the rat intestinal epithelial cell line, IEC-6. J Nutr 1999, 129:1791-8.
16.Simonetti O, Cirioni O, Goteri G, et al. Temporin A is effective in MRSA-infected wounds through bactericidal activity and acceleration of wound repair in a murine model. Peptides 2008,29:520-8.
17.Clària J. Regulation of cell proliferation and apoptosis by bioactive lipid mediators. Recent Pat Anti-Canc 2006, 1:369-82.
18.Medhora M, Dhanasekaran A, Gruenloh SK, et al. Emerging mechanisms for growth and protection of the vasculature by cytochrome P450-derived products of arachidonic acid and other eicosanoids. Prostag Oth Lipid M 2007, 82:1-4.
19.Savla U, Appel HJ, Sporn PH, et al. Prostaglandin E(2) regulates wound closure in airway epithelium. Am J Physiol-Lung C 2001, 280: L421-31.
20.Pozzi A, Macias-Perez I, Abair T, et al. Characterization of 5,6- and 8,9-epoxyeicosatrienoic acids (5,6- and 8,9-EET) as potent in vivo angiogenic lipids. J Biol Chem 2005, 280:27138-46.
21.Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 1974, 52:741-4.
22.Pattanayak SP, Sunita P. Wound healing, anti-microbial and antioxidant potential of Dendrophthoe falcata (L.f) Ettingsh. J Ethnopharmacol 2008, 120:241-7.
23.Khanna S, Roy S, Bagchi D, et al. Upregulation of oxidantinduced VEGFA expression in cultured keratinocytes by a grape seed proanthocyanidin extract. Free Radical Bio Med 2001, 31:38-42.
24.Cho M, Hunt TK, Hussain MZ. Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release. Am J Physiol-Heart C 2001, 280: H2357-63.
25.Chandrakasan G, Bhatnagar RS. Stimulation of collagen synthesis in fibroblast cultures by superoxide. Cell Mo Biol 1991, 37:751-5.
26.Houghton PJ, Hylands PJ, Mensahb AY, et al. In vitro tests and ethnopharmacological investigations: wound healing as an example. J Ethnopharmacol 2005, 100:100-7.
27.Srinivas RB, Kiran KR, Naidu VG, et al. Evaluation of antimicrobial, antioxidant and wound-healing potentials of Holoptelea integrifolia. J Ethnopharmacol 2007, 115:249-56.
28.Sun D, McCrae KR. Endothelial-cell apoptosis induced by cleaved highmolecular-weight kininogen (HKa) is matrix dependent and requires the generation of reactive oxygen species. Blood 2006, 107:4714-20.
29.杜冠华.中药复方有效成分组学研究.中成药2002, 24:78-880.
1.Martin P. Wound healing– aiming for perfect skin regeneration. Science 1997;276:75–81.
2.Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med 1999;341:738–46.
3.Szpaderska A, Egozi EI, Gamelli RL, et al. The effect of thrombocytopenia on dermal wound healing. J Invest Dermatol 2003;120:1130–7.
4.Simpson DM, Ross R. The neutrophilic leukocyte in wound repair. A study with antineutrophil serum. J Clin Invest 1972;51:2009–23.
5.Leibovich SJ, Ross R. The role of the macrophage in wound repair. Am J Pathol 1975;78:71–100.
6.Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 2005;15:599–607.
7.Eming SA, Krieg T, Davidson JM. Inflammation in tissue repair: molecular and cellular mechanisms. J Invest Dermatol 2007;127:514–25.
8.Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989;320:365–76.
9.Schruefer R, Sulyok S, Schymeinsky J, et al. The proangiogenic capacity of PMN delineated by microarray technique and by measurement of neovascularisation in wounded skin of CD-18-deficient mice. J Vasc Res 2006;43:1–11.
10.Ohki Y, Heissig B, Sato Y, et al. G-CSF promotes neovascularization by releasing VEGF from neutrophils. FASEB J 2005;19:739–50.
11.Ancelin M, Chollet-Martin S, Herve M, et al. VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism. Lab Invest 2004;84:502–12.
12.DiPietro LA, Burdick M, Low Q, et al. MIP-1a as critical macrophage chemoattractant in murine wound repair. J Clin Invest 1998;101:1693–8.
13.Wetzler C, Kampfer H, Stallmeyer B, et al. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol 2000; 115:245–53.
14.Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003;83: 835–70.
15.Gordon S. Alternative activation of macrophages. Nat Rev 2003;3:23–35.
16.Ramanathan M, Giladi A, Leibovich SJ. Regulation of VEGF gene expression in murine macrophages vy nitric oxide and hypoxia. Exp Biol Med 2003;228:697–705.
17.Pinhal-Enfield G, Ramanathan M, Hasko G, et al. An angiogenid switch in macrophages involving synergy between TLR 2, 4, 7, and 9 and adenosine A2A receptors. Am J Pathol2003;163:711–21.
18.Polverini P, Cotran RS, Gimbrone MA, et al. Activated macrophages induce vascular proliferation. Nature 1977;269:804–6.
19.Crowther M, Brown NJ, Bishop ET, et al. Microenviromental influence on macrophage regulation of angiogenesis in wounds and malignat tumors. J Leukoc Biol 2001;70:478–90.
20.Martin P, D’Souza D, Martin J, Grose R, Cooper L, Maki R, et al. Wound healing in the PU.1 null mouse tissue repair is not dependent on inflammatory cells. Curr Biol 2003;13:1122–8.
21.Reed Ja, Albino AP, McNutt NS. Human cutaneous mast cells express bFGF. Lab Invest 1995;72:215–22.
22.Blair RJ, Meng H, Marchese MJ, et al. Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. J Clin Invest 1997;99: 2691–700.
23.Grutzkau A, Kruger-Krasakages S, Baumeister H, et al. Synthesis storage and release of VEGF by human mast cell: implications for the biological significance of VEGF206. Mol Biol Cell 1998;9:875–84.
24.Trautmann A, Toksoy A, Engelhardt E, et al. Mast cell involvement in normal human skin wound healing: expression of MCP-1 is correlated with recruitment of mast cells which synthesize IL-4 in vivo. J Pathol 2000;190:100–6.
25.Egozi EI, Ferreira AM, Burns AL, et al. Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Rep Reg 2003;11:46–54.
26.Iba Y, Shibata A, Kato M, et al. Possible involvement of mast cells in collagen remodelling in the late phase of cutaneous wound healing in mice. Int Immunopharmacol 2004;4:1873–80.
27.Weller K, Foitzik K, Paus R, et al. Mast cells are required for normal wound healing of skin wound in mice. FASEB J 2006;20(13):2366–8.
28.Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechanoregulation of connective tissue remodeling. Nat Rev 2002;3:349–63.
29.Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007;127: 526–37.
30.Smola H, Thiekotter G, Fusenig NE. Mutual induction of growth factor gene expression by epidermal–dermal cell interaction. J Cell Biol 1993;122:417–29.
31.Smola H, Stark HJ, Thiekotter G, et al. Dynamics of basement membrane formation by keratinocyte–fibroblast interactions in organotypic skin culture. Exp Cell Res 1998;239:399–410.
32.Desmouliere A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995;146:56–66.
33.Polverini P, DiPietro LA, Dixit VM, et al. Thrombospondin-1 knock out mice show delayed organization and prolonged neovascularization of skin wounds. FASEB J 1995;9:A272.
34.Streit M, Velasco P, Piccardi L, et al. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J 2000;19:3272–82.
35.Przybylski M. A review of the current research on the role of bFGF and VEGF in angiogenesis.J Wound Care 2009;18(12):516-9.
36.Dvorak HF. Angiogenesis. Update 2005. J Thromb Haemost 2005;3:1835–42.
37.Barrientos S, Stojadinovic O, Golinko MS, et al. Growth factors and cytokines in wound healing. Wound Repair Regen 2008;16(5):585-601.
38.Poschl E, Schlotzer-Schrehardt U, Brachvogel B, et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 2004;131:1619–28.
39.Yurchenco PD, Amenta PS, Patton BL. Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol 2004;22:521–38.
40.Roy R, Zhang B, Moses MA. Making the cut: protease-mediated regulation of angiogenesis. Exp Cell Res 2006;312:608–22.
41.Reyes M, Dudek A, Jahagirdar B, et al. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002;109(3):337–46.
42.Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999;5(4):434–8.
43.Velazquez OC. Angiogenesis & Vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow derived progenitor cell mobilization and homing. J Vasc Surg 2007; 45(Suppl A): A39–A47.
44.Nakamura Y, Tajima F, Ishiga K, et al. Soluble c-kit receptor mobilizes hematopoietic stem cells to peripheral blood in mice. Exp Hematol 2004;32(4):390–6.
45.Rehman J, Li J, Parvathaneni L, et al. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. J Am Coll Cardiol 2004;43(12):2314–8.
46.Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9 (11):1370–6.
47.Aicher A, Zeiher AM, Dimmeler S. Mobilizing endothelial progenitor cells. Hypertension 2005;45 (3):321–5.
48.Reichman-Fried M, Minina S, Raz E. Autonomous modes of behavior in primordial germ cell migration. Dev Cell 2004;6(4):589–96.
49.Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004;10(8):858–64.
50.Gallagher KA, Liu ZJ, Xiao M, et al. Diabetic impairments in NO-mediated endothelial progenitor-cell mobilization and homing are reversed by hyperoxia and SDF-1α. J Clin Invest 2007;117(5):1219-22.
51.Ferrara N. VEGF: basic science and clinical progress. Endocrine Rev 2004;25:581–611.
52.Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor. Signalling–in control of vascular function. Nat Rev Mol Cell 2006;7:359–71.
53.Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascities fluid. Science 1983;219:983–5.
54.Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–8.
55.Tischer E, Mitchell R, Hartmann T, et al. The human gene for VEGF. J Biol Chem 1991;266:11947–54.
56.Keyt BA, Nguyen HV, Berleau LT, et al. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. J Biol Chem 1996; 271:5638–46.
57.Hutchings H, Ortega N, Plouet J. Extracellular matrix-bound VEGF promotes endothelial cell adhesion, migration, and survival through integrin ligation. FASEB J 2003;17:1520–2.
58.Dor Y, Djonov V, Abramovitch R, et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 2002;21:1939–47.
59.Ruhrberg C, Gerhardt H, Golding M, et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A morphogenesis. Gene Dev 2002;16:2684–98.
60.Brown LF, Yeo KT, Berse B, et al. Expression of VEGF by epidermal keratinocytes during wound healing. J Exp Med 1992;176:1375–9.
61.Pages G, Pouyssegur J. Transcriptional regulation of the VEGF gene–a concert of activating factors. Cardiovascular Res 2005;65:564–73.
62.Galiano RD, Tepper OM, Pelo CR, et al. Topical VEGF accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrowderived cells. Am J Pathol 2004;164:1935–47.
63.Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005;437:497–504.
64.Frank S, Hubner G, Breier G, et al. Regulation of VEGF expression in cultured keratinocytes. J Biol Chem 1995;270:12607–13.
65.Howdieshell TR, Callaway D, Webb WL, et al. Antibody neutralization of VEGF inhibitswound granulation tissue formation. J Surg Res 2001;96:173–82.
66.Corral CJ, Siddiqui A, Wu L, et al. VEGF is more important that bFGF during ischemic wound healing. Arch Surg 1999;134:200–5.
67.Roth D, Piekarek M, Christ H, et al. Plasmin modulates VEGF-A mediated angiogenesis during wound repair. Am J Pathol 2006;168:670–84.
68.Hong YK, Lange-Aschenfeld B, Velasco P, et al. VEGF-A tissue repair-associated lymphatic vessel formation via VEGFR-2 and the a1b1 andα2β1 integrins. FASEB J 2004;18:1111–3.
69.Grimmond S, Lagercrantz J, Drinkwater C, et al. Cloning and characterization of a novel human gene related to VEGF. Genome Res 1996;6:124–31.
70.Olofsson B, Pajusola K, von Euler G, et al. Genomic organization of the mouse and human genes for VEGF B and characterization of a second splice isoform. J Biol Chem 1996;271:19310–7.
71.Li X, Aase K, Li H, et al. Isoform-specific expression of VEGF-B in normal tissues and tumors. Growth Factors 2001;19:49–59.
72.Enholm B, Paavonen K, Ristimaki A, et al. Comparision of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997;14:2475–83.
73.Bellomo D, Headrick JP, Silions GU, et al. Micce lacking the VEGF-B-gene have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res 2000;86:E29–35.
74.Silvestre JS, Tamarat R, Ebrahimian TG, et al. VEGF-B promotes in vivo angiogenesis. Circ Res 2003;93:114–23.
75.Mould AW, Tonks ID, Cahill MM, et al. VEGFB gene knockout mice display reduced pathology and synovial anhiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis Rheum 2003;48:2660–9.
76.Trompezinski S, Berthier-Vergnes O, Denis A, et al. Comparative expression of VEGF family members, VEGF-B, -C and -D, normal human kertainocytes and fibroblasts. Exp Dermatol 2004;13:98–105.
77.Joukov V, Sorsa T, Kumar V, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 1997;16:3898–911.
78.McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med 2003;198:863–8.
79.Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423–5.
80.Witzenbichler B, Asahara T, Murohara T, et al. VEGF-C/VEGF-2 promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 1998;153:381–94.
81.Saaristro A, Tammela T, Farkkila A, et al. VEGF-C accelerates diabetic wound healing. Am J Pathol 2006;169:1080–7.
82.Paavonen K, Puolakkainen P, Jussilia L, et al. VEGFR-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;156:1499–504.
83.Ji RC, Miura M, Qu P, et al. Expression of VEGFR-3 and 50-nase in regenerating lymphatic vessels of the cutaneous wound healing. Microsc Res Technol 2004;64:279–86.
84.Baldwin ME, Catimel B, Nice EC, et al. The specificity of receptor binding by VEGF-D is different in mouse and man. J Biol Chem 2001;276:19166–71.
85.Ogawa S, Oku A, Sawano A, et al. A novel type of VEGF, VEGF-E, (NZ-7 VEGF), preferentially utilizes KDT/Flk-1 receptor and caries a potent mitogenic activity without heparin-binding domain. J Biol Chem 1998;273:31273–82.
86.Meyer M, Clauss M, Lepple-Wienhues A, et al. A novel VEGF encoded by Orf virus, VEGF-E, mediates angiogenesis via signaling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 1999;18:363–74.
87.Wise LM, Veikkola T, Mercer A, et al. VEGF-like protein from orf virus NZ2 binds to VEGFR-2 and neuropilin-1. Proc Natl Acad Sci 1999;96:3071–6.
88.Kiba A, Sagara H, Hara T, et al. VEGFR-2-specific ligand VEGF-E induces non-edematous hyper vascularization in mice. Biochem Biophys Res Commun 2003;301:371–7.
89.Wirzenius M, Tammela T, Uutela M, et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 2007;204(6):1431–40.
90.Zheng Y, Watanabe M, Kuraishi T, et al. Chimeric VEGF-ENZ7/PlGF specifically binding to VEGFR-2 accelerated skin wound healing via enhancement of neovascularization. Arterioscler Thromb Vasc Biol 2007;27:1–9.
91.Suto K, Yamazaki Y, Morita T, et al. Crystal structures of novel VEGFs from snake venoms. J Biol Chem 2005;280:2126–31.
92.Yamazaki Y, Takani K, Atoda H, et al. Snake venom VEGFs exhibit potent activity through their specific recognition of KDR. J Biol Chem 2003;278:51985–8.
93.Maglione D, Guerriero V, Viglietto G, et al. Isolation of human placenta cDNA coding for protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991;88: 9267–71.
94.Persico MG, Vincenti V, DiPalma T. Structure, expression and receptor-binding properties of PlGF. Curr Top Microbiol Immunol 1999;237:31–40.
95.De Falco S, Gigante B, Persico MG. Structure and function of PlGF. Trends CardiovascMed2002;12:241–6.
96.Maglione D, Guerriero V, Viglietto G, et al. Two alternative mRNAs coding for the angiogenic factor, PlGF, are transcribed form a single gene of chromosome 14. Oncogene 1993;8:925–31.
97.Cao Y, Ji WR, Qi P, et al. PlGF: identification and characterization of a novel isodorm generated by RNA alternative splicing. Biochem Biophys Res Commun 1997;235:493–8.
98.Yang W, Ahn H, Hinrichs M, et al. Evidence of a novel isoform of PlGF (PlGF-4) expressed in human trophoblast and endothelial cells. J Reprod Immunol 2003;60:53–60.
99.DiPalma T, Tucci M, Russo G, et al. The placenta growth factor gene of the mouse. Mamm Genome 1996;7:6–12.
100.Park JE, Chen HH, Winer J, et al. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994;269:25646–54.
101.Autiero M, Luttun A, Tjwa M, et al. PlGF and its receptor, VEGFR-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J ThromboHaemost 2003;1:1356–70.
102.DiSalvo J, Bayne ML, Conn G, et al. Purification and characterization of a naturally occurring vascular endothelial growth factor/placenta growth factor heterodimer. J Biol Chem 1995;270:7717–23.
103.Hattori K, Heissig B, Wu Y, et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone marrow microenviroment. Nat Med 2002;8:841–9.
104.Xu L, Cochran DM, Tong RT, et al. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res 2006;66:3971–7.
105.Carmeliet P, Moons L, Luttun A, et al. Synergism between VEGF and PIGF contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001;7:575–83.
106.Luttun A, Tjwa M, Moons L, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt-1. Nat Med 2002;8:831–40.
107.Nagy JA, Dvorak AM, Dvorak HF. VEGF-A 164/165 and PlGF. Roles in angiogenesis and arteriogenesis. Trends Cardiovasc Med 2003;13:169–75.
108.Tamarat R, Silvestre JS, Le Ricousse-Roussanne S, et al. Impairment in ischemia-induced neovascularization in diabetes. Bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. Am J Pathol 2004;164: 457–66.
109.Maes C, Coenegrachts L, Stockmans I, et al. Placental growth factor mediates mesenchymal celldevelopment, cartilage turnover, and bone remodeling during fracture repair. J Clin Invest 2006;116:1230–42.
110.Failla CM, Odorisio T, Cianfarani F, et al. PlGF is induced in human keratinocytes during wound healing. J Invest Dermatol 2000;115:388–95.
111.Cianfarani F, Zambruno G, Brogelli L, et al. PlGF in diabetic wound healing. Altered expression and therapeutic potential. Am J Pathol 2006;169:1167–82.
112.付小兵,王正国,吴祖泽.再生医学原理与实践.上海:上海科学技术出版社.2008
2.Courtenay M, Church JC, Ryan TJ. Larva therapy in wound management. J R Soc Med. 2000; 93(2):72-4.
3.Baer WS. The treatment of chronic osteomyelitis with the maggot (larva of the blowfly). J Bone Joint Surg 1931;13-438-475.
4.李时珍.本草纲目.第二版.北京:人民卫生出版社. 2005.
5.赵其光.本草求原.广东:广东科技出版社. 2009.
6.张秉成.本草便读.上海:上海科学技术出版社. 1958.
7.黄宫秀.本草求真.上海:上海科学技术出版社. 1959.
8.中国医学科学院药物研究所等.中药志.北京:人民卫生出版社. 1979.
9.吉林医科大学第四临床学院.东北动物药.长春:吉林人民出版社. 1972.
10.邓明鲁.中国动物药.长春:吉林人民出版社. 1981.
11.Martin P. Wound healing– aiming for perfect skin regeneration. Science 1997;276:75–81.
12.Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med 1999;341:738–46.
13.王寿宇,吕德成,王江宁,等.蛆虫治疗糖尿病足溃疡的临床与实验研究.中国实用美容整形外科杂志2005,16:349-50.
14.王寿宇,张振,刁云鹏,等.活体五谷虫对压疮创面的生物清创技术研究.中华中医药学刊2010,28:741-3.
15.Wollina U, Karte K, Herold C, et al. Biosurgery in wound healing—the renaissance of maggot therapy. J Eur Acad Dermatol Venereol 2000;14:285-9.
16.Chambers L, Woodrow S, Brown AP, et al. Degradation of extracellular matrix components by defined proteinases from the greenbottle larva Lucilia sericata used for the clinical debridement of non-healing wounds. Br J Dermatol 2003;148:14-23.
17.Huberman L, Gollop N, Mumcuoglu KY, et al. Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata. Med Vet Entomol. 2007 ,21(2):127-131.
18.Bexfield A, Nigam Y, Thomas S, et al. Detection and partial characterisation of two antibacterial factors from the excretions/secretions of the medicinal maggot Lucilia sericata and their activity against methicillinresistant Staphylococcus aureus (MRSA). Microbes Infect 2004;6:1297-304.
19.Horobin AJ, Shakesheff KM, Pritchard DI. Promotion of human dermal fibroblast migration, matrix remodelling and modification of fibroblast morphology within a novel 3D model by Lucilia sericata larval secretions. J Invest Dermatol 2006;126:1410-8.
20.陈平,王明扬.皮肤病临床常用中药指南.北京:科学技术文献出版社. 2005.
21.申斗垣.外科启玄.北京:人民卫生出版社. 1955.
22.陶永富,戈隆阿弘.象形医学.昆明:云南民族出版社. 1996.
1.Baer WS: The treatment of chronic osteomyelitis with the maggot (larva of the blowfly). J Bone Joint Surg 1931,13:438-75.
2.Sherman RA: Maggot versus conservative debridement therapy for the treatment of pressure ulcer. Wound Repair Regen 2002,10:208-14.
3.Mumcuoglu KY, Ingber A, Gilead L, et al. Maggot therapy for the treatment of intractable wounds. Int J Dermatol 1999,38: 623-27.
4.Courtenay M, Church JC, Ryan TJ. Larva therapy in wound management. J R Soc Med 2000, 93:72-4.
5.Wang J, Wang S, Zhao G, et al. Treatment of infected wounds with maggot therapy after replantation. J Reconstr Microsurg 2006;22:277-80.
6.王寿宇,吕德成,王江宁,等.蛆虫治疗糖尿病足溃疡的临床与实验研究.中国实用美容整形外科杂志2005,16:349-50.
7.王寿宇,张振,刁云鹏,等.活体五谷虫对压疮创面的生物清创技术研究.中华中医药学刊2010,28:741-3.
8.Dinman S. Medical maggots. Plast Surg Nurs 2007, 27:212–4.
9.Chan DC, Fong DH, Leung JY, et al. Maggot debridement therapy in chronic wound care. Hong Kong Med J 2007, 13:382–6.
10.Kerridge A, Lappin-Scott H, Stevens JR. Antibacterial properties of larval secretions of the blowfly, Lucilia sericata. Med Vet Entomol 2005, 9:333–7.
11.Huberman L, Gollop N, Mumcuoglu KY, et al. Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata. Med Vet Entomol 2007, 21:127–31.
12.Hosgood G. Stages of wound healing and their clinical relevance. Vet Clin North Am Small Anim Pract 2006, 36:667–85.
13.Zheng ZZ, Liu ZX. Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates CD151-induced endothelial cell proliferation and cell migration. Int J Biochem Cell Biol 2007, 39:340–8.
14.Gentilini D, Busacca M, Di Francesco S, et al. PI3K/Akt and ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17beta-estradiol and growth factors. Mol Hum Reprod 2007,13:317–22.
15.Jiang Q, Zhou C, Bi Z, et al. EGF-induced cell migration is mediated by ERK and PI3K/AKT pathways in cultured human lens epithelial cells. J Ocul Pharmacol Ther 2006,22:93–102.
16.Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007,129:1261–74.
17.Somanath PR, Razorenova OV, Chen J, et al. Akt1 in endothelial cell and angiogenesis. Cell Cycle 2006,5:512–8.
18.Goren I, Muller E, Schiefelbein D, et al. Akt1 controls insulin-driven VEGF biosynthesis from keratinocytes: implications for normal and diabetes-impaired skin repair in mice. J Invest Dermatol 2009,129:529–31.
19.Mizutani K, Ito H, Iwamoto I, et al. Essential roles of ERK-mediated phosphorylation of vinexin in cell spreading, migration and anchorage-independent growth. Oncogene 2007, 26:7122–31.
20.Ray RM, Vaidya RJ, Johnson LR. MEK/ERK regulates adheres junctions and migration through Rac1. Cell Motil Cytoskeleton 2007,64:143–56.
21.Cheng B, Liu HW, Fu XB, et al. Recombinant human platelet-derived growth factor enhanced dermal wound healing by a pathway involving ERK and c-fos in diabetic rats. J Dermatol Sci 2007,45:193–201.
22.Smith AG, Powis RA, Pritchard DI, et al. Green-bottle (Lucilia sericata) larval secretions delivered from a prototype hydrogel wound dressing accelerate the closure of model wounds. Biotechnol Prog 2006,2:1690–6.
23.Horobin AJ, Shakesheff KM, Pritchard DI . Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon the migration of human dermal fibroblasts over a fibronectin-coated surface. Wound Repair Regen 2005,13:422–33.
24.Chambers L, Woodrow S, Brown AP, et al. Degradation of extracellular matrix components by defined proteinases from the greenbottle larva Lucilia sericata used for the clinical debridement of non-healing wounds. Br J Dermatol 2003;148:14-23.
25.Bexfield A, Nigam Y, Thomas S, et al. Detection and partial characterisation of two antibacterial factors from the excretions/secretions of the medicinal maggot Lucilia sericata and their activity against methicillinresistant Staphylococcus aureus (MRSA). Microbes Infect 2004;6:1297-304.
26.Eming SA, Brachvogel B, Odorisio T, et al. Regulation of angiogenesis: wound healing as a model. Prog Histochem Cytochem 2007,42:115–70.
27.Menke MN, Menke NB, Boardman CH, et al. Biologic therapeutics and molecular profiling to optimize wound healing. Gynecol Oncol 2008, 111:S87–S91.
28.Krauss G. Biochemistry of signal transduction and regulation, third edition. Wiley-VCH 2003, 187-9.
29.Chong H, Vikis HG, Guan KL. Mechanisms of regulating the Raf kinase family. Cell Signal 2003,
15:463-9.
30.Hagemann C, Blank JL. The ups and downs of MEK kinase interactions. Cell Signal 2001, 13:863-75.
1.Engin C, Demirkan F, Ayhan S, et al. Delayed effect of denervation on wound contraction in rat skin. Plast Reconstr Surg. 1996; 98(6): 1063-7.
2.Liu M, Warn JD, Fan Q, et al. Relationships between nerves and myofibroblasts during cutaneous wound healing in the developing rat. Cell Tissue Res. 1999; 297(3): 423-33.
3.Kishimoto S, Maruo M, Ohse C, et al. The regeneration of the sympathetic catecholaminergic nerve fibers in the process of burn wound healing in guinea pigs. J Invest Dermatol. 1982; 79(3): 141-6.
4.Atkins S, Smith KG, Loescher AR, et al. Scarring impedes regeneration at sites of peripheral nerve repair. Neuroreport. 2006;17(12):1245-9.
5.Imaizumi T, Akita S, Akino K, et al. Acceleration of sensory neural regeneration and wound healing with human mesenchymal stem cells in immunodeficient rats. Stem Cells. 2007; 25(11):2956-63.
6.Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001; 9(4):513-21.
7.Peters EM, Ericson ME, Hosoi J, et al. Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol. 2006; 126(9):1937-47.
8.Delgado AV, McManus AT, Chambers JP. Exogenous administration of Substance P enhances wound healing in a novel skin-injury model. Exp Biol Med. 2005; 230(4):271-80.
9.Dallos A, Kiss M, Polyánka H, et al. Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides. 2006; 40(4):251-63.
10.Rook JM, Hasan W, McCarson KE. Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. .Biochem Pharmacol. 2009; 77(11):1747-55.
11.Rook JM, Hasan W, McCarson KE. Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology 2008; 109(1):130-6.
12.Scott JR, Muangman P, Gibran NS. Making sense of hypertrophic scar: a role for nerves. Wound Repair Regen 2008; 16(4):582.
13.Thompson RJ, Doran JF, Jackson P, et al. PGP9.5-a new marker for vertebrate neurons and neuroendocrine cells. Brain Res. l983, 278: 224-8.
14.Taylor AM, Peleshok JC, Ribeiro-da-Silva A. Distribution of P2X(3)-immunoreactive fibers inhairy and glabrous skin of the rat. J Comp Neurol 2009; 514(6):555-66.
15.Furukawa M, Shimoda H, Kajiwara T, et al. Topographic study on nerve-associated lymphatic vessels in the murine craniofacial region by immunohistochemistry and electron microscopy. Biomed Res, 2008; 29(6):289-96.
16.Brewer KL, Lee JW, Downs H, et al, Dermatomal scratching after intramedullary quisqualate injection: correlation with cutaneous denervation. J Pain 2008; 9(11):999-1005.
17.Maddison B, Namazi MR, Samuel LS, et al. Unexpected diminished innervation of epidermis and dermoepidermal junction in lichen amyloidosus. Br J Dermatol. 2008;159(2):403-6.
18.Mumcuoglu KY, Ingber A, Gilead L, et al. Maggot therapy for the treatment of diabetic foot ulcers. Diabetes Care 1998,21(11):2030-31.
19.Sherman RA. Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy. Diabetes Care 2003,26(2):446-51.
20.Mumcuoglu KY, Ingber A, Gilead L, et al. Maggot therapy for the treatment of intractable wounds. Int J Dermatol. 1999;38(8):623-627.
21.Sherman RA. Maggot versus conservative debridement therapy for the treatment of pressure ulcers. Wound Repair Regen. 2002; 10(4):208-14. PMID: 12191002
22.Chan DC, Fong DH, Leung JY, et al. Maggot debridement therapy in chronic wound care. Hong Kong Med J. 2007,13(5):382-6.
23.Nuesch R, Rahm G, Rudin W, et al. Clustering of bloodstream infections during maggot debridement therapy using contaminated larvae of Protophormia terraenovae. Infection. 2002; 30(5): 306-9.
24.The Ministry of Science and Technology of the People’s Republic of China. Guidance suggestion of caring laboratory animals.2006-09-30.
25.Batchelor PE, Wills TE, Hewa AP, et al. Stimulation of axonal sprouting by trophic factors immobilized within the wound core. Brain Res. 2008; 1209:49-56.
26.Kishi K, Ohyama K, Satoh H, et al. Mutual dependence of murine fetal cutaneous regeneration and peripheral nerve regeneration. Wound Repair Regen.2006;14(1):91-9.
27.Gantus MA, Nasciutti LE, Cruz CM, et al. Modulation of extracellular matrix components by metalloproteinases and their tissue inhibitors during degeneration and regeneration of rat sural nerve. Brain Res. 2006;1122:36-46.
28.Zhang WG, Lv DC, Wang SY, et al. Effects of tacrolimus (FK506) on sciatic nerve regeneration in rats. Neural Regen Res. 2009; 4(5), 333-8.
29.Duchossoy Y, Horvat JC, Stettler O. MMP-related gelatinase activity is strongly induced in scar tissue of injured adult spinal cord and forms pathways for ingrowing neurites. Mol Cell Neurosci.2001;17(6):945-56.
30.Yu CQ, Zhang M, Matis KI, et al. Vascular endothelial growth factor mediates corneal nerve repair. Invest Ophthalmol Vis Sci. 2008;49(9):3870-8.
31.Ansel JC, Kaynard AH, Armstrong CA, et al. Skin-nervous system interactions. J Invest Dermatol. 1996;106(1):198-204.
32.Oudega M. Schwann cell and olfactory ensheathing cell implantation for repair of the contused spinal cord. Acta Physiol (Oxf). 2007; 189(2):181-9.
1.Martin P. Wound healing–aiming for perfect skin regeneration. Science 1997, 276:75-81.
2.Singer AJ, Clark RA. Cutaneous wound healing. New Engl J Med 1999, 341:738-46.
3.Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukocyte Biol 2001, 69:513-21.
4.Peters EM, Ericson ME, Hosoi J, et al. Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol 2006, 126:1937-47.
5.Carmeliet P. Angiogenesis in health and disease. Nat Med 2003, 9:653-60.
6.Bluff JE, O’Ceallaigh S, O’Kane S, et al. The microcirculation in acute murine cutaneous incisional wounds shows a spatial and temporal variation in the functionality of vessels. Wound Repair Regen 2006, 14:434-42.
7.Risau W. Mechanisms of angiogenesis. Nature 1997, 386:671-4.
8.Velazquez OC. Angiogenesis and vasculogenesis: inducing the growth of new blood vessels and wound healing by stimulation of bone marrow derived progenitor cell mobilization and homing. J Vasc Surg 2007, 45(Suppl A):39-47.
9.Sen CK, Khanna S, Babior BM, et al. Oxidant-induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J Biol Chem 2002, 277:33284-90.
10.Galiano RD, Tepper OM, Pelo CR, et al. Topical VEGF accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrowderived cells. Am J Pathol 2004,164:1935–47.
11.Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005, 437:497–504.
12.Frank S, Hubner G, Breier G, et al. Regulation of VEGF expression in cultured keratinocytes. J Biol Chem 1995, 270:12607–13.
13.Sellmayer A, Hrboticky N, Weber PC. Lipids in vascular function. Lipids 1999, 34:13-8.
14.Cardoso CR, Souza MA, Ferro EA, et al. Influence of topical administration of n-3 and n-6 essential and n-9 nonessential fatty acids on the healing of cutaneous wounds. Wound Repair Regen 2004, 12:235-43.
15.Ruthig DJ, Meckling-Gill KA. Both (n-3) and (n-6) fatty acids stimulate wound healing in the rat intestinal epithelial cell line, IEC-6. J Nutr 1999, 129:1791-8.
16.Simonetti O, Cirioni O, Goteri G, et al. Temporin A is effective in MRSA-infected wounds through bactericidal activity and acceleration of wound repair in a murine model. Peptides 2008,29:520-8.
17.Clària J. Regulation of cell proliferation and apoptosis by bioactive lipid mediators. Recent Pat Anti-Canc 2006, 1:369-82.
18.Medhora M, Dhanasekaran A, Gruenloh SK, et al. Emerging mechanisms for growth and protection of the vasculature by cytochrome P450-derived products of arachidonic acid and other eicosanoids. Prostag Oth Lipid M 2007, 82:1-4.
19.Savla U, Appel HJ, Sporn PH, et al. Prostaglandin E(2) regulates wound closure in airway epithelium. Am J Physiol-Lung C 2001, 280: L421-31.
20.Pozzi A, Macias-Perez I, Abair T, et al. Characterization of 5,6- and 8,9-epoxyeicosatrienoic acids (5,6- and 8,9-EET) as potent in vivo angiogenic lipids. J Biol Chem 2005, 280:27138-46.
21.Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 1974, 52:741-4.
22.Pattanayak SP, Sunita P. Wound healing, anti-microbial and antioxidant potential of Dendrophthoe falcata (L.f) Ettingsh. J Ethnopharmacol 2008, 120:241-7.
23.Khanna S, Roy S, Bagchi D, et al. Upregulation of oxidantinduced VEGFA expression in cultured keratinocytes by a grape seed proanthocyanidin extract. Free Radical Bio Med 2001, 31:38-42.
24.Cho M, Hunt TK, Hussain MZ. Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release. Am J Physiol-Heart C 2001, 280: H2357-63.
25.Chandrakasan G, Bhatnagar RS. Stimulation of collagen synthesis in fibroblast cultures by superoxide. Cell Mo Biol 1991, 37:751-5.
26.Houghton PJ, Hylands PJ, Mensahb AY, et al. In vitro tests and ethnopharmacological investigations: wound healing as an example. J Ethnopharmacol 2005, 100:100-7.
27.Srinivas RB, Kiran KR, Naidu VG, et al. Evaluation of antimicrobial, antioxidant and wound-healing potentials of Holoptelea integrifolia. J Ethnopharmacol 2007, 115:249-56.
28.Sun D, McCrae KR. Endothelial-cell apoptosis induced by cleaved highmolecular-weight kininogen (HKa) is matrix dependent and requires the generation of reactive oxygen species. Blood 2006, 107:4714-20.
29.杜冠华.中药复方有效成分组学研究.中成药2002, 24:78-880.
1.Martin P. Wound healing– aiming for perfect skin regeneration. Science 1997;276:75–81.
2.Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med 1999;341:738–46.
3.Szpaderska A, Egozi EI, Gamelli RL, et al. The effect of thrombocytopenia on dermal wound healing. J Invest Dermatol 2003;120:1130–7.
4.Simpson DM, Ross R. The neutrophilic leukocyte in wound repair. A study with antineutrophil serum. J Clin Invest 1972;51:2009–23.
5.Leibovich SJ, Ross R. The role of the macrophage in wound repair. Am J Pathol 1975;78:71–100.
6.Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 2005;15:599–607.
7.Eming SA, Krieg T, Davidson JM. Inflammation in tissue repair: molecular and cellular mechanisms. J Invest Dermatol 2007;127:514–25.
8.Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989;320:365–76.
9.Schruefer R, Sulyok S, Schymeinsky J, et al. The proangiogenic capacity of PMN delineated by microarray technique and by measurement of neovascularisation in wounded skin of CD-18-deficient mice. J Vasc Res 2006;43:1–11.
10.Ohki Y, Heissig B, Sato Y, et al. G-CSF promotes neovascularization by releasing VEGF from neutrophils. FASEB J 2005;19:739–50.
11.Ancelin M, Chollet-Martin S, Herve M, et al. VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism. Lab Invest 2004;84:502–12.
12.DiPietro LA, Burdick M, Low Q, et al. MIP-1a as critical macrophage chemoattractant in murine wound repair. J Clin Invest 1998;101:1693–8.
13.Wetzler C, Kampfer H, Stallmeyer B, et al. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol 2000; 115:245–53.
14.Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003;83: 835–70.
15.Gordon S. Alternative activation of macrophages. Nat Rev 2003;3:23–35.
16.Ramanathan M, Giladi A, Leibovich SJ. Regulation of VEGF gene expression in murine macrophages vy nitric oxide and hypoxia. Exp Biol Med 2003;228:697–705.
17.Pinhal-Enfield G, Ramanathan M, Hasko G, et al. An angiogenid switch in macrophages involving synergy between TLR 2, 4, 7, and 9 and adenosine A2A receptors. Am J Pathol2003;163:711–21.
18.Polverini P, Cotran RS, Gimbrone MA, et al. Activated macrophages induce vascular proliferation. Nature 1977;269:804–6.
19.Crowther M, Brown NJ, Bishop ET, et al. Microenviromental influence on macrophage regulation of angiogenesis in wounds and malignat tumors. J Leukoc Biol 2001;70:478–90.
20.Martin P, D’Souza D, Martin J, Grose R, Cooper L, Maki R, et al. Wound healing in the PU.1 null mouse tissue repair is not dependent on inflammatory cells. Curr Biol 2003;13:1122–8.
21.Reed Ja, Albino AP, McNutt NS. Human cutaneous mast cells express bFGF. Lab Invest 1995;72:215–22.
22.Blair RJ, Meng H, Marchese MJ, et al. Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. J Clin Invest 1997;99: 2691–700.
23.Grutzkau A, Kruger-Krasakages S, Baumeister H, et al. Synthesis storage and release of VEGF by human mast cell: implications for the biological significance of VEGF206. Mol Biol Cell 1998;9:875–84.
24.Trautmann A, Toksoy A, Engelhardt E, et al. Mast cell involvement in normal human skin wound healing: expression of MCP-1 is correlated with recruitment of mast cells which synthesize IL-4 in vivo. J Pathol 2000;190:100–6.
25.Egozi EI, Ferreira AM, Burns AL, et al. Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Rep Reg 2003;11:46–54.
26.Iba Y, Shibata A, Kato M, et al. Possible involvement of mast cells in collagen remodelling in the late phase of cutaneous wound healing in mice. Int Immunopharmacol 2004;4:1873–80.
27.Weller K, Foitzik K, Paus R, et al. Mast cells are required for normal wound healing of skin wound in mice. FASEB J 2006;20(13):2366–8.
28.Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechanoregulation of connective tissue remodeling. Nat Rev 2002;3:349–63.
29.Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007;127: 526–37.
30.Smola H, Thiekotter G, Fusenig NE. Mutual induction of growth factor gene expression by epidermal–dermal cell interaction. J Cell Biol 1993;122:417–29.
31.Smola H, Stark HJ, Thiekotter G, et al. Dynamics of basement membrane formation by keratinocyte–fibroblast interactions in organotypic skin culture. Exp Cell Res 1998;239:399–410.
32.Desmouliere A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995;146:56–66.
33.Polverini P, DiPietro LA, Dixit VM, et al. Thrombospondin-1 knock out mice show delayed organization and prolonged neovascularization of skin wounds. FASEB J 1995;9:A272.
34.Streit M, Velasco P, Piccardi L, et al. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J 2000;19:3272–82.
35.Przybylski M. A review of the current research on the role of bFGF and VEGF in angiogenesis.J Wound Care 2009;18(12):516-9.
36.Dvorak HF. Angiogenesis. Update 2005. J Thromb Haemost 2005;3:1835–42.
37.Barrientos S, Stojadinovic O, Golinko MS, et al. Growth factors and cytokines in wound healing. Wound Repair Regen 2008;16(5):585-601.
38.Poschl E, Schlotzer-Schrehardt U, Brachvogel B, et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 2004;131:1619–28.
39.Yurchenco PD, Amenta PS, Patton BL. Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol 2004;22:521–38.
40.Roy R, Zhang B, Moses MA. Making the cut: protease-mediated regulation of angiogenesis. Exp Cell Res 2006;312:608–22.
41.Reyes M, Dudek A, Jahagirdar B, et al. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002;109(3):337–46.
42.Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999;5(4):434–8.
43.Velazquez OC. Angiogenesis & Vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow derived progenitor cell mobilization and homing. J Vasc Surg 2007; 45(Suppl A): A39–A47.
44.Nakamura Y, Tajima F, Ishiga K, et al. Soluble c-kit receptor mobilizes hematopoietic stem cells to peripheral blood in mice. Exp Hematol 2004;32(4):390–6.
45.Rehman J, Li J, Parvathaneni L, et al. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. J Am Coll Cardiol 2004;43(12):2314–8.
46.Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9 (11):1370–6.
47.Aicher A, Zeiher AM, Dimmeler S. Mobilizing endothelial progenitor cells. Hypertension 2005;45 (3):321–5.
48.Reichman-Fried M, Minina S, Raz E. Autonomous modes of behavior in primordial germ cell migration. Dev Cell 2004;6(4):589–96.
49.Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004;10(8):858–64.
50.Gallagher KA, Liu ZJ, Xiao M, et al. Diabetic impairments in NO-mediated endothelial progenitor-cell mobilization and homing are reversed by hyperoxia and SDF-1α. J Clin Invest 2007;117(5):1219-22.
51.Ferrara N. VEGF: basic science and clinical progress. Endocrine Rev 2004;25:581–611.
52.Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor. Signalling–in control of vascular function. Nat Rev Mol Cell 2006;7:359–71.
53.Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascities fluid. Science 1983;219:983–5.
54.Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–8.
55.Tischer E, Mitchell R, Hartmann T, et al. The human gene for VEGF. J Biol Chem 1991;266:11947–54.
56.Keyt BA, Nguyen HV, Berleau LT, et al. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. J Biol Chem 1996; 271:5638–46.
57.Hutchings H, Ortega N, Plouet J. Extracellular matrix-bound VEGF promotes endothelial cell adhesion, migration, and survival through integrin ligation. FASEB J 2003;17:1520–2.
58.Dor Y, Djonov V, Abramovitch R, et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 2002;21:1939–47.
59.Ruhrberg C, Gerhardt H, Golding M, et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A morphogenesis. Gene Dev 2002;16:2684–98.
60.Brown LF, Yeo KT, Berse B, et al. Expression of VEGF by epidermal keratinocytes during wound healing. J Exp Med 1992;176:1375–9.
61.Pages G, Pouyssegur J. Transcriptional regulation of the VEGF gene–a concert of activating factors. Cardiovascular Res 2005;65:564–73.
62.Galiano RD, Tepper OM, Pelo CR, et al. Topical VEGF accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrowderived cells. Am J Pathol 2004;164:1935–47.
63.Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005;437:497–504.
64.Frank S, Hubner G, Breier G, et al. Regulation of VEGF expression in cultured keratinocytes. J Biol Chem 1995;270:12607–13.
65.Howdieshell TR, Callaway D, Webb WL, et al. Antibody neutralization of VEGF inhibitswound granulation tissue formation. J Surg Res 2001;96:173–82.
66.Corral CJ, Siddiqui A, Wu L, et al. VEGF is more important that bFGF during ischemic wound healing. Arch Surg 1999;134:200–5.
67.Roth D, Piekarek M, Christ H, et al. Plasmin modulates VEGF-A mediated angiogenesis during wound repair. Am J Pathol 2006;168:670–84.
68.Hong YK, Lange-Aschenfeld B, Velasco P, et al. VEGF-A tissue repair-associated lymphatic vessel formation via VEGFR-2 and the a1b1 andα2β1 integrins. FASEB J 2004;18:1111–3.
69.Grimmond S, Lagercrantz J, Drinkwater C, et al. Cloning and characterization of a novel human gene related to VEGF. Genome Res 1996;6:124–31.
70.Olofsson B, Pajusola K, von Euler G, et al. Genomic organization of the mouse and human genes for VEGF B and characterization of a second splice isoform. J Biol Chem 1996;271:19310–7.
71.Li X, Aase K, Li H, et al. Isoform-specific expression of VEGF-B in normal tissues and tumors. Growth Factors 2001;19:49–59.
72.Enholm B, Paavonen K, Ristimaki A, et al. Comparision of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997;14:2475–83.
73.Bellomo D, Headrick JP, Silions GU, et al. Micce lacking the VEGF-B-gene have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res 2000;86:E29–35.
74.Silvestre JS, Tamarat R, Ebrahimian TG, et al. VEGF-B promotes in vivo angiogenesis. Circ Res 2003;93:114–23.
75.Mould AW, Tonks ID, Cahill MM, et al. VEGFB gene knockout mice display reduced pathology and synovial anhiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis Rheum 2003;48:2660–9.
76.Trompezinski S, Berthier-Vergnes O, Denis A, et al. Comparative expression of VEGF family members, VEGF-B, -C and -D, normal human kertainocytes and fibroblasts. Exp Dermatol 2004;13:98–105.
77.Joukov V, Sorsa T, Kumar V, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 1997;16:3898–911.
78.McColl BK, Baldwin ME, Roufail S, et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med 2003;198:863–8.
79.Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423–5.
80.Witzenbichler B, Asahara T, Murohara T, et al. VEGF-C/VEGF-2 promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 1998;153:381–94.
81.Saaristro A, Tammela T, Farkkila A, et al. VEGF-C accelerates diabetic wound healing. Am J Pathol 2006;169:1080–7.
82.Paavonen K, Puolakkainen P, Jussilia L, et al. VEGFR-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;156:1499–504.
83.Ji RC, Miura M, Qu P, et al. Expression of VEGFR-3 and 50-nase in regenerating lymphatic vessels of the cutaneous wound healing. Microsc Res Technol 2004;64:279–86.
84.Baldwin ME, Catimel B, Nice EC, et al. The specificity of receptor binding by VEGF-D is different in mouse and man. J Biol Chem 2001;276:19166–71.
85.Ogawa S, Oku A, Sawano A, et al. A novel type of VEGF, VEGF-E, (NZ-7 VEGF), preferentially utilizes KDT/Flk-1 receptor and caries a potent mitogenic activity without heparin-binding domain. J Biol Chem 1998;273:31273–82.
86.Meyer M, Clauss M, Lepple-Wienhues A, et al. A novel VEGF encoded by Orf virus, VEGF-E, mediates angiogenesis via signaling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 1999;18:363–74.
87.Wise LM, Veikkola T, Mercer A, et al. VEGF-like protein from orf virus NZ2 binds to VEGFR-2 and neuropilin-1. Proc Natl Acad Sci 1999;96:3071–6.
88.Kiba A, Sagara H, Hara T, et al. VEGFR-2-specific ligand VEGF-E induces non-edematous hyper vascularization in mice. Biochem Biophys Res Commun 2003;301:371–7.
89.Wirzenius M, Tammela T, Uutela M, et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 2007;204(6):1431–40.
90.Zheng Y, Watanabe M, Kuraishi T, et al. Chimeric VEGF-ENZ7/PlGF specifically binding to VEGFR-2 accelerated skin wound healing via enhancement of neovascularization. Arterioscler Thromb Vasc Biol 2007;27:1–9.
91.Suto K, Yamazaki Y, Morita T, et al. Crystal structures of novel VEGFs from snake venoms. J Biol Chem 2005;280:2126–31.
92.Yamazaki Y, Takani K, Atoda H, et al. Snake venom VEGFs exhibit potent activity through their specific recognition of KDR. J Biol Chem 2003;278:51985–8.
93.Maglione D, Guerriero V, Viglietto G, et al. Isolation of human placenta cDNA coding for protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991;88: 9267–71.
94.Persico MG, Vincenti V, DiPalma T. Structure, expression and receptor-binding properties of PlGF. Curr Top Microbiol Immunol 1999;237:31–40.
95.De Falco S, Gigante B, Persico MG. Structure and function of PlGF. Trends CardiovascMed2002;12:241–6.
96.Maglione D, Guerriero V, Viglietto G, et al. Two alternative mRNAs coding for the angiogenic factor, PlGF, are transcribed form a single gene of chromosome 14. Oncogene 1993;8:925–31.
97.Cao Y, Ji WR, Qi P, et al. PlGF: identification and characterization of a novel isodorm generated by RNA alternative splicing. Biochem Biophys Res Commun 1997;235:493–8.
98.Yang W, Ahn H, Hinrichs M, et al. Evidence of a novel isoform of PlGF (PlGF-4) expressed in human trophoblast and endothelial cells. J Reprod Immunol 2003;60:53–60.
99.DiPalma T, Tucci M, Russo G, et al. The placenta growth factor gene of the mouse. Mamm Genome 1996;7:6–12.
100.Park JE, Chen HH, Winer J, et al. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994;269:25646–54.
101.Autiero M, Luttun A, Tjwa M, et al. PlGF and its receptor, VEGFR-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J ThromboHaemost 2003;1:1356–70.
102.DiSalvo J, Bayne ML, Conn G, et al. Purification and characterization of a naturally occurring vascular endothelial growth factor/placenta growth factor heterodimer. J Biol Chem 1995;270:7717–23.
103.Hattori K, Heissig B, Wu Y, et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone marrow microenviroment. Nat Med 2002;8:841–9.
104.Xu L, Cochran DM, Tong RT, et al. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res 2006;66:3971–7.
105.Carmeliet P, Moons L, Luttun A, et al. Synergism between VEGF and PIGF contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001;7:575–83.
106.Luttun A, Tjwa M, Moons L, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt-1. Nat Med 2002;8:831–40.
107.Nagy JA, Dvorak AM, Dvorak HF. VEGF-A 164/165 and PlGF. Roles in angiogenesis and arteriogenesis. Trends Cardiovasc Med 2003;13:169–75.
108.Tamarat R, Silvestre JS, Le Ricousse-Roussanne S, et al. Impairment in ischemia-induced neovascularization in diabetes. Bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. Am J Pathol 2004;164: 457–66.
109.Maes C, Coenegrachts L, Stockmans I, et al. Placental growth factor mediates mesenchymal celldevelopment, cartilage turnover, and bone remodeling during fracture repair. J Clin Invest 2006;116:1230–42.
110.Failla CM, Odorisio T, Cianfarani F, et al. PlGF is induced in human keratinocytes during wound healing. J Invest Dermatol 2000;115:388–95.
111.Cianfarani F, Zambruno G, Brogelli L, et al. PlGF in diabetic wound healing. Altered expression and therapeutic potential. Am J Pathol 2006;169:1167–82.
112.付小兵,王正国,吴祖泽.再生医学原理与实践.上海:上海科学技术出版社.2008