CN1027136C - 伤口的愈合 - Google Patents

伤口的愈合 Download PDF

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CN1027136C
CN1027136C CN88109273A CN88109273A CN1027136C CN 1027136 C CN1027136 C CN 1027136C CN 88109273 A CN88109273 A CN 88109273A CN 88109273 A CN88109273 A CN 88109273A CN 1027136 C CN1027136 C CN 1027136C
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哈里·N·安东尼亚迪斯
塞缪尔·E·林奇
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    • C07K14/49—Platelet-derived growth factor [PDGF]
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Abstract

通过给哺乳动物涂敷一种组合制剂使哺乳动物外伤愈合、骨骼再生，该组合制剂包含纯化的血小板衍生的生长因子和α转移生长因子。

Description

本发明有关愈合伤口。
生长因子是能刺激一定数目靶细胞的多肽激素。生长因子的例子包括：血小板衍生的生长因子（PDGF）、胰岛素类生长因子（IGF-I）、β转移生长因子（TGF-β）、α转移生长因子（TGF-α）、皮肤生长因子（FGF）、和成纤维细胞生长因子（FGF）。PDGF是一种在循环血小板颗粒中可以找到的热稳定的阳离子蛋白质，据知循环血小板颗粒能刺激体外蛋白质合成和通过成纤维细胞的胶原生成。还知道，它对成纤维细胞起体外分裂素和趋化剂的作用，还起平滑的肌肉血胞的作用。
已有人提出使用PDGF来促进体内伤口愈合的建议。例如，Grotendorst（1984）J.Trauma24：549-52描述了：将PDGF加到Hunt-Schilling线网室（该室中浸入了胶原凝胶），并植入小鼠的背部;结果发现，PDGF增加了新合成的胶原量。但是，只使用PDGF，或者PDGF与EGF和FGF联合使用，Leitzel等人（1985）J.Dermatol.Surg.Oncol.11：617-22却不能加快大田鼠内普通伤口的愈合速度。
Michaeli等人（1984）在“Soft    and    Hard    Tissue    Repair”一书中（Hunt，T.K.等编，纽约、Praeger出版人，PP380-394）报告说，敷用从富血小板的血浆获得的部分纯的PDGF制剂刺激了在将其植入兔角膜时的血管生成。因为PDGF不是血管生长因子，因此研究人员建议，在它们的部分纯PDGF制剂中可能存在一种未知的因子，该未知因子引起血管生长效应。
Schultz，G.S.等人（1984）在“Science”中报告：对猪的部分厚度的皮肤烧伤部位进行局部敷用TGF-α，和未被处理的烧伤部位相比，加速了皮肤的再生过程。
一般来说，本发明的特点是通过给伤口敷用有效剂量的组合制剂来愈合哺乳动物（例如病人）的外伤，该制剂包括纯化的PDGF和纯化的TGF-α的组合。TGF-α最好是人的TGF-α，但是也可以是其它哺乳类的TGF-α，例如鼠的。TGF-α可以从天然源分离出来，通过重组体细胞或固相肽合成来制取TGF-α则更好。本发明的组合制剂通过促进上皮和连接组织的生长以及整个蛋白质和胶原的合成来帮助伤口的愈合，至少是部分愈合。使用本发明的组合制剂进行伤口愈合比不经治疗（即不敷用外原剂）、或经过只使用纯化的PDGF的治疗或只使用纯化的TGF-α的治疗得到的伤口愈合效果都更加有效。
在本发明的最佳实施例中，该组合制剂的制备方法是，在一种药物学上允许的载体物质内，例如在市场上可买到的惰性凝胶或液体（如补充了白蛋或甲基纤维素的盐水）内，将纯化的PDGF和TGF-α（两者皆可在市场上购到）组合在一起。组合纯化的PDGF和TGF-α的最佳重量比在1∶4和25∶1之间，在1∶2和10∶1之间较好，并且1∶1或2∶1则更好些。纯化的PDGF可以从人类的血小板中获得，或者通过重组的DNA（脱氧核糖核酸）技术得到。因此，谈到术语“PDGF”，我们指的是哺乳动物的血小板衍生物和重组体两者，指的是灵长类血统较贴切;该灵长类是人类则最贴切，但也可以是黑猩猩或其它的灵长类。重组的PDGF可以是重组的异二聚体，它是通过将对两个亚单体编码的DNA序列插入被培养的原核细胞或真核细胞中制得的，然后让这些细胞去处理这些被转译的亚单体从而即形成了异二聚体，或者将只对一个亚单体（最好是β或“2”链）编码的DNA插入这些细胞中，然后对其进行培养从而得到异二聚体的PDGF（PDGF-1或PDGF-2异二聚体）。
这里所用的术语“纯化的”指的是，PDGF或TFG-α在与其它物质混合前按重量计占95%或更高些的PDGF或TGF-α，即这样的PDGF或TGF-α基本上不含本来就与之相关的糖类、酯或其它蛋白质。
对于每一种PDGF和TGF-α组分，一种纯 化在蛋白质制剂一般来说在聚丙烯酰胺凝胶中都要产生一个主带。在本发明的组合制剂中使用的纯化PDGF或TGF-α最好达到通过氨基末端氨基酸序列分析方法测定的纯度。
本发明的组合制剂对于哺乳动物外伤的愈合提供了一种快速有效的方法，例如对于褥疮、裂伤和烧伤的治疗。和自然愈合（即不使用任何外原剂）或只使用纯PDGF或只使用TGF-α相比，该组合制剂加速了连接组织的生成。和只使用纯PDGF不同，该组合制剂促进了新的连接组织和上皮组织两者的显著增长。其所得到的上皮层比自然愈合或只使用TGF-α生长出来的上皮层厚，并且还包含更多的将上皮层连到新连接组织的上皮突起;这样，就使上皮层的粘结更加牢固并且使其得到了保护。
本发明的其它特点和优点将从下述对最佳实施例的描述中和权利要求书中变得更加清楚。
我们现在描述本发明的最佳实施例。
根据本发明用PDGF/TGF-α混合物来治疗外伤，如褥疮和烧伤，该混合物是通过组合纯PDGF和TGF-α制备出来的。从Peninsula实验室（Belmont，CA）可以买到化学合成的人和鼠的TGF-α。从人体血小板衍生得到的纯化PDGF和纯化重组的PDGF可从PDGF公司（Boston，MA）、Collaborative研究中心（Waltham，MA）和Amgen公司（Thousand    Oaks，CA）买到。纯化PDGF也可按下述方法制得。
将500至1000单位的洗过的人体血小板粒悬浮于1M    Nacl（每个血小板单位2ml）中，并将其在100℃加热15分钟。然后通过离心来分离该上清液，并用1M    Nacl两次提取沉淀物。
该提取物靠0.08M    NaCl-0.01M磷酸钠缓冲液（pH7.4）进行结合和透析，并在4℃和与该缓冲液平衡的CM-Sephadex    C-50混合一夜。然后将该混合物倒入一个柱（5×100cm）中，用0.08MNaCl-0.01M磷酸钠缓冲液进行大面积的清洗，并且在要收集其中的10ml部分时用1M    Nacl进行洗提。
有效部分靠0.3M    NaCl-0.01M磷酸钠缓冲液（PH7.4）进行汇集和透析，然后进行离心，并在4℃时使其通过与0.3M    NaCl-0.01M磷酸钠缓冲液（PH7.4）平衡的2.5×25cm的Blue    Sepharose（Pharmacia）柱。之后用该缓冲液清洗该柱，并且用1M    NaCl和乙二烯乙醇的1∶1溶液洗提部分纯化的PDGF。
经部分地纯化了的PDGF部分用1M    NaCl洗提（1∶1），并且靠1M醋酸透析，然后进行冻干。冻干后的样品被溶于0.8M    NaCl-0.01M磷酸钠缓冲液（PH7.4）中，然后让其通过与该缓冲液平衡的1.2×40cm的CM-Sephadex    C-50柱。然后借助于NaCl的变化梯度（0.08M至1M）对PDGF进行洗提。
该有效部分靠1M醋酸组合、透析，并且予以冻干，然后将其溶解在少量的1M醋酸中。将其中的0.5ml部分加到与1M醋酸平衡的1.2×100cmBiogel    P150柱（100至200个网眼）中。在要收集2ml部分时，用1M醋酸洗提PDGF。
每一个包含100至200mg蛋白质的有效部分被冻干，并将其溶解在100ml的0.4%三氟醋酸中，并使之在苯基的Bondapak柱（Waters）中经受反相的高性能液体层析法处理。用线性的乙腈梯度（0至60%）的洗提即产生了纯PDGF。
可按下述方法制备通过重组的DNA技术制得的PDGF：
从人体血小板得到的血小板衍生增长因子（PDGF）包含两个多肽序列（PDGF-1和PDGF-2;Antoniades，H.N.和Hunkapiller，M.（1983）Science    220∶963-965）。PDGF-1是由位于染色体7中的基因编码的（Betsholtz，C.等人，Nature320∶695-699），PDGF-2是由位于染色体22（Dalla-Favera，R.（1982）Science218∶686-688）的病态致肿瘤基因编码的（Doolittle，R.等人（1983）Science221∶275-277）。病态致肿瘤基因对与PDGF-2多肽紧密相关的猿肉瘤病毒（SSV）的转移蛋白质进行编码。人类的细胞的C-病态也对PDGF-2链进行编码（Rao，C.D.等人（1986），Proc.Natl.Acad.Sci.USA    83∶2392-2396）。由于PDGF的两个多肽链是由位于不同的染色体中的两个不同基因编码的，所以存在下述可能性：人的PDGF由PDGF-1和PDGF-2的一种由双硫醚连接的异二聚体组成，或者是两种单二聚体（PDGF-1单二聚体和PDGF-2单二聚体）的一种混合物，或者是包括异二聚体和两个单二聚体的一种混合物。
受猿的肉瘤病毒感染的、正在培养中的哺乳动物细胞（含对PDGF-2链编码的基因）显示出PDGF-2多肽的合成，并且将其处理成双硫醚连接的单二聚体（Robbims，K.等人（1983）Nature305∶605-608）。此外，PDGF-2单二聚体与抗人体PDGF升高的抗血清发生反应。再有，分泌的PDGF-2单二聚体的功能性在下述方面与血小板衍生的PDGF类似：它刺激了被培养的成纤维细胞中的DNA合成，它在185kd细胞膜蛋白质的酪氨酸基上导致了磷酸化，并且为了束缚到特殊的细胞表面PDGF受体上能和人体的（125I）-PDGF相竞争（Owen，A.等人（1984）Science225∶54-56）。对于从培养的正常人体细胞（如人体的动脉内皮细胞）衍生的病态/PDGF-2基因产物、或者从表达病态/PDGF-2基因的人体恶性肿瘤细胞衍生的上述基因产物，也表示出类似的性质（Antoniades，H.等人（1985）Cancer Cells3∶145-151）。
通过使用表达媒介动物将C-病态/PDGF-2基因的CDNA细胞素引入到小鼠细胞，来获得重组的PDGF-2单二聚体（这里称之为重组的PDGF）。用于表达的C-病态/PDGF-2细胞素是从正常人体培养的内皮细胞得到的（Collians，T.等人（1985）Nature216∶748-750）。
为确定PDGF/TGF-α混合物对促进伤口愈合的效果，进行了下述试验。
让重量在10到15公斤的小白约克夏猪（Parson农场，Hadley，MA）在术前禁食至少六小时，然后进行麻醉。在无菌状态下，对其背部和胸部剪毛、剃净、并用温和的肥皂水洗净。然后用70%酒精对要做成伤口的部位消毒。
用一种改进的Castroviejo电植皮刀（Storz，St.Louis，Mo，由Brownells公司改进）造成1cm×2cm、深度为0.5mm的一些伤口。这些伤口系完全除去了上皮，并除去其真皮下方的一部分（可与二度烧伤相比拟）。各个伤口之间至少由15mm未受伤的皮肤隔开。将接受相同治疗的伤口编成一组，并且与另一些组隔开至少3cm。不接受生长因子治疗的伤口与接受这种治疗的伤口至少隔开10cm。
这些伤口用单次敷用悬浮在生物凝胶中的下述生长因子进行治疗的：1）单独使用500ng纯人体PDGF（通过高性能液体层析法纯化的）或重织的PDGF;2）与下述的每一种进行组合的500ng纯重组的PDGF：a）500ng人体的TGF-α;b）500ng鼠的TGF-α;3）单独使用500ng人或鼠的TGF-α。
在制作了伤口之后的第3天至第10天取活组织检查标本。将用于组织学评价的活组织检查标本取成楔形，约3mm深，并将其放入10%的福尔马林中。使用一种电植皮刀来获取用于放化分析和自动射线照相的标本。标本的最终尺寸为1.5mm×10mm×1.5mm。对于进行放化分析的每个伤口收集三个标本，而对于自动射线，对每个伤口收集两个标本。在提取标本之后，将标本贮存在补充了10%牛胎儿血清的冷的EMEM（Eagle′s    Modified    Essential    Medium）介质中。对活组织检查标本进行如下的分析：
组织学的评价
使用标准的石蜡浸渗和植入技术来制备组织标本。制作4微米切片并使用过滤的Harris血毒素（hemotoxylin）和乙醇酒精进行染色;然后在显微镜下进行观察。由两个研究人员在整个这些切片的等分布点上对所有标本进行随意的计数。使用置于显微镜的目镜中的网格对上皮和连接组织层的宽度进行计数;通过使用在相同条件下进行观测的一个测微仪，将测量结果转换为毫米。
DNA和蛋白质的测定
通过使用对Labarca等人（1980）在Anal.Biochem.120∶344-52中的方法的改进方法来进行DNA测定。将在浓缩的氢氧化铵中的50ul等分试样的组织提取物加到400μl的缓冲液中，该缓冲液中含1M磷酸钠和2M氯化钠（pH7.0）;使用HCl将最终溶液的pH值调节到7.4。之后，使最终的溶液体积为500μl，同时维持pH值为7.4。然后，将该溶液加到含Hoesht染剂（1.14mg/ml）的2.5ml的被缓冲的溶液（0.05M磷酸钠，2M氯化钠，PH为7.4）中。在352nm的激发波长处激发了荧光并且在454nm测到了辐射。使用通过相同的治疗方法制备的小牛胸腺DNA来绘制标准曲线。
通过Bradford方法（Bradford（1976），Anal.Biochem.72∶248-54）来测量在浓缩的氢氧化铵中组织提取物的蛋白质浓度，其中以牛血清蛋白作为标准。
结果
组织学评价结果表明，和不接受任何治疗、或和单独使用人或鼠TGF-α治疗、或和单独使用纯PDGF治疗的伤口相比，用纯化的人体PDGF或重组的PDGF和化学合成的人或鼠的TGF-α的组合进行治疗的伤口具有较厚的连接组织和上皮层，并且具有与这些层相连的更大范围的上皮突起。
PDGF/TGF-α治疗的伤口具有较大的DNA、蛋白质和胶原含量。
剂量
为了确定纯化的PDGF的合适剂量，要重复上述这些实验，只是这些伤口是用弥散在30μi生物相容凝胶中的、每平方毫米伤口2.5ng、5.0ng和10ng的纯化PDGF的等价物进行治疗的。结果表明，在PDGF含量是5.0ng/cm2或更高些时得到的效果最佳。
为了确定纯PDGF加TGF-α的适当剂量，按上述方法对组合制剂进行估计，其中PDGF与TGF-α的重量比范围为自1∶10∶至25∶1。在重量比范围在1∶1和2∶1之间得到的结果最佳。

Claims (3)

1、一种用于愈合伤口的组合物的制备方法，包括按1∶4和25∶1之间的一个重量比混合纯化的血小板衍生物的生长因子和纯化的α转化生长因子，所述生长因子的混合物再与一种药用载体混合。
2、一种如权利要求1所述的方法，其中所说的重量比在1∶2和10∶1之间。
3、一种如权利要求1所述的方法，其中所说的重量比约为1∶1或2∶1。
CN88109273A 1987-12-22 1988-12-21 伤口的愈合 Expired - Lifetime CN1027136C (zh)

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