JP5869219B2 - 治療および美容適用のためのエリスロポイエチンおよびフィブロネクチン組成物 - Google Patents
治療および美容適用のためのエリスロポイエチンおよびフィブロネクチン組成物 Download PDFInfo
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- JP5869219B2 JP5869219B2 JP2010520684A JP2010520684A JP5869219B2 JP 5869219 B2 JP5869219 B2 JP 5869219B2 JP 2010520684 A JP2010520684 A JP 2010520684A JP 2010520684 A JP2010520684 A JP 2010520684A JP 5869219 B2 JP5869219 B2 JP 5869219B2
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Description
ビタミンC、ビタミンD、ビタミンB1〜6、ビタミンK、ビタミンAおよびビタミンPP)、炭水化物(例えば、単糖/二糖/多糖、これらには、グルコース、マンノース、マルトースおよびフルクトースが含まれる)、イオン、キレーター(例えば、Feキレーター、Caキレーター)、抗酸化剤(例えば、ビタミンE、ケルセチン、超酸化物スカベンジャー、スーパーオキシドジスムターゼ、H2O2スカベンジャー、フリーラジカルスカベンジャー、Feスカベンジャー)、脂肪酸(例えば、トリグリセリド、リン脂質、コレステロール、遊離脂肪酸および非遊離脂肪酸、脂肪アルコール、リノール酸、オレイン酸およびリポ酸)、抗生物質(例えば、ペニシリン、セファロスポリンおよびテトラサイクリン)、鎮痛剤、麻酔剤、抗菌剤、抗酵母剤、抗真菌剤、抗ウイルス剤、プロバイオティック剤、抗原虫剤、かゆみ止め剤、抗皮膚炎剤、制吐剤、抗炎症剤、抗高角質溶解剤、制汗剤、抗乾癬剤、抗脂漏剤、抗ヒスタミン剤、アミノ酸(例えば、必須アミノ酸および非必須アミノ酸(A〜Z)、特に、グルタミンおよびアルギニン)、塩(例えば、ピルビン酸塩および硫酸塩)、硫酸塩(例えば、硫酸カルシウム)、ステロイド(例えば、アンドロゲン、エストロゲン、プロゲスタゲン、グルココルチコイドおよびミネラルコルチコイド)、カテコールアミン(例えば、エピネフリンおよびノルエピネフリン)、ヌクレオシドおよびヌクレオチド(例えば、プリンおよびピリミジン)、プロスタグランジン(例えば、プロスタグランジンE2)、ロイコトリエン、エリスロポイエチン(例えば、トロンボポイエチン)、プロテオグリカン(例えば、ヘパラン硫酸、ケラタン硫酸)、ヒドロキシアパタイト[例えば、ヒドロキシアパタイト(Ca10(PO4)6(OH)2)]、ヘパトグロビン(Hp1−1、Hp2−2およびHp1−2)、スーパーオキシドジスムターゼ(例えば、SOD1/2/3)、一酸化窒素、一酸化窒素供与体(例えば、ニトロプルシド(Sigma Aldrich、St.Louis、MO、アメリカ合衆国))、グルタチオンペルオキシダーゼ、水和化合物(例えば、バソプレシン)、細胞(例えば、血小板)、細胞培地(例えば、M199、DMEM/F12、RPMI、Iscovs)、血清(例えば、ヒト血清、ウシ胎児血清)、緩衝剤(例えば、HEPES、重炭酸ナトリウム)、界面活性剤(例えば、Tween)、消毒剤、薬草、果実抽出物、野菜抽出物(例えば、キャベツ、キュウリ)、花抽出物、植物抽出物、フラビノイド(例えば、ザクロ果汁)、香辛料、葉(例えば、緑茶、カモミール)、ポリフェノール(例えば、赤ワイン)、ハチミツ、レクチン、マイクロ粒子、ナノ粒子(リポソーム)、ミセル、炭酸カルシウム(CaCO3、例えば、沈降炭酸カルシウム、粉砕/微粉化炭酸カルシウム、albacar、PCC、GCC)、方解石、石灰石、破砕大理石、粉砕大理石、石灰、チョーク(白亜、シャンパンチョーク、フレンチチョーク)、ならびに、補因子(例えば、BH4(テトラヒドロビオブテリン))。
エリスロポイエチンによる局所処置は糖尿病ラットの皮膚創傷において血管形成および創傷治癒を改善する
材料および実験手順
実験動物
30匹のオスSprague−Dawleyラット(8週齢)(Harlan(Jerusalem、イスラエル)から得られる)を、一定の温度および湿度を含む環境で、かつ、人工的な12時間の明暗サイクルとともに飼育した。すべてのラットは、食物および水を自由に取ることが許された。すべての実験手順が、Rappaport Faculty of Medicine−Technion Animal Centerの動物管理使用委員会のガイドラインに従った。
糖尿病を、生理食塩水−クエン酸ナトリウム緩衝液(Sigma Aldrich、St.Louis、MO、アメリカ合衆国、pH4.5)におけるストレプトゾトシン(STZ、Sigma Aldrich、St.Louis、MO、アメリカ合衆国)(インスリン産生細胞に対して特異的な毒素)の60mg/kgの1回の腹腔内注射によって誘導した。血中グルコースレベルを、鋭敏なグルコメータ(FreeStyle、Alameda、CA、アメリカ合衆国)を使用して測定した。STZを受けた10日後、300mg/dLを越える血中グルコースレベルを示すラットを糖尿病とみなし、研究においてさらに使用した。
300mg/dLを越えるグルコースレベルが確認された糖尿病ラットをケタミン(100mg/kg体重)およびキシラジン(50mg/kg)により腹腔内麻酔した。各ラットの背側の皮膚を剃毛し、ヨウ素溶液により消毒し、2つの全層皮膚創傷(創傷あたり直径がおよそ30mm)を各ラットの背中の右側および左側に作製した。その後、糖尿病ラットを、10匹のラットを各群に含む3つの処置群に無作為に分けた:第1群)傷を、生理食塩水を含有する基礎クリームにより処置した(コントロール群と呼ばれる);第2群)傷を、低いエリスロポイエチン濃度(EPO、500U/ml)を含有するクリームにより処置した(低用量群と呼ばれる;Cytolab/Peprotech、Rehovot、イスラエル);および、第3群)傷を、高EPO濃度(3000U/ml)を含有するクリームにより処置した(高用量群と呼ばれる)。すべてのラットを適切なクリームにより(12日間にわたって)1日に1回処置した。
創傷治癒割合を計算するために、透明な紙を傷の場所に置き、その形状を紙に描いた。次いで、創傷面積を、傷の形状を方眼紙に照合することによって測定した。創傷治癒割合をWalker式(式I、下記)によって計算した。創傷治癒割合を、実験開始時(0日目)に、また、その後、再び、2、4、6、8、10および12日目に計算した。
式I:
%創傷面積=[(X日目の創傷面積)/(初日の創傷面積)]×100
創傷治癒割合=100−創傷面積の割合
免疫組織化学を、以前に定義された手順を使用して行った。簡単に記載すると、ラットを実験12日目に屠殺し、各群から組織サンプルを採取し、10%ホルマリンにおいて固定処理した。パラフィン包埋された組織を切片化し(5μm)、抗原回復を、クエン酸塩緩衝液(Sigma Aldrich、St.Louis、MO、アメリカ合衆国)を使用して行った。組織を一次抗体の抗CD31(R&D Systems、MN、アメリカ合衆国)で処理し、続いて、適切な二次抗体(R&D Systems、MN、アメリカ合衆国)で処理した。スライドをヘマトキシリンで対比染色し、カバースリップにより固定した。
ラットを実験12日目に屠殺し、創傷部に存在する血管内皮増殖因子(VEGF)の量をELISAによって求めた。簡単に記載すると、創傷組織を、完全プロテアーゼ阻害剤カクテル(Sigma)を含有する1.0mlのPBSにおいてホモジネートした。ホモジネートを遠心分離して、破片を除き、1.2μm細孔のシリンジフィルタによりろ過した。分析を市販のヒトVEGF特異的ELISAキット(R&D Systems、MN、アメリカ合衆国)によって行った。VEGFの量をピコグラム/創傷部として示した。
HPがほとんど例外なくコラーゲンに見出されるので、HPを、創傷組織に存在するコラーゲンの量の指標として使用した。創傷部のHP濃度を、以前に記載されたように求めた[Kwon他、Exp Biol Med(Maywood)(2007)、232(7):935〜41]。簡単に記載すると、創傷組織(実験12日目の屠殺ラットから採取される)を、130℃で4時間、2mlのHCL(6mol/l)において加水分解した。その後、混合物を2.5mol/lの水酸化ナトリウムによりpH7.0に中和し、脱イオン水により40倍に希釈した。次いで、2mlの希釈された混合物を1mlのクロラミン−T溶液(0.05mol/l)と混合し、室温で20分間インキュベーションした。その後、1mlの20%p−ジメチルアミノベンズアルデヒドを加え、溶液を60℃で20分間インキュベーションした。各サンプルの吸光度を蛍光マイクロプレートリーダーによって557nmにおいて求め、HPの量を標準曲線との比較によって求めた。
コルモゴロフ−スミルノフ検定によれば、データは正規分布を有していた。さらに、スチューデントt検定およびANOVAを、異なる実験群の間での差を明らかにするために使用した。P<0.05のとき、差は、有意であると見なした。結果を値の平均±標準偏差として示した。
糖尿病のラットモデルをSTZ注射によって作製した。血中グルコースレベルにおける緩やかな増大が期間を通して認められ、これには、体重減少が伴った。STZ投与(研究の初日)の10日後、ラットは、それらのSTZ前の状態と比較して、8.7±2.3gの体重を失い、(研究の最終日で測定されたとき)12日後では体重をさらに失っていた(それらのSTZ前の状態と比較して、19.4±7.1gの体重を失っていた)。本研究で使用された糖尿病ラットの血中グルコースレベルは一貫して300mg/mLよりも高く、EPOまたはビヒクルのどちらかを含有する外因性クリームの局所適用によって変化しなかった。
図1に示されるように、創傷治癒割合における有意な統計学的差(P<0.05)が、高用量のEPOと、(ビヒクルにより処置された)コントロールラットとの間において実験の6日目に記録された。しかしながら、低用量のEPOと、コントロールラットとの間での有意な統計学的差(P<0.05)が、実験の10日目でのみ検出された。重要なことに、これら2つのEPO処置群(低用量のEPOおよび高用量のEPO)の間の比較では、実験の6、8、10および12日目での創傷治癒割合における有意な統計学的差(P<0.05)が存在したことが明らかにされた。
CD31(内皮細胞および血管細胞に特異的なマーカー)の免疫組織化学的染色を使用して、各処置群からの組織サンプルを、処置終了時に、新血管形成を実証するために微小血管密度(MVD)について評価した。図2に示されるように、MVDの評価では、統計学的に有意な差が、ビヒクルにより処置されたコントロールラット(2.83±0.98)と比較して、EPOにより処置されたラット(低用量のEPOおよび高用量のEPO、それぞれ、5±1.55および8.5±1.05)との間において示された(P<0.05)。さらに、創傷部へのEPOの局所適用はMVDを用量依存的な様式で増大させた(図2)。
図3に示されるように、血管内皮増殖因子(VEGF)のレベルが、処置された創傷部と非処置の創傷部との間で著しく異なっていた。ビヒクルによってのみ処置されたコントロールラットのサンプルはVEGFの非常に低い含有量を示した(0.3±0.02pg/mgタンパク質)。しかしながら、低用量のEPOによる処置ラットおよび高用量のEPOによる処置ラットからのサンプルはVEGFの著しく高いレベルを示した(それぞれ、0.9±0.2および1.1±0.2pg/mgタンパク質)。したがって、創傷治癒には、VEGFにおける有意な増大が伴った。
HPがほとんど例外なくコラーゲンに見出されるという事実のために、HPを、創傷組織に存在するコラーゲンの量の指標として使用した。図4に示されるように、EPOによる創傷部の局所的処置は組織のHP含有量を高めた。結果は、有意な差を、低用量のEPOまたは高用量のEPOのどちらかにより処置されたラット(それぞれ、39±5または48±7μg/創傷部)と、ビヒクルだけにより処置されたコントロールラット(22±6μg/創傷部)との間で示した。EPO処置は、創傷組織のコラーゲン含有量における増大を用量依存的な様式でもたらした。このことは、結合組織再建および創傷治癒における示された用量のEPOの治療的価値を実証している。
エリスロポイエチンおよびフィブロネクチンによる局所的処置による糖尿病マウスにおける加速された皮膚創傷治癒
材料および実験手順
実験動物
32匹のCD1ヌードマウス(6週齢)(Harlan(Jerusalem、イスラエル)から得られる)を、一定の温度および湿度を含む環境で、かつ、人工的な12時間の明暗サイクルとともに飼育した。すべてのラットは、食物および水を自由に取ることが許された。すべての実験手順が、Rappaport Faculty of Medicine−Technion Animal Centerの動物管理使用委員会のガイドラインに従った。
糖尿病を、生理食塩水−クエン酸ナトリウム緩衝液(Sigma Aldrich、St.Louis、MO、アメリカ合衆国、pH4.5)におけるストレプトゾトシン(STZ、Sigma Aldrich、St.Louis、MO、アメリカ合衆国)(インスリン産生細胞に対して特異的な毒素)の60mg/kgの1回の腹腔内注射によって誘導した。血中グルコースレベルを、鋭敏なグルコメータ(FreeStyle、Alameda、CA、アメリカ合衆国)を使用して測定した。STZ注射の5日後、300mg/dLを越える血中グルコースレベルを示すマウスを糖尿病として定義し、研究においてさらに使用した。
300mg/dLを越えるグルコースレベルが確認された糖尿病マウスをケタミン(100mg/kg体重)およびキシラジン(20mg/kg)により腹腔内麻酔した。各マウスの背側の皮膚を剃毛し、ヨウ素溶液により消毒し、2つの全層皮膚創傷(創傷あたり直径がおよそ20mm)を各マウスの背中の右側および左側に作製した(図5A)。その後、糖尿病マウスを、8匹のマウスを各群に含む4つの処置群に無作為に分けた:第1群)傷を、生理食塩水を含有する基礎クリームにより処置した(コントロール群、図5B);第2群)傷を、エリスロポイエチン(EPO、3000U/mL、Cytolab/Peprotech、Rehovot、イスラエル)を含有するクリームにより処置した;第3群)傷を、フィブロネクチン(FN、200μg/mL、Chemicon International Inc.、Temecula、CA、アメリカ合衆国)を含有するクリームにより処置した;および、第4群)傷を、EPOおよびFN(それぞれ、3000U/mLおよび200μg/mL)を含有するクリームにより処置した(図5B〜C)。すべてのマウスを適切なクリームにより(12日間にわたって)1日に1回処置した。
上記で実施例1において詳しく説明される通りである。
上記で実施例1において詳しく説明される通りである。
上記で実施例1において詳しく説明される通りである。
上記で実施例1において詳しく説明される通りである。
上記で実施例1において詳しく説明される通りである。
糖尿病のマウスモデルをSTZ注射によって作製した。血中グルコースレベルにおける緩やかな増大が期間を通して認められ、これには、体重減少が伴った(データは示されず)。STZ投与(研究の初日)の5日後、マウスは、それらのSTZ前の状態と比較して、1.3±0.3gの体重を失い、(研究の最終日に測定されるとき)12日後では体重をさらに失っていた(それらのSTZ前の状態と比較して、2.2±0.7gの体重を失っていた)。本研究で使用された糖尿病マウスの血中グルコースレベルは一貫して300mg/mLよりも高く、EPO、FN、EPO/FNまたはビヒクルを含有する外因性クリームの局所適用によって変化しなかった。
FNにより処置されたマウスと比較して、EPOにより処置されたマウスとの間での統計学的差は有意でなかった(P>0.05)。これに対して、創傷治癒割合における有意な統計学的差(P<0.05)が、ビヒクルによって処置されたマウスに対して、EPOまたはFNによって処置されたマウスとの間で実験の6日目から12日目まで記録された(図6)。しかしながら、EPOおよびFNによる併用処置は、創傷治癒における有意な統計学的差(P<0.05)を、EPO、FNまたはビヒクルによる処置と比較して、処置後4日もの早くにもたらした(図6および7A〜D)。創傷治癒における際立った増大がさらに、実験の6日目に記録され(図6)、このとき、達成された治癒割合が、EPOにより処置されたマウス(およそ46%、P<0.001)、FNにより処置されたマウス(およそ41%、P<0.001)、または、コントロールマウス(およそ30%、P<0.001)と比較して、EPOおよびFNにより処置されたマウスについてはおよそ86%であった。それ以降、8日目において、EPOおよびFNの併用により処置されたマウスにおける全体的な創傷閉鎖が、記録された創傷閉鎖が著しくより低かった他の処置群(EPOについてはおよそ65%、FNについてはおよそ55%、および、コントトールマウスについてはおよそ41%、図6、ならびに、8A〜Cおよび8F〜G)と比較して、およそ96%であった(図6、ならびに、図8A、8D、8Eおよび8G)。さらに、12日目において、EPOおよびFNの併用により処置されたマウスのみが完全な創傷閉鎖を達成し(およそ99%、P<0.001)、これに対して、すべての他の処置群は完全な創傷閉鎖を達成していなかった(図6、図9A〜F、および、図10A〜L)。したがって、EPOおよびFNの併用による創傷処置は創傷治癒プロセスを大きく加速させていたこと、また、完全な創傷閉鎖を達成していたことが、これらの結果から明らかである。
処置終了時(12日目)に、CD31の免疫染色を、各処置群からの組織サンプルにおける新血管形成(微小血管密度、MVD)を確認するために行った。図11に示されるように、MVDの評価は、統計学的に有意な差を、ビヒクルにより処置されたコントロールマウスと比較して、EPOを含有するクリームにより処置されたマウスとの間で示し(それぞれ、2.33±1.033に対して6.83±1.47、P<0.01)、しかし、有意な差が、ビヒクルにより処置されたマウスと比較して、FNを含有するクリームにより処置されたマウスとの間では検出されなかった(それぞれ、2.33±1.03に対して3.17±0.75、P>0.05)。しかしながら、EPOおよびFNを含有するクリームの局所適用はMVDを顕著に増大させ、この増大は、他の処置群のすべてと比較して、統計学的に有意であった(P<0.001)。
図12に示されるように、血管形成因子(VEGF)のレベルが、処置終了時(12日目)に、異なる処置群の間で著しく異なっていた。ビヒクルにより処置されたコントロールマウス、または、FNを含有するクリームにより処置されたマウスから採取されたサンプルでは、非常に低いレベルのVEGF(それぞれ、0.31±0.08または0.39±0.12pg/mgタンパク質)が、EPOまたはEPOおよびFNを含有するクリームにより処置されたマウスから採取されたサンプル(それぞれ、0.74±0.15または0.87±0.13pg/mgタンパク質)と比較して示された(P<0.001)。有意な統計学的差が、コントロールマウスと、FNを含有するクリームにより処置されたマウスとの間において何ら認められなかった(P>0.05)。そのうえ、有意な統計学的差が、EPOを含有するクリームにより処置されたマウスと、EPOおよびFNを含有するクリームにより処置されたマウスとの間において何ら認められなかった(P>0.05)。
HPを、創傷組織に存在するコラーゲンの量の指標として使用した。図13に示されるように、EPOのみまたはFNのみを含有するクリームによる局所的処置は同等に、創傷組織におけるHP含有量を高め(それぞれ、44±6.1または45.3±7.2μg/創傷部)、また、ビヒクルによる処置(16.2±4.7μg/創傷部)と比較して著しくより高かった(P<0.001)。逆に、EPOおよびFNの両方を含有するクリームによる局所的処置は、創傷組織におけるHP含有量を著しく増大させた(81±8.8μg/創傷部;P<0.001)。したがって、EPOのみまたはFNのみを含有するクリームによる処置と比較して2倍であり、また、ビヒクルによる処置と比較して5倍であった。まとめると、これらの結果は、EPOおよびFNの両方を含有するクリームによる創傷処置は、組織修復において、コラーゲンにおける際立った増大をもたらし、EPOとFNとの間における密接な相互作用の存在を示すことを示している。
EPOはHEMCにおけるβ1−インテグリンの発現をアップレギュレーションする
材料および実験手順
ヒト表皮微小血管細胞培養および実験条件
初代ヒト表皮微小血管細胞(HEMC)をPromoCell(GmbH、Heidelberg、ドイツ)から購入した。HEMCを、15mMのHEPES、10%のウシ胎児血清(FBS)、増殖因子(ヘパリンにより安定化された酸性FGF)、ならびに、ストレプトマイシン、ネオマイシンおよびペニシリン(Biological Industries、Beit Haemek、イスラエル)を含有する1%の抗生物質溶液が補充される改変および最適化されたDMEM/F−12(1:1)であるヒト表皮微小血管内皮培地(PromoCell,GmbH、Heidelberg、ドイツ)で維持した。すべての実験を3〜6代目の継代培養物で行った。HEMCを、フィブロネクチン(10μg/ml、Chemicon International、Temecula、CA、アメリカ合衆国)で被覆された培養ディッシュに播種した。培養されたHEMCをトリプシン処理によって剥がし、フィブロネクチン被覆の24×ウエルプレートに三連で再播種した(2.5×105細胞/ウエル)。これらの培養されたHEMCを、培養培地を毎日取り替えながら、3日間連続して、増大する用量のEPO(0.01、0.1および1μg/ml/日)により処理した。3日目が終了したとき、HEMCをトリプシン処理によって剥がし、ウエスタンブロットによってβ−1インテグリンの発現について試験した。
採取された細胞をRIPA緩衝液(Sigma Aldrich、St.Louis、MO、アメリカ合衆国)によって溶解した。30μgのタンパク質サンプルを、5%のβ−メルカプトエタノールを含有する還元性緩衝液において変性し、ドデシル硫酸ナトリウム(12%)ポリアクリルアミドゲルでの電気泳動によって分離した。分離されたタンパク質を、転写緩衝液を使用して、200mAで1時間、ニトロセルロースメンブランに転写した。メンブランを、室温で1時間、TBS/0.1%Tweenにおける5%脱脂乾燥乳によりブロッキング処理し、洗浄し、TBS/0.1%Tweenにおける一次β−1インテグリン抗体(Abcam、Cambridge、英国)と4℃で一晩インキュベーションした。TBS/0.15%Tweenで洗浄した後、メンブランを適切な二次抗体(R&D Systems、MN、アメリカ合衆国)と室温で1時間インキュベーションした。洗浄後、メンブランを、製造者のプロトコル(Amersham、英国)に従って増強化学発光システムによって分析した。
β1−インテグリン(フィブロネクチンの受容体)の発現が、HEMCをEPOにさらすことによって著しく増強された(図14A〜B)。β1−インテグリンの発現が用量依存的な様式で増大し、この場合、低用量のEPO(0.01μg/ml)は2.3±0.9の発現レベルをもたらし、0.1μg/mlのEPOによる刺激は5.3±1.1の発現レベルをもたらし、高用量のEPO(1μg/ml)は18±1.4の発現レベルをもたらした(図14B)。HEMCでのβ1−インテグリン発現における際立った増大は、EPOによる刺激の結果としてであるが、EPOの結果として生じるFNの生物学的作用における増大を示唆した。したがって、このことから、血管新生、コラーゲン沈着および創傷治癒におけるEPOおよびFNの相乗作用が説明される。
FNの存在下および非存在下でのEPOは、線維芽細胞およびケラチノサイト細胞において、増殖、スーパーオキシドジスムターゼ活性およびアクアポリン−3発現をアップレギュレーションする
材料および実験手順
細胞培養
初代ヒト皮膚線維芽細胞(NHDF)および成人皮膚のケラチノサイト(KRCT)の凍結保存された二次培養物をともにLonza(Lonza、Walkersville、MD、アメリカ合衆国)から得た。NHDFおよびKRCT細胞の増殖に対するエリスロポイエチン(EPO)およびフィブロネクチン(FN)の影響を評価した。簡単に記載すると、細胞を、10%のFBSをそれぞれが含有する線維芽細胞成長培地(FGM−2、Lonza、Walkersville、MD、アメリカ合衆国)およびケラチノサイト成長培地(KGM、Lonza、Walkersville、MD、アメリカ合衆国)とともにそれぞれ穏やかに解凍した。細胞を1×107細胞/mlの密度で60mmのプレートに播種し、15%のFBS、ペニシリンGナトリウムおよび硫酸ストレプトマイシンがそれぞれに補充されたFGM−2またはKGMで12日間、5%CO2および95%空気での加湿インキュベータにおいて37℃で培養した。培地を毎日交換し、細胞を3回複製させた。8日目に、すべての非接着性細胞を培養物から除き、接着性細胞を、4日までのさらなる期間、成長させた。その後の実験において、培養の開始を0日目として定義した。実験当日に、細胞をRIPA緩衝液によって溶解し、溶解物をタンパク質発現測定のために採取した。
NHDFおよびKRCT細胞をフィブロネクチン(10μg/ml)被覆または非被覆の6ウエルプレートに1×107細胞/mlの密度で播種し、5日間培養して、(それぞれ、15%のFBSがそれぞれに補充されたFGM−2およびKGM培地において)60%〜70%のコンフルエンスに到達させた。細胞をEPO(1、5および10μg/ml)で48時間処理した。実験の24時間前に、培養物を、0.1%のFBSが補充されたフェノールレッド非含有の成長培地に入れた。24時間後、細胞を、7.5%のデキストラン−木炭処理FBSを含有するフェノールレッド非含有の成長培地に入れた。それぞれのウエルにおける細胞を、インキュベーションの最後の24時間、10μCiの[3H]−チミジン(Shanghai、中国)により標識した。その後、細胞をリン酸塩緩衝化生理食塩水(PBS)により3回洗浄し(それぞれの洗浄について5分)、その後、10%トリクロロ酢酸によるさらなる濯ぎを30分間行った。最後に、細胞を0.2mlの0.2mol/lのNaOHに溶解し、4℃で一晩放置した。放射能をシンチレーション計数によって求めた。
スーパーオキシドジスムターゼ(SOD)活性を求めるために、各サンプルの接着性NHDF細胞または接着性KRCT細胞を穏やかなトリプシン処理(0.5%トリプシン、0.2%EDTA)によって剥がし、計数し、RIPA溶解緩衝液によって溶解した。このキットでは、SOaにより還元されたとき、水溶性のホルマザン色素を生じさせたテトラゾリウム塩WST−1(4−[3−(4−ヨードフェニル)−2−(4−ニトロフェニル)−2H−5−テトラゾリオ]−1,3−ベンゼンジスルホネートナトリウム塩)が利用された。O2−による還元の速度が、キサンチンオキシダーゼ活性に対して直線的に関連づけられ、SODによって阻害された。WST−1ホルマザンの形成を400nmの吸光度変化により測定した。各サンプルの阻害率(%)を、阻害(%)=100×(H0−H1)/H0(式中、H0およびH1は、コントロールおよびSODを含有するサンプルにおいて観測されたピーク高さをそれぞれ表した)として計算した。
タンパク質を非還元条件下のPAGEによって分析し、ポリビニルジフルオライドメンブラン(Millipore、Molsheim、フランス)に電気ブロットした。メンブランを、5%の脱脂乾燥乳および0.05%のTween20を含有する0.1M Tris緩衝化生理食塩水において1:200で希釈されたAQP3抗体(Calbiochem、Nottingham、英国)、または、1:1000で希釈されたアクチン抗体(Calbiochem)と2時間インキュベーションした。その後、メンブランをTris緩衝化生理食塩水/脱脂乾燥乳/Tween20で洗浄し、1:2000で希釈された西洋ワサビペルオキシダーゼコンジュゲート化ヤギ抗ウサギIg(R&D systems)と1時間インキュベーションした。最後に、メンブランをTris緩衝化生理食塩水で洗浄し、反応生成物を、化学発光検出キット(Amersham Biosciences、Freiburg、ドイツ)を使用して検出した。生じたシグナルをデンシトメトリーによって分析し、結果を、アクチンの光学濃度に対するAQP3対応バンドの光学濃度の比率として表した。
データを平均±SEMとして、または、コントロールの百分率として表した。結果の統計学的比較を、分散分析(ANOVA)を使用して行った。コントロール群および試験群の平均間の有意な差(P<0.05)をダネット検定によって分析した。*P<0.05、**P<0.01、***P<0.001。
成人皮膚のケラチノサイト(KRCT)を、細胞増殖に対するその影響を評価するために、フィブロネクチン(FN)の存在下または非存在下、エリスロポイエチン(EPO)により処理した。図15Aから明白であるように、EPO(特に10μg)によるKRCTの処理は細胞増殖における有意な増大をもたらした。さらに、FNをこれらの細胞に加えることにより、細胞増殖における相乗的な増大がもたらされた(図15B)。
EPOはBcI−xLの発現をアップレギュレーションし、アポトーシス感受性を低下させる
材料および実験手順
実験動物
上記で実施例1において詳しく説明される通りである。
ウエスタンブロットを行った。簡単に記載すると、各群の創傷化組織のサンプルを実験12日目に得て、サンプルを、プロテアーゼ阻害剤(2.5μg/mlのロイペプチン、0.95μg/mlのアプロチニンおよび2.5mMのフェニルメチルスルホニルフッ化物)が補充されたRIPA緩衝液(50mMのTris、150mMのNaCl、2.5mg/mlのデオキシコール酸、1mMのEGTA、10μg/mlのNonidet−40、pH7.4)とともにホモジネートし、処理した。全組織溶解物に由来するタンパク質を12%SDS−PAGEに負荷した(40μg/ウエル)。ゲル内の分画化されたタンパク質をクーマシーブルーR−250により染色し、または、ウエスタンブロットを行うためにニトロセルロースメンブランに転写した。TBS−T緩衝液(50mMのトリス(ヒドロキシメチル)アミノメタン、175mMのNaCl、HClでpH7.5に調節され、0.1%のTween20が補充された)における5%の低脂肪乳をブロッキング溶液として使用した。メンブランをマウスモノクローナル抗Bax(クローンYTH6A7)一次抗体およびマウスモノクローナル抗Bcl−xL(クローンYTH2H12)一次抗体(ともに、R&D Systmesから得られる)とインキュベーションした。抗体をブロッキング溶液で1/500で希釈した。インキュベーション条件を各抗体について最適化した。二次抗体:IgGロバ抗マウス西洋ワサビペルオキシダーゼ(HRP)標識物(R&D Systems)をブロッキング溶液で1/2000で希釈した。インキュベーションを室温で1時間行った。結果を、調べられているタンパク質のデンシトメトリー単位と、負荷されたタンパク質の総μgとの比率から得られる平均±S.E.M.任意設定単位(AU)として表した。
コルモゴロフ−スミルノフ検定によれば、データは正規分布を有していた。さらに、スチューデントt検定およびANOVAを、異なる実験群の間での差を明らかにするために使用した。P<0.05のとき、差は、有意であると見なした。結果を値の平均±標準偏差として示した。
EPOは、抗アポトーシスタンパク質のBcl−xLをアップレギュレーションすることによってアポトーシスを阻害する[Dolzing(2001)]。加えて、以前の研究では、いずれか1つのメンバーの絶対的な発現レベルではなく、Bcl−2ファミリーのアポトーシス促進メンバーと抗アポトーシスメンバーとの間での比率における変化により、アポトーシス感受性が決定されることが示されている[Zhang(2000)]。
EPO、FN、または、両者を含有するクリームの配合
材料および実験手順
EPOおよびFNの配合
A=エリスロポイエチン(EPO)
B=フィブロネクチン(FN)
クリームAについて:25μg/g(最終調製物の2.50mg%)
クリームBについて:250μg/g(最終調製物の25mg%)
クリームA/B(併用クリーム)について:25μg/g(最終調製物の2.50mg%)および250μg/g(最終調製物の25mg%)
1.有効成分 必要量
2.メチルパラベン 0.20%
3.Laureth&イソパラフィン&ポリアクリルアミド 9%
4.脱イオン水 12%
5.リン酸塩緩衝溶液 100%まで
1.調製のために必要な量を計算する。
2.#2および#3を乾燥した清浄なガラス容器に計り取る。
3.下記をまとめる:
1.#2〜#4を加え、撹拌する。
2.混合物を、#2が溶解するまで撹拌しながら、ガラス容器において55℃〜60℃に加熱する。溶液を室温に冷却する。
3.#5の70%を加え、撹拌する。
4.有効成分(#1)を溶液に加え、撹拌する。
5.撹拌しながら、#3を溶液に徐々に加える。
6.#5の残りを(必要とされる体積を得るために)加え、撹拌を、均質な調製物が得られるまで続ける。
7.気密性の閉じた暗色容器において4℃で貯蔵する。
白色で、不透過性の半固体調製物が得られる。得られた調製物のpHは約6.40である。調製物は調製時のまま使用することができる。
Claims (11)
- 創傷治癒または結合組織再建をその必要性のある対象において促進するための局所投与用の医薬の製造におけるエリスロポイエチンとフィブロネクチンの使用であって、前記エリスロポイエチンの用量が創傷組織1cm2あたり10〜30μgであり、前記フィブロネクチンの用量が創傷組織1cm2あたり100〜300μgである、使用。
- 前記対象が虚血を有する、請求項1に記載の使用。
- 結合組織はコラーゲンを含む、請求項1または2に記載の使用。
- 前記エリスロポイエチンの用量が組織1cm2あたり18〜22μgである、請求項1または2に記載の使用。
- 前記フィブロネクチンの用量が組織1cm2あたり180〜220μgである、請求項1または2に記載の使用。
- 前記エリスロポイエチンおよび前記フィブロネクチンが共配合物に存在する、請求項1または2に記載の使用。
- 前記エリスロポイエチンおよび前記フィブロネクチンが別個の配合物に存在する、請求項1または2に記載の使用。
- エリスロポイエチンを10〜30μgの用量で含み、フィブロネクチンを100〜300μgの用量で含む単位投薬形態物。
- 有効成分としての10〜30μg/mlのエリスロポイエチンおよび100〜300μg/mlのフィブロネクチン、および、局所投与のためのキャリアまたは希釈剤を含む組成物。
- 細胞外マトリックス成分、増殖因子、ホルモン、血管形成因子、凝固因子、サイトカイン、ケモカイン、酵素、神経伝達物質、ビタミン、炭水化物、イオン、鉄キレーター、脂肪酸、抗生物質およびアミノ酸からなる群から選択される因子をさらに含む、請求項9に記載の組成物。
- (i)有効成分としてのエリスロポイエチンおよびフィブロネクチン、ただし、前記エリスロポイエチンの濃度が10〜30μg/mLであり、前記フィブロネクチンの濃度が100〜300μg/mLである、
(ii)0.18〜0.22%のメチルパラベン、
(iii)8.1〜9.9%のラウリルアルコールのポリエチレングリコールエーテルおよびイソパラフィンおよびポリアクリルアミド、
(iv)10.8〜13.2%の脱イオン水、ならびに、
(v)100%までのリン酸塩緩衝液
を含む配合物。
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2008
- 2008-08-13 JP JP2010520684A patent/JP5869219B2/ja active Active
- 2008-08-13 WO PCT/IL2008/001119 patent/WO2009022338A2/en active Application Filing
- 2008-08-13 EP EP08789793.0A patent/EP2192907B1/en active Active
- 2008-08-13 US US12/673,519 patent/US20110123481A1/en not_active Abandoned
- 2008-08-13 PL PL08789793T patent/PL2192907T3/pl unknown
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2014
- 2014-02-10 US US14/176,257 patent/US20140154205A1/en not_active Abandoned
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- 2015-10-14 US US14/882,608 patent/US10792338B2/en active Active
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US20190117740A1 (en) | 2019-04-25 |
PL2192907T3 (pl) | 2018-10-31 |
JP2010536745A (ja) | 2010-12-02 |
EP2192907A4 (en) | 2011-07-06 |
US20110123481A1 (en) | 2011-05-26 |
EP2192907B1 (en) | 2018-04-18 |
US20170056480A1 (en) | 2017-03-02 |
EP2192907A2 (en) | 2010-06-09 |
US10792338B2 (en) | 2020-10-06 |
US20220000987A1 (en) | 2022-01-06 |
US20190192637A1 (en) | 2019-06-27 |
WO2009022338A2 (en) | 2009-02-19 |
US20160030525A1 (en) | 2016-02-04 |
US20140154205A1 (en) | 2014-06-05 |
WO2009022338A3 (en) | 2010-03-04 |
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