( ) (margination) (migration) interleukin -6 (platelet-derived growth factor, PDGF) (transforming growth factor-, TGF- ) (epidermal growth factor, EGF

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wound healing DNA (recombinant human epidermal growth factor, rhegf) (recombinant human platelet-derived growth factor, rhpdgf) 3 ( r

1 郭緒東 1,2 張天長 3 前言 (chemokines) ( a d h e s i o n moleculars) (cumulative injury) 1 林新醫院家庭醫學部 2 國立中興大學生物醫學工程研究所 3 張天長診所 recombinant human epidermal growth factor, recombinant human platelet-derived growth factor, recombinant human transforming growth factor- 3, wound healing DNA (recombinant human epidermal growth factor, rhegf) (recombinant human platelet-derived growth factor, rhpdgf) 3 ( r e c o m b i n a n t h u m a n transforming growth factor- 3, rhtgf- 3) 傷口癒合的病理與生理 (po2) <30mmHg <10mmHg (remodelling) 家庭醫學與基層醫療第二十五卷第十期 389

( ) (margination) (migration) interleukin -6 (platelet-derived growth factor, PDGF) (transforming growth factor-, TGF- ) (epidermal growth factor, EGF) PDGF TGF- (tensile strength) (degradation)

2 ( ) (margination) (migration) interleukin -6 (platelet-derived growth factor, PDGF) (transforming growth factor-, TGF- ) (epidermal growth factor, EGF) PDGF TGF- (tensile strength) (degradation) (matrix metalloproteinases, MMPs) ( t i s s u e i n h i b i t o r s o f m a t r i x 圖一癒合的生理過程與細胞激素作用 * 資料來源 : 參考資料 3 *FGF: Fibroblast growth factors, IL-8: interleukin-8, MCP-1: monocyte chemotactic protein-1, PDGF: platelet-derived growth factor, PF-4: platelet factor-4, TGF-β: transforming growth factor-β, VEGF: Vascular endothelial growth factor, β-thg: β-thromboglobulin. 390 家庭醫學與基層醫療第二十五卷第十期

3 metalloproteinases, TIMPs) MMPs TIMPs TGF- MMPs TIMPs (synthesis) I III V I III IV (basement membrane) MMPs MMPs III I MMPs TIMPs MMPs TIMPs E G F PDGF EGF EGF (proliferating cell nuclear antigen) ( -smooth muscle actin) prolyl 4-hydroxylase (migration) EGF EGF (Cu/Zn superoxide dismutase) PDGF T G F - EGF >99% >42% 生長因子在傷口癒合的角色 ( ) (proto-oncogene) 家庭醫學與基層醫療第二十五卷第十期 391

4 rhegf, rhpdgf, rhtgf- 3 (randomized controlled studies, RCS) ( p o s t - m a r k e t i n g surveillance, PMS) 一重組人類血小板生長因子 (rhpdgf) 的相關研究表一生長因子在傷口癒合的角色 1980 PDGF PDGF TGF- (glycosaminoglycan) (fibronectin) I PDGF PDGF PDGF 生長因子主要來源癒合功能角色 Va s c u l a r e n d o t h e l i a l growth factor (VEGF) Fibroblast growth factors (FGFs) K e r a t i n o c y t e g r o w t h factors (KGFs) Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF) Granulocyte macrophagecolony stimulating factor (GM-CSF) T r a n s f o r m i n g g r o w t h factor-α (TGF-α) T r a n s f o r m i n g g r o w t h factor-β (TGF-β) Insulin-like growth factor-1 (IGF-1) Platelets, neutrophils Fibroblasts, endothelial cells, smooth muscle cells, m a c r o p h a g e s ; a l s o b r a i n, pituitary Fibroblasts P l a t e l e t s, m a c r o p h a g e s, keratinocytes; also saliva, urine, milk, plasma P l a t e l e t s, f i b r o b l a s t s, macrophages, endothelial cells M o n o c y t e s, f i b r o b l a s t s, lymphocytes A c t i v a t e d m a c r o p h a g e s, platelets, epithelial cells P l a t e l e t s, m a c r o p h a g e s, fibroblasts, neutrophils, keratinocytes Fibroblasts, plasma, liver Interleukin-8( 細胞激素 ) P l a t e l e t s, M a c r o p h a g e s, Endothelial cells 資料來源 : 參考資料刺激肉芽組織血管新生刺激周邊間接血管生成纖維母細胞及表皮細胞增生傷口攣縮及加速肉芽生成角質細胞增生刺激分化, 增生與吞噬反應角質細胞增生與重組刺激平滑肌, 血管內皮細胞, 纖維母細胞活化趨化嗜中性白血球與巨噬細胞刺激 TGF-β, MCP-1 生成調節表皮細胞增生刺激表皮細胞和纖維母細胞活化血管新生與肉芽生成趨化巨噬細胞和活化纖維母細胞產生 TIMP 而活化膠原重塑纖維母細胞增生刺激蛋白醣與膠原新生趨化嗜中性白血球和纖維母細胞 392 家庭醫學與基層醫療第二十五卷第十期

5 PDGF PDGF DNA rhpdgf rhpdgf-bb 0.01% rhpdgf RCS PMS (po2) >30mmHg 0.003% 23% 0.01% 0.003% 14% % rhpdgf rhpdgf 10 (parabens) ( ) ( 15gm) 45gm 0.01% rhpdgf 3% 2.7 guideline E G F Stanley C Rita LM EGF EGF EGF m i t o g e n - a c t i v a t e d protein kinase(mapk) pathway phospholipase-c (PLC ) pathway ( ) EGF 1996 Robson EGF EGF rhegf EGF (pemphigus vulgaris) EGF rhegf 29% EGF (ulcerative colitis) 家庭醫學與基層醫療第二十五卷第十期 393

圖二 EGF 接受體轉錄刺激各種訊號 * TARGET CELL EGF EGF-R 核轉導轉錄因子資料來源 : 參考資料 7 *EGF: Epidermal growth factor. EGF-R: Epidermal growth factor receptor. IP3: inositol 1,4,5,-triphosphate. DAG: diacylglycerol.

6 圖二 EGF 接受體轉錄刺激各種訊號 * TARGET CELL EGF EGF-R 核轉導轉錄因子資料來源 : 參考資料 7 *EGF: Epidermal growth factor. EGF-R: Epidermal growth factor receptor. IP3: inositol 1,4,5,-triphosphate. DAG: diacylglycerol. MAPK: mitogen-activated protein kinase. PLCγ: phospholipase-cγ. PKC: protein kinase C. PIP2: lipid phosphatidylinositol(4,5)bisphosphate. STAT: signal transducers and activators of transcription. Diabetes Care 2003 rhegf 150mcg/g PMS % 10 69% 48% 2 rhegf rhegf Wagner's grade I II 2008 Hardwicke g / m L rhegf rhegf 394 家庭醫學與基層醫療第二十五卷第十期

7 三重組人類變形生長因子 β 3 (rhtgf-β3) 的相關研究 T G F TGF- 3 TGF- 1 2 TGF- 3 TGF- 1 2 TGF- 3 rhtgf- 3 7 rhtgf ng/100 L/cm rhtgf- 3 生長因子與致癌基因的關係 rhpdgf (actin) (reorganization) (1) (2) (3) (transport protein) (4) (transcription activator) (5) DNA ( ) 表二前致癌基因與蛋白和其相關的不正常細胞調節機轉 * 前致癌基因調節對象基因類型引發活化機制 erb-b1 EGF receptor 生長因子接受體基因增幅 erb-b2 EGF-like receptor 生長因子接受體基因增幅 sis PDGF-β chain 生長因子過量表現 hst-1 FGF 生長因子過量表現 bcl-2 Mitochondrion protein 抑制凋亡轉位啟動 abl Tyrosine kinase 訊息傳導轉位啟動 ras GTP 訊息傳導點突變 myc Transcription 細胞核調節轉位啟動資料來源 : 參考資料 4 *EGF: Epidermal growth factor, PDGF: platelet-derived growth factor, FGF: Fibroblast growth factors GTP: guanine triphosphate. 家庭醫學與基層醫療第二十五卷第十期 395

8 M M P s TIMPs IV (micrometastasis) rhegf 結語 EGF rhegf 參考資料 1. Robson MC, Mustoe TA, Hunt TK: The future of recombinant growth factors in wound healing. Am J Surg 1998;176: Inoue M, Ono I, Tateshita T, Kuroyanagi Y, Shioya N: Effect of a collagen matrix containing epidermal growth factor on wound contraction. Wound Rep Reg 1998;6: Halloran CM, Slavin JP: Pathophysiology of wound healing. Surgery 2002;20: Stevens A, Lowe J: Pathology. 2nd ed. Yi-Hsien Publishing Co., 2004: Anil B, Venkatesh S, Pinaki D, Dhillon MS, Sambit D, Aditya A: Which is the better option? recombinant human PDGF-BB 0.01% gel or standard wound care, in diabetic neuropathic large plantar ulcers off-loaded by a customized c o n t a c t c a s t?. D i a b e t e s R e s C l i n P r a c t 2009;83: Repertinger SK, Campagnaro E, Fuhrman J, et al: EGFR enhances early healing after cutaneous i n c i s i o n a l w o u n d i n g. J I n v e s t D e r m a t o l 2004;123: Hardwicke J, Ferguson EL, Moseley R, Stephens P, Thomas DW, Duncan R: Dextrinr-rhEGF conjugates as bioresponsive nanomedicines for wound repair. J Contr Release 2008;130: Sinha A, Nightingale J, West KP, et al: Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003;349: Viswanathan V, Pendsey S, Sekar N, Murthy GSR: A phase III study to evaluate the safety and efficacy of rhegf (REGEN-D TM 150) in healing diabetic foot ulcers. Wounds 2006;18: Ferguson MWJ, Duncan J, Bond J, et al: Prophylactic administration of Avotermin for improvement of skin scarring: three doubleblind, placebo-controlled, phase I/II studies. The Lancet 2009;373: 家庭醫學與基層醫療第二十五卷第十期

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