本論文目的為研究一種GLP-1R類似物exendin-4 (Ex4)，對於糖尿病模型大鼠切除性傷口之促進癒合潛力。傷口手術前72小時，以腹腔注射鏈佐酶素 (Streptozotocin，STZ)，誘導大鼠糖尿病模型，之後在其背部開創傷口，2*2 cm2，隨機分組給予安慰劑或是GLP-1R類似物exendin-4 (以腹腔注射低濃度劑量0.5 g/公斤/天)連續治療兩週。術後癒合程度會與原始傷口面積以比例換算進行比較；測量術後第三天與第十四天傷口組織中的超氧陰離子 (Superoxide anions)與前發炎 (Pro-inflammatory)細胞激素，以了解不同傷口癒合進程的發炎狀況，並測定前血管新生因子與細胞外基質以評估血管新生 (Angiogenesis)表現。結果發現經低濃度劑量治療，可在不影響血糖下，顯著抑制糖尿病傷口組織發炎；同時在術後第十一天以18G針頭將matrigel植入大鼠腹部皮下，在術後第十四天犧牲分析，從定性外觀與matrigel血紅素分析也證實exendin-4能幫助微血管新生；exendin-4連續治療14天後，能讓糖尿病鼠傷口組織中的促血管內皮生長因子受體-2 (Vascular endothelial growth factor receptor 2，VEGFR2)、磷酸化内皮型一氧化氮合酶 (Endothelial nitric oxide synthase，eNOS)、基質金屬蛋白酶 (Matrix metalloproteinase-2，MMP-2)與轉型生長因子 (Transforming growth factor，TGF-)蛋白質表現量上升；傷口組織切片結果也證明exendin-4促進血管形成，並能夠影響皮膚表皮層與真皮層細胞增殖。結論利用GLP-1R類似物exendin-4治療後，經由減緩早期發炎、促進增殖期血管新生並增強成熟期TGF-/MMP路徑表現，最後改善糖尿病傷口癒合。 This study investigated the therapeutic potential of exendin-4, a GLP-1 receptor analogue, in a diabetic rat model of excisional wound injury. After creation of wound on the dorsal skin, the streptozotocin-induced diabetic rats were randomly assigned to receive saline or a GLP-1R analogue (exendin-4, 0.5 g/kg/d, i.p.) for 2 weeks. Wound healing was compared by measuring the final-to-initial wound area ratio. Generation of superoxide anions and pro-inflammatory cytokines in the wound was determined. Levels of angiogenesis, expressions of pro-angiogenic factors and extracellular matrix were assayed. Treatment with exendin-4 restored the wound closure in diabetic rats, and significantly suppressed the tissue generation of superoxide anions and interleukins (IL)-6 in the wounds. Circulating endothelial progenitor (CD34+/KDR+) cells increased significantly and the in vivo matrigel assay also demonstrated increased capillary tube formation. Expressions of VEGFR2, phosphorylated eNOS, MMP-2 and TGF- were enhanced during .the wound healing phases. Histological examination confirmed that enxedin-4 enhanced vascularity, dermal and epidermal regeneration, and increased proliferative cells in the dermis. Agonism of GLP-1R using exendin-4 attenuates inflammatory response and enhances angiogenesis at the early proliferation phases, and augments the TGF-/MMP regenerative pathway at the maturation phase of diabetic wound healing.
