粒-巨噬細胞集落刺激因子促進草酸鉑腹腔化療下大鼠結腸吻合口愈合機制的初步研究_《中國修復重建外科雜志》

作者：

劉勇 ¹ , 楊陽 ² , 劉輝 ³ , 宋云駿 ⁴ , 賈喜花 ¹ , 張曉偉 ¹ , 郭建美 ¹

1保定市第一中心醫院腫瘤內科（河北保定，071000）;;
2河北大學中醫學院;;
3中國醫學科學院北京協和醫學院基礎醫學研究所;;
4承德市腫瘤醫院腫瘤外科;

關鍵詞：

粒-巨噬細胞集落刺激因子結腸吻合口草酸鉑愈合機制大鼠

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目的觀察粒-巨噬細胞集落刺激因子（granulocyte macrophage-colony stimulating factor，GM-CSF）局部應用于草酸鉑腹腔化療下大鼠結腸吻合口愈合過程中的組織學變化，探討其作用機制。方法10周齡清潔級雄性Wistar大鼠60只，體重（235 ± 18） g，制備結腸吻合模型，隨機分為3組（n=20）。術后1 d，A、B組腹腔對應注射10 mL 5%葡萄糖溶液、10 mL含草酸鉑（25 mg/kg）的5%葡萄糖溶液；C組術后即刻吻合口區域注射50 μg GM-CSF，術后1 d腹腔注射10 mL含草酸鉑（25 mg/kg）的5%葡萄糖溶液。術后觀察大鼠一般情況，于2、3、5、7 d測量吻合口破裂壓，組織學觀察并計算吻合口愈合指數，免疫組織化學染色檢測Ⅰ型膠原纖維陽性染色面積。結果術后各組大鼠均存活至實驗完成。術后2、3 d 各組吻合口破裂壓相似（P gt; 0.05）；5、7 d時，B組吻合口破裂壓顯著低于A、C組（P lt; 0.05），A、C組間差異無統計學意義（P gt; 0.05）。吻合口愈合指數結果示，術后各時間點，A、C組間單核細胞浸潤、黏膜上皮細胞覆蓋、黏膜下層-肌層銜接程度及肉芽組織形成相似（P gt; 0.05），A、C組黏膜上皮細胞覆蓋及肉芽組織形成均顯著優于B組（P lt; 0.05）；術后2、3 d，A、C組單核細胞浸潤顯著優于B組（P lt; 0.05），5、7 d黏膜下層-肌層銜接程度優于B組（P lt; 0.05）。術后2、3 d，各組Ⅰ型膠原纖維陽性染色面積比較差異均無統計學意義（P gt; 0.05）；5、7 d時A、C組Ⅰ型膠原纖維陽性染色面積顯著高于B組（P lt; 0.05），A、C組間比較差異無統計學意義（P gt; 0.05）。結論局部注射GM-CSF可通過早期動員巨噬細胞浸潤，提高大鼠黏膜下層膠原纖維沉積，從而加速結腸愈合進程。

引用本文： 劉勇,楊陽,劉輝,宋云駿,賈喜花,張曉偉,郭建美. 粒-巨噬細胞集落刺激因子促進草酸鉑腹腔化療下大鼠結腸吻合口愈合機制的初步研究. 中國修復重建外科雜志, 2012, 26(10): 1232-1236. doi: 復制

1.	Lipska MA, Bissett IP, Parry BR, et al. Anastomotic leakage after lower gastrointestinal anastomosis: men are at a higher risk. ANZ J Surg, 2006, 76(7): 579-585.
2.	Mann A, Niekisch K, Schirmacher P, et al. Granulocyte-macrophage colony-stimulating factor is essential for normal wound healing. J Investig Dermatol Symp Proc, 2006, 11(1): 87-92.
3.	劉勇, 楊陽, 王娟. 早期腹腔化療與胃腸吻合口的愈合. 國際腫瘤學雜志, 2007, 34(1): 65-67.
4.	劉勇, 楊陽, 劉輝, 等. 草酸鉑腹腔化療對大鼠結腸吻合口愈合影響及粒-巨噬細胞集落刺激因子的干預效應. 中華臨床醫師雜志(電子版), 2011, 5(20): 5960-5963.
5.	Verhofstad MH, Lange WP, van der Laak JA, et al. Microscopic analysis of anastomotic healing in the intestine of normal and diabetic rats. Dis Colon Rectum, 2001, 44(3): 423-431.
6.	Güven A, Pehlivan M, Gökpinar I, et al. Early glutamine-enriched enteral feeding facilitates colonic anastomosis healing: light microscopic and immunohistochemical evaluation. Acta Histochem, 2007, 109(2): 122-129.
7.	Hribaschek A, Pross M, Kuhn R, et al. Prevention and treatment of peritoneal carcinomatosis in experimental investigations with CPT-11 and oxaliplatin. Anticancer Drugs, 2002, 13(6): 605-614.
8.	Mann A, Breuhahn K, Schirmacher P, et al. Keratinocyte-derived granulocyte-macrophage colony stimulating factor accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization. J Invest Dermatol, 2001, 117(6): 1382-1390.
9.	Fatouros MS, Vekinis G, Bourantas KL, et al. Influence of growth factors erythropoietin and granulocyte macrophage colony stimulating factor on mechanical strength and healing of colonic anastomoses in rats. Eur J Surg, 1999, 165(10): 986-992.
10.	De Waard JW, Wobbes T, van der Linden CJ, et al. Retinol may promote fluorouracil-suppressed healing of experimental intestinal anastomoses. Arch Surg, 1995, 130(9): 959-965.
11.	郝光榮. 實驗動物學. 2版. 上海: 第二軍醫大學出版社, 2002: 276.
12.	Dinc S, Gulcelik MA, Kuru B, et al. Effects of locally applied recombinant human granulocyte-macrophage colony-stimulating factor on ischemic bowel anastomoses in rat. Eur Surg Res, 2004, 36(1): 59-63.
13.	Dinc S, Alagol H, Gulcelik MA, et al. Locally applied granulocyte-macrophage colony-stimulating factor improves the impaired bowel anastomoses in rats with long-term corticosteroid treatment. World J Surg, 2002, 26(10): 1208-1213.
14.	Dinc S, Ozbirecikli B, Gulcelik MA, et al. The effects of locally injected granulocyte macrophage-colony stimulating factor on the healing of intraoperatively irradiated intestinal anastomoses in rats. J Exp Clin Cancer Res, 2004, 23(1): 77-82.
15.	Fang Y, Shen J, Yao M, et al. Granulocyte-macrophage colony-stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines. Br J Dermatol, 2010, 162(3): 478-486.
16.	Miao M, Niu Y, Xie T, et al. Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation. Wound Repair Regen, 2012, 20(2): 203-213.
17.	Jyung RW, Wu L, Pierce GF, et al. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: differential action on incisional wound healing. Surgery, 1994, 115(3): 325-334.
18.	Witte MB, Barbul A. Repair of full-thickness bowel injury. Crit Care Med, 2003, 31(8 Suppl): S538-546.
19.	Thornton FJ, Barbul A. Healing in the gastrointestinal tract. Surg Clin North Am, 1997, 77(3): 549-573.
20.	Cross KJ, Mustoe TA. Growth factors in wound healing. Surg Clin North Am, 2003, 83(3): 531-545.

1. Lipska MA, Bissett IP, Parry BR, et al. Anastomotic leakage after lower gastrointestinal anastomosis: men are at a higher risk. ANZ J Surg, 2006, 76(7): 579-585.
2. Mann A, Niekisch K, Schirmacher P, et al. Granulocyte-macrophage colony-stimulating factor is essential for normal wound healing. J Investig Dermatol Symp Proc, 2006, 11(1): 87-92.
3. 劉勇, 楊陽, 王娟. 早期腹腔化療與胃腸吻合口的愈合. 國際腫瘤學雜志, 2007, 34(1): 65-67.
4. 劉勇, 楊陽, 劉輝, 等. 草酸鉑腹腔化療對大鼠結腸吻合口愈合影響及粒-巨噬細胞集落刺激因子的干預效應. 中華臨床醫師雜志(電子版), 2011, 5(20): 5960-5963.
5. Verhofstad MH, Lange WP, van der Laak JA, et al. Microscopic analysis of anastomotic healing in the intestine of normal and diabetic rats. Dis Colon Rectum, 2001, 44(3): 423-431.
6. Güven A, Pehlivan M, Gökpinar I, et al. Early glutamine-enriched enteral feeding facilitates colonic anastomosis healing: light microscopic and immunohistochemical evaluation. Acta Histochem, 2007, 109(2): 122-129.
7. Hribaschek A, Pross M, Kuhn R, et al. Prevention and treatment of peritoneal carcinomatosis in experimental investigations with CPT-11 and oxaliplatin. Anticancer Drugs, 2002, 13(6): 605-614.
8. Mann A, Breuhahn K, Schirmacher P, et al. Keratinocyte-derived granulocyte-macrophage colony stimulating factor accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization. J Invest Dermatol, 2001, 117(6): 1382-1390.
9. Fatouros MS, Vekinis G, Bourantas KL, et al. Influence of growth factors erythropoietin and granulocyte macrophage colony stimulating factor on mechanical strength and healing of colonic anastomoses in rats. Eur J Surg, 1999, 165(10): 986-992.
10. De Waard JW, Wobbes T, van der Linden CJ, et al. Retinol may promote fluorouracil-suppressed healing of experimental intestinal anastomoses. Arch Surg, 1995, 130(9): 959-965.
11. 郝光榮. 實驗動物學. 2版. 上海: 第二軍醫大學出版社, 2002: 276.
12. Dinc S, Gulcelik MA, Kuru B, et al. Effects of locally applied recombinant human granulocyte-macrophage colony-stimulating factor on ischemic bowel anastomoses in rat. Eur Surg Res, 2004, 36(1): 59-63.
13. Dinc S, Alagol H, Gulcelik MA, et al. Locally applied granulocyte-macrophage colony-stimulating factor improves the impaired bowel anastomoses in rats with long-term corticosteroid treatment. World J Surg, 2002, 26(10): 1208-1213.
14. Dinc S, Ozbirecikli B, Gulcelik MA, et al. The effects of locally injected granulocyte macrophage-colony stimulating factor on the healing of intraoperatively irradiated intestinal anastomoses in rats. J Exp Clin Cancer Res, 2004, 23(1): 77-82.
15. Fang Y, Shen J, Yao M, et al. Granulocyte-macrophage colony-stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines. Br J Dermatol, 2010, 162(3): 478-486.
16. Miao M, Niu Y, Xie T, et al. Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation. Wound Repair Regen, 2012, 20(2): 203-213.
17. Jyung RW, Wu L, Pierce GF, et al. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: differential action on incisional wound healing. Surgery, 1994, 115(3): 325-334.
18. Witte MB, Barbul A. Repair of full-thickness bowel injury. Crit Care Med, 2003, 31(8 Suppl): S538-546.
19. Thornton FJ, Barbul A. Healing in the gastrointestinal tract. Surg Clin North Am, 1997, 77(3): 549-573.
20. Cross KJ, Mustoe TA. Growth factors in wound healing. Surg Clin North Am, 2003, 83(3): 531-545.

《中國修復重建外科雜志》

粒-巨噬細胞集落刺激因子促進草酸鉑腹腔化療下大鼠結腸吻合口愈合機制的初步研究

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《中國修復重建外科雜志》

粒-巨噬細胞集落刺激因子促進草酸鉑腹腔化療下大鼠結腸吻合口愈合機制的初步研究

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