Keratinocyte Growth Factor Combined with a Sodium Hyaluronate Gel Inhibits Postoperative Intra-Abdominal Adhesions.
Keratinocyte Growth Factor Combined with a Sodium Hyaluronate Gel Inhibits Postoperative Intra-Abdominal Adhesions.
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角质形成细胞生长因子与透明质酸钠凝胶相结合可抑制术后腹腔粘连。
DOI：
10.3390/ijms17101611
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发表时间：
2016-09-22
影响因子：
5.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Wei G;Zhou C;Wang G;Fan L;Wang K;Li X
腹腔粘连是腹部手术后常见的并发症。一个尚待解决的临床问题是确定一种理想的策略来预防腹腔粘连。角质细胞生长因子（KGF）已被证明可以促进间皮细胞的增殖，这可能会增强纤溶活性，以抑制术后粘连。本研究探讨了KGF和透明质酸钠（HA）凝胶联合给药是否可以通过改善腹膜间皮细胞的有序修复来预防腹腔粘连。还探讨了可能的预防机制。剖腹手术后，盲肠壁及其对侧壁层腹膜被磨损，以诱导腹腔内粘连形成。将动物随机分配以接受HA、KGF、KGF + HA或生理盐水（对照）的局部应用。术后第7天，采用视觉评分系统评估粘连评分。Masson三色染色、天狼星红染色和羟脯氨酸测定用于评估粘连和组织纤维化的程度。免疫组化检测间皮细胞的标志物细胞角蛋白。采用酶联免疫吸附法（ELISA）检测腹腔液中组织型纤溶酶原激活物（tPA）、白细胞介素6（IL-6）和转化生长因子β1（TGF-β1）的水平。Western blotting检测大鼠腹膜粘连组织中TGF-β1、纤维蛋白原和α-平滑肌肌动蛋白（α-SMA）的表达。联合应用KGF和HA可显著减少腹腔粘连形成和纤维蛋白沉积，促进腹膜间皮细胞有序修复。KGF和HA联合应用可显著提高腹腔液中tPA水平，降低腹腔液中IL-6、TNF-α和TGF-β1水平。KGF和HA联合应用后，大鼠腹膜或粘连组织中TGF-β1、纤维蛋白原和α-SMA蛋白及mRNA的表达水平均明显下调。联合应用KGF和HA可通过维持损伤腹膜的分离和促进间皮细胞再生，显著预防术后腹腔粘连的形成。其机制可能与腹膜损伤后间皮细胞的快速修复有关。本研究提示，KGF与HA联合应用可能是一种很有前途的预防腹腔粘连的药物治疗策略，值得进一步研究，具有潜在的临床应用价值。
Postoperative intra-abdominal adhesion is a very common complication after abdominal surgery. One clinical problem that remains to be solved is to identify an ideal strategy to prevent abdominal adhesions. Keratinocyte growth factor (KGF) has been proven to improve the proliferation of mesothelial cells, which may enhance fibrinolytic activity to suppress postoperative adhesions. This study investigated whether the combined administration of KGF and a sodium hyaluronate (HA) gel can prevent intra-abdominal adhesions by improving the orderly repair of the peritoneal mesothelial cells. The possible prevention mechanism was also explored. The cecum wall and its opposite parietal peritoneum were abraded after laparotomy to induce intra-abdominal adhesion formation. Animals were randomly allocated to receive topical application of HA, KGF, KGF + HA, or normal saline (Control). On postoperative day 7, the adhesion score was assessed with a visual scoring system. Masson’s trichrome staining, picrosirius red staining and hydroxyproline assays were used to assess the magnitude of adhesion and tissue fibrosis. Cytokeratin, a marker of the mesothelial cells, was detected by immunohistochemistry. The levels of tissue plasminogen activator (tPA), interleukin-6 (IL-6), and transforming growth factor β1 (TGF-β1) in the abdominal fluid were determined using enzyme-linked immunosorbent assays (ELISAs). Western blotting was performed to examine the expression of the TGF-β1, fibrinogen and α-smooth muscle actin (α-SMA) proteins in the rat peritoneal adhesion tissue. The combined administration of KGF and HA significantly reduced intra-abdominal adhesion formation and fibrin deposition and improved the orderly repair of the peritoneal mesothelial cells in the rat model. Furthermore, the combined administration of KGF and HA significantly increased the tPA levels but reduced the levels of IL-6, tumor necrosis factor α (TNF-α) and TGF-β1 in the abdominal fluid. The expression levels of TGF-β1, fibrinogen and α-SMA protein and mRNA in the rat peritoneum or adhesion tissues were also down-regulated following the combined administration of KGF and HA. The combined administration of KGF and HA can significantly prevent postoperative intra-abdominal adhesion formation by maintaining the separation of the injured peritoneum and promoting mesothelial cell regeneration. The potential mechanism may be associated with rapid mesothelial cell repair in the injured peritoneum. This study suggests that combined administration of KGF and HA may be a promising pharmacotherapeutic strategy for preventing abdominal adhesions, which is worth further study, and has potential value in clinical applications.
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