Mast cells facilitate local VEGF release as an early event in the pathogenesis of postoperative peritoneal adhesions
Mast cells facilitate local VEGF release as an early event in the pathogenesis of postoperative peritoneal adhesions
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DOI：
10.1016/j.surg.2006.01.020
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发表时间：
2006-07-01
期刊：
影响因子：
3.8
通讯作者：
Redmond, H. Paul
中科院分区：
文献类型：
--
作者：
Cahill, Ronan A.;Wang, Jiang Huai;Redmond, H. Paul
背景剖腹手术中持续的腹膜损伤可能引起局部炎症反应，导致粘连形成。腹膜肥大细胞可能启动这一过程，而血管通透性/内皮生长因子（VEGF）可能促进后续粘连形成的程度。肥大细胞缺陷小鼠（WBB 6 F1-/-），沿着其肥大细胞充足的对应物（WBB 6 F1 +/+），进行标准化的粘附诱导手术（AIS），随后在14天后以盲法处死并进行粘附评估。在手术后2、6、12和24小时处死另外的CD-1和WBB 6 F1 +/+以及WBB 6 F1-/-小鼠，以通过ELISA测量全身血清和腹腔灌洗液中的VEGF。另外两组CD-1小鼠进行AIS，并接受单次围手术期剂量的抗VEGF单克隆抗体（10 μ g/小鼠）或相似体积的IgG同种型抗体，并在2周后评估粘连形成。WBB 6 F1-/-小鼠的粘连比WBB 6 F1 +/+小鼠的粘连更少（中位[四分位距]粘连评分分别为3[3-3] vs 1.5[1-2]; P < .003）。在WBB 6 F1 +/+和CD-1小鼠中，局部VEGF释放在AIS后6小时达到峰值，而在WBB 6 F1-/-小鼠中水平保持在基线。在手术期间接受单剂量抗VEGF治疗的CD-1小鼠的粘连比对照组少（2[1.25-2] vs 3[2.25-3]，P = .0002）。肥大细胞和VEGF是术后腹腔粘连形成的中心，肥大细胞直接或间接地负责VEGF在术后释放到腹腔中。与最近抗VEGF单克隆抗体在肿瘤学实践中的临床成功相结合，我们的观察结果表明，抗粘附策略的研究和开发是一个有趣的途径。
Background. Peritoneal injury sustained at laparotomy may evoke local inflammatory responses that result in adhesion formation. Peritoneal mast cells are likely to initiate this process, whereas vascular permeability/endothelial growth factor (VEGF) may facilitate the degree to which subsequent adhesion formation occurs.Methods. Mast cell deficient mice (WBB6F1-/-), along with their mast cell sufficient counterparts (WBB6F1+/+), underwent a standardized adhesion-inducing operation (AIS) with subsequent sacrifice and adhesion assessment 14 days later in a blinded fashion. Additional CD-1 and WBB6F1+/+, and WBB6F1-/- mice were killed 2, 6, 12, and 24 hours after operation for measurement of VEGF by ELISA in systemic serum and peritoneal lavage fluid. Two further groups of CD-I mice underwent AIS and received either a single perioperative dose of anti-VEGF monoclonal antibody (10 mu g/mouse) or a similar volume of IgG isotypic antibody and adhesion formation 2 weeks later was evaluated.Results. WBB6F1-/- mice had less adhesions then did their WBB6F1+/+ counterparts (median [interquartile range] adhesion score 3[3-3] vs 1.5[1-2] respectively; P < .003). Local VEGF release peaked 6 hours after AIS in both WBB6F1+/+ and CD-1 mice whereas levels remained at baseline in WBB6F1-/- mice. CD-1 mice treated with a single dose of anti-VEGF therapy during operation had less adhesions than controls (2[1.25-2] vs 3[2.25-3], P = .0002).Conclusions. Mast cells and VEGF are central to the formation of Postoperative intra-abdominal adhesions with mast cells being responsible, either directly or indirectly, for VEGF release into the peritoneal cavity after operation. In tandem with the recent clinical success of anti-VEGF monoclonal antibodies in oncologic practice, our observations suggest an intriguing avenue for research and development of anti-adhesion strategy.