Fairweather Mark, Heit Yvonne I, Buie Justin, Rosenberg Laura M, Briggs Alexandra, Orgill Dennis P, Bertagnolli Monica M
Division of Surgical Oncology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Plastic, Aesthetic and Hand Surgery, University of Magdeburg, Germany.
J Surg Res. 2015 Apr;194(2):717-724. doi: 10.1016/j.jss.2014.12.026. Epub 2014 Dec 18.
Cyclooxygenase-2 (COX-2) is an inducible enzyme that is rapidly upregulated in response to injury, resulting in the production of prostaglandin E2 (PGE2), a primary mediator of inflammation and wound healing. The selective COX-2 inhibitor, celecoxib, is was used to treat pain and inflammation. When used to treat injuries, we postulated that loss of PGE2 activity by COX-2 inhibition would have detrimental effects on wound healing. Our objective was to study the effect of selective COX-2 inhibition with celecoxib on cutaneous wound healing.
C57BL/6J mice with uniform full-thickness wounds (1 cm(2)) to their dorsum were fed diet with or without celecoxib (1500 ppm). Wound closure analysis measured wound contraction, reepithelialization, and open wound as a percentage of the initial wound area, and was quantified by planimetry. Wounds were excised en bloc at day 7 to examine cellular proliferation, angiogenesis, cytokine production, and extracellular matrix (ECM) formation.
Celecoxib-induced reduction in wound PGE2 levels was documented by enzyme-linked immunosorbent assay on day 7 after wounding. Wound contraction and reepithelialization were significantly reduced by celecoxib treatment, resulting in a 20% greater open wound area at day 7 (P < 0.05). In response to celecoxib treatment, immunohistochemistry analysis showed epithelial cell proliferation, angiogenesis, and ECM components including collagen and myofibroblasts were significantly decreased.
Wound healing is significantly delayed by celecoxib treatment. These data indicate that COX-2 and its downstream product PGE2 modulate the activity of multiple essential functions of the inflammatory stroma, including epithelial proliferation, angiogenesis, and ECM production. As a result, reepithelialization and wound closure are delayed by celecoxib treatment. These findings have potential clinical implications in postoperative wound management.
环氧化酶 - 2（COX - 2）是一种诱导性酶，在受到损伤时会迅速上调，导致前列腺素E2（PGE2）的产生，PGE2是炎症和伤口愈合的主要介质。选择性COX - 2抑制剂塞来昔布曾被用于治疗疼痛和炎症。当用于治疗损伤时，我们推测通过抑制COX - 2导致PGE2活性丧失会对伤口愈合产生不利影响。我们的目的是研究塞来昔布选择性抑制COX - 2对皮肤伤口愈合的影响。
给背部有均匀全层伤口（1平方厘米）的C57BL/6J小鼠喂食含或不含塞来昔布（1500 ppm）的饮食。伤口闭合分析测量伤口收缩、再上皮化以及开放伤口占初始伤口面积的百分比，并通过平面测量法定量。在第7天整块切除伤口以检查细胞增殖、血管生成、细胞因子产生和细胞外基质（ECM）形成。
通过酶联免疫吸附测定法在受伤后第7天记录到塞来昔布导致伤口PGE2水平降低。塞来昔布治疗显著降低了伤口收缩和再上皮化，导致第7天开放伤口面积增大20%（P < 0.05）。针对塞来昔布治疗，免疫组织化学分析显示上皮细胞增殖、血管生成以及包括胶原蛋白和成肌纤维细胞在内的ECM成分显著减少。
塞来昔布治疗显著延迟伤口愈合。这些数据表明COX - 2及其下游产物PGE2调节炎症基质多种基本功能的活性，包括上皮增殖、血管生成和ECM产生。因此，塞来昔布治疗会延迟再上皮化和伤口闭合。这些发现对术后伤口管理具有潜在的临床意义。
