Tumor necrosis factor-alpha (TNF-α) is a therapeutic target for impaired cutaneous wound healing.
Tumor necrosis factor-alpha (TNF-α) is a therapeutic target for impaired cutaneous wound healing.
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DOI：
10.1111/j.1524-475x.2011.00748.x
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Wahl SM
中科院分区：
文献类型：
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作者：
Ashcroft GS;Jeong MJ;Ashworth JJ;Hardman M;Jin W;Moutsopoulos N;Wild T;McCartney-Francis N;Sim D;McGrady G;Song XY;Wahl SM
受损的伤口愈合状态导致相当大的发病率和治疗成本，仅在美国每年就导致数十亿美元的支出。慢性伤口和受损的急性伤口都以过度炎症、增强的蛋白水解和减少的基质沉积为特征。这些混杂因素在老年人中加重，正如我们在此报告的，部分与局部和全身肿瘤坏死因子α（TNFα）水平升高有关。此外，我们使用了分泌性白细胞蛋白酶抑制剂（SLPI）无效小鼠模型（与年龄相关的人类愈合延迟相当），以证明局部应用抗TNF α中和抗体可减弱白细胞募集和NFκB活化，改变M1和M2巨噬细胞之间的平衡，并加速伤口愈合。在TNFα拮抗作用后，基质合成增强，与炎症参数和NFκB结合活性的抑制相关。我们的数据表明，抑制TNFα是逆转与缺乏SLPI相关的严重受损愈合反应的关键事件，可能适用于预防和/或治疗人类伤口愈合受损状态。
Impaired wound healing states lead to substantial morbidity and cost with treatment resulting in an expenditure of billions of dollars per annum in the USA alone. Both chronic wounds and impaired acute wounds are characterized by excessive inflammation, enhanced proteolysis, and reduced matrix deposition. These confounding factors are exacerbated in the elderly, in part, as we report here, related to increased local and systemic tumor necrosis factor alpha(TNFα) levels. Moreover, we have used a secretory leukocyte protease inhibitor(SLPI) null mouse model of severely impaired wound healing and excessive inflammation, comparable to age-related delayed human healing, to demonstrate that topical application of anti-TNFα neutralizing antibodies blunts leukocyte recruitment and NFκB activation, alters the balance between M1 and M2 macrophages, and accelerates wound healing. Following antagonism of TNFα, matrix synthesis is enhanced, associated with suppression of both inflammatory parameters and NFκB binding activity. Our data suggest that inhibiting TNFα is a critical event in reversing the severely impaired healing response associated with the absence of SLPI, and may be applicable to prophylaxis and/or treatment of impaired wound healing states in humans.