Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana 46556, United States.
ACS Chem Biol. 2022 Jun 17;17(6):1357-1363. doi: 10.1021/acschembio.2c00382. Epub 2022 Jun 7.
Pressure ulcers (PUs) are chronic wounds that lead to amputations and death. Little is known about why PUs are recalcitrant to healing. Wound healing is mediated by matrix metalloproteinases (MMPs). The 24 MMPs in humans each exist in three forms, of which only one is catalytically competent. We analyzed human PU samples using an affinity resin that exclusively binds to the catalytically competent MMPs. We identified by mass spectrometry the active forms of MMP-1, MMP-8, MMP-9, and MMP-14. Concentrations of MMP-8, MMP-9, and MMP-14 were higher in human PUs compared to the healthy tissue, whereas those for MMP-1 did not change. Decreasing levels of active MMP-9 as the PU improved argued for a detrimental role for this enzyme. In a mouse model of PUs, a highly selective inhibitor for MMP-9 and MMP-14, ()-ND-336, accelerated wound closure in parallel with significant amelioration of ulcer stage. ()-ND-336 holds promise as a first-in-class treatment for PUs.
压力性溃疡（PU）是导致截肢和死亡的慢性伤口。目前人们对于为什么 PU 难以愈合知之甚少。伤口愈合是由基质金属蛋白酶（MMPs）介导的。人类的 24 种 MMP 以三种形式存在，其中只有一种具有催化能力。我们使用专门与催化活性 MMP 结合的亲和树脂分析了人类 PU 样本。通过质谱法鉴定了 MMP-1、MMP-8、MMP-9 和 MMP-14 的活性形式。与健康组织相比，人 PU 中 MMP-8、MMP-9 和 MMP-14 的浓度更高，而 MMP-1 的浓度没有变化。随着 PU 的改善，活性 MMP-9 的水平降低表明该酶具有有害作用。在 PU 的小鼠模型中，MMP-9 和 MMP-14 的高选择性抑制剂 ()-ND-336 与溃疡分期的显著改善平行加速了伤口闭合。()-ND-336 有望成为治疗 PU 的首创疗法。
