Matrix metalloproteinase 9 (MMP-9) has a key role in many biological processes, and while it is crucial for a normal immune response, excessive release of this enzyme can lead to severe tissue damage, as evidenced by proteolytic digestion and perforation of the cornea during infectious keratitis. Current medical management strategies for keratitis mostly focus on antibacterial effects, but largely neglect the role of excess MMP activity. Here, a cyclic tissue inhibitor of metalloproteinase (TIMP) peptidomimetic, which downregulated MMP-9 expression both at the mRNA and protein levels as well as MMP-9 activity in THP-1-derived macrophages, is reported. A similar downregulating effect could also be observed on α smooth muscle actin (α-SMA) expression in fibroblasts. Furthermore, the TIMP peptidomimetic reduced Pseudomonas aeruginosa-induced MMP-9 activity in an ex vivo porcine infectious keratitis model and histological examinations demonstrated that a decrease of corneal thickness, associated with keratitis progression, was inhibited upon peptidomimetic treatment. The presented approach to reduce MMP-9 activity thus holds great potential to decrease corneal tissue damage and improve the clinical success of current treatment strategies for infectious keratitis.

中文翻译：

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金属蛋白酶（TIMP）拟肽的组织抑制剂作为传染性角膜炎的辅助治疗

基质金属蛋白酶9（MMP-9）在许多生物学过程中都起着关键作用，尽管对于正常的免疫反应至关重要，但这种酶的过度释放会导致严重的组织损伤，这是由蛋白水解消化和角膜穿孔所证明的在传染性角膜炎期间。当前用于角膜炎的医学管理策略主要集中在抗菌作用上，但是在很大程度上忽略了过量的MMP活性的作用。在此，报道了一种金属蛋白酶（TIMP）拟肽的环状组织抑制剂，该抑制剂在THP-1衍生的巨噬细胞中在mRNA和蛋白质水平以及MMP-9活性上均下调了MMP-9的表达。还可以观察到对成纤维细胞中α平滑肌肌动蛋白（α-SMA）表达的类似下调作用。此外，TIMP拟肽减少了在离体猪传染性角膜炎模型中，铜绿假单胞菌诱导的MMP-9活性和组织学检查表明，拟肽治疗可抑制角膜厚度的减少（与角膜炎的进展有关）。因此，所提出的降低MMP-9活性的方法具有减少角膜组织损伤和提高当前治疗感染性角膜炎策略的临床成功的巨大潜力。