Laboratory for Biointerfaces, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014 St. Gallen, Switzerland.
Ophthalmology Section, Equine Department, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland.
Biomacromolecules. 2021 Feb 8;22(2):629-639. doi: 10.1021/acs.biomac.0c01473. Epub 2020 Dec 21.
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 -induced MMP-9 activity in an 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.
基质金属蛋白酶 9（MMP-9）在许多生物过程中发挥着关键作用，虽然它对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，这在感染性角膜炎中表现为角膜的蛋白水解消化和穿孔。目前，角膜炎的医学治疗策略主要集中在抗菌作用上，但在很大程度上忽视了过量 MMP 活性的作用。在这里，报告了一种环状基质金属蛋白酶抑制剂（TIMP）肽模拟物，它在 THP-1 衍生的巨噬细胞中下调了 MMP-9 的表达水平，包括 mRNA 和蛋白质水平，以及 MMP-9 的活性。在成纤维细胞中也观察到类似的下调α平滑肌肌动蛋白（α-SMA）表达的作用。此外，TIMP 肽模拟物降低了诱导的 MMP-9 活性，在猪传染性角膜炎模型中，组织学检查表明，在肽模拟物治疗后，角膜厚度的减少与角膜炎的进展有关，这一减少受到了抑制。因此，这种降低 MMP-9 活性的方法具有很大的潜力，可以减少角膜组织损伤，提高当前治疗感染性角膜炎的临床成功率。
