Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Int J Mol Sci. 2020 Sep 18;21(18):6840. doi: 10.3390/ijms21186840.
Prior work has indicated that thymosin beta 4 (Tβ4) administered with ciprofloxacin markedly improves disease outcome for (PA)-induced keratitis. As a result, the goal of the current study was to elucidate mechanisms by which Tβ4 mitigates the corneal response; specifically, regarding its bactericidal influence and potential synergy with ciprofloxacin. An in vitro approach was carried out using minimum inhibitory concentration (MIC) assays to assess bactericidal activity against PA. In addition, antimicrobial peptide (AMP) production was evaluated at the mRNA levels using human corneal epithelial cells in response to lipopolysaccharide (LPS) challenge. The results of the MIC assays did not show direct bactericidal activity with Tβ4 alone, although ciprofloxacin exhibited significant killing at concentrations far lower than clinically dosed. Tβ4, however, displayed an indirect effect on bacterial killing, as shown by an upregulation of AMPs and related molecules. The cumulative data from this study indicate an indirect bactericidal role of Tβ4, as well as a synergistic relationship with ciprofloxacin. Furthermore, ciprofloxacin alone was found to influence cellular functions that otherwise have yet to be reported. These results highlight a mechanism of intracellular communication for Tβ4 and further strengthen its development as an adjunct therapy with antibiotics for corneal infections.
先前的研究表明，与环丙沙星联合使用胸腺素β 4（Tβ4）可显著改善肺炎克雷伯菌诱导的角膜炎的疾病结局。因此，本研究的目的是阐明 Tβ4 减轻角膜反应的机制；具体而言，关于其杀菌作用以及与环丙沙星的潜在协同作用。采用最低抑菌浓度（MIC）测定法进行体外研究，以评估对 PA 的杀菌活性。此外，还使用人角膜上皮细胞评估了抗菌肽（AMP）在 mRNA 水平上对脂多糖（LPS）刺激的反应。MIC 测定的结果并未显示 Tβ4 单独具有直接杀菌活性，尽管环丙沙星的杀菌浓度远低于临床剂量。然而，Tβ4 对细菌的杀伤作用表现出间接影响，这表现为 AMP 及其相关分子的上调。这项研究的综合数据表明 Tβ4 具有间接杀菌作用，并且与环丙沙星具有协同作用。此外，还发现环丙沙星本身会影响尚未报道的细胞功能。这些结果突出了 Tβ4 的细胞内通讯机制，并进一步加强了将其作为抗生素治疗角膜感染的辅助疗法的开发。
