Studies on the effects of carbapenems on leukocyte-endothelial cell interaction in models of pulmonary inflammation and viral infection

碳青霉烯类药物对肺部炎症和病毒感染模型白细胞-内皮细胞相互作用影响的研究

• 批准号: 512477758
• 负责人: Professor Dr. Robert Fürst
• 金额: --
• 依托单位: Paul-Ehrlich-Institut - Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/512477758?language=en
• 关键词: Studies; effects; carbapenems; leukocyte; endothelial

Imipenem is a reserve antibiotic from the class of β-lactams that interfere with bacterial cell wall synthesis and thus have a bactericidal effect on a broad spectrum of germs. Imipenem is used intravenously in the clinic for severe infections such as sepsis. In preliminary experiments, we were able to show that in the mouse model of LPS-induced pulmonary inflammation, the administration of 100 mg/kg imipenem resulted in a significantly reduced number of various immune cells and erythrocytes in the bronchio-alveolar lavage. Imipenem also significantly inhibited inflammatory mediators in serum. The effects on leukocyte migration and serum markers were more pronounced when mice were treated with the fixed combination of imipenem and the metabolisation inhibitor cilastatin (Zienam) compared to imipenem administered alone. In addition, clinically relevant doses of 20 mg/kg zienam were therapeutically effective in this disease model. In the cellular system, imipenem and zienam significantly decreased the adhesion of primary human monocytes to human endothelial cells. Our hypothesis is that the adhesion and migration of leukocytes to and through the vascular endothelium is strongly inhibited by an unknown mechanism that is not related to the antibiotic effect of imipenem. In the first subproject, the effect of imipenem on immune cell adhesion and migration will be characterized in detail using a model system of the endothelium and the underlying mechanism will be investigated. Using imipenem derivatives, we would like to investigate in the medicinal chemistry part of this project whether the anti-inflammatory of the parent compound imipenem can be separated from its antibiotic effect with the question of a potential increase of anti-inflammatory effects by further structural modifications. Moreover, we want to characterize in more detail the anti-inflammatory effects of imipenem using a mouse model of LPS-induced pulmonary inflammation and also viral infection. Based on the new findings from this application, some clinically highly relevant antibiotics could be better targeted according to their immunomodulatory effects. In addition, based on the knowledge of the structure of the target of imipenem, which should be highly important for the regulation of immune cell adhesion and migration, novel drug candidates (structurally different from imipenem) could be developed by means of structure-based drug design.

亚胺培南是β-内酰胺类的一种储备抗生素，它干扰细菌细胞壁的合成，因此对广泛的细菌有杀菌作用。亚胺培南在临床上用于静脉注射治疗严重感染，如败血症。在初步实验中，我们能够证明，在lps诱导的肺部炎症小鼠模型中，给药100 mg/kg亚胺培南导致细支气管肺泡灌洗液中各种免疫细胞和红细胞数量明显减少。亚胺培南还能显著抑制血清中的炎症介质。与单独使用亚胺培南相比，亚胺培南与代谢抑制剂西司他汀（Zienam）的固定组合对小鼠的白细胞迁移和血清标志物的影响更为明显。此外，临床相关剂量20mg /kg zienam在该疾病模型中具有治疗效果。在细胞系统中，亚胺培南和zienam显著降低了原代人单核细胞对人内皮细胞的粘附。我们的假设是，白细胞的粘附和通过血管内皮的迁移受到一种未知机制的强烈抑制，这种机制与亚胺培南的抗生素作用无关。在第一个子项目中，亚胺培南对免疫细胞粘附和迁移的影响将通过内皮模型系统进行详细表征，并研究其潜在机制。利用亚胺培南衍生物，在本项目的药物化学部分，我们想研究母体化合物亚胺培南的抗炎作用能否与抗生素作用分离，进一步的结构修饰是否有可能增加抗炎作用。此外，我们希望通过lps诱导的肺部炎症和病毒感染小鼠模型来更详细地表征亚胺培南的抗炎作用。基于这一应用的新发现，一些临床高度相关的抗生素可以根据其免疫调节作用更好地靶向治疗。此外，基于亚胺培南对免疫细胞粘附和迁移调控的重要作用靶点结构的了解，可以通过基于结构的药物设计开发新的候选药物（结构上不同于亚胺培南）。