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

亚胺培南是β-内酰胺类的储备抗生素，其干扰细菌细胞壁合成，因此对广谱细菌具有杀菌作用。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，我们能够表明，在LPS诱导的肺部炎症的小鼠模型中，给予100 mg/kg亚胺培南导致支气管肺泡灌洗液中各种免疫细胞和红细胞的数量显著减少。亚胺培南还显著抑制血清中的炎症介质。与亚胺培南单独给药相比，用亚胺培南和代谢抑制剂西司他丁（Zienam）的固定组合治疗小鼠时，对白细胞迁移和血清标志物的影响更明显。 此外，20 mg/kg zienam的临床相关剂量在该疾病模型中是治疗有效的。 在细胞系统中，亚胺培南和zienam显着降低原代人单核细胞与人内皮细胞的粘附。我们的假设是，粘附和迁移的白细胞，并通过血管内皮细胞被强烈抑制的未知机制，是不相关的抗生素作用的亚胺培南。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使用内皮模型系统进行详细描述，并研究其潜在机制。使用亚胺培南衍生物，我们希望在本项目的药物化学部分研究母体化合物亚胺培南的抗炎作用是否可以与其抗生素作用分开，并通过进一步的结构修饰来增加抗炎作用。此外，我们希望使用LPS诱导的肺部炎症和病毒感染的小鼠模型更详细地描述亚胺培南的抗炎作用。基于本申请的新发现，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。此外，基于对亚胺培南的靶结构的了解，这对于调节免疫细胞粘附和迁移是非常重要的，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）。

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.