The role of the histamine H4-receptor in DSS-induced colitis

炎症性肠病(IBD)是一个日益严重的医疗和卫生经济挑战，在过去的几十年里，患者的数量不断上升。除了炎症症状，IBD患者患肿瘤和精神疾病的风险更高。然而，IBD的治疗只包括治疗炎症症状，尽管在许多情况下使用昂贵的药物，但只有大约一半的患者的症状得到改善。因此，迫切需要新的治疗方案。申请该项目的起点是一些研究，这些研究表明IBD患者结肠中组胺的浓度增加，肥大细胞的活性增加，肥大细胞是组胺的主要制造者。因此，可以得出结论，阻断组胺效应可能会改善IBD患者的炎症症状。通过阻断特定受体来干扰组胺效应是已经成熟的药物的作用机制，这些药物已经被成功地用于治疗其他疾病(过敏、与酸有关的胃肠道疾病)。然而，这些针对组胺H1受体(H1R)和组胺H1受体(H2R)的药物被发现在治疗IBD方面无效。最有可能参与炎症性疾病的受体是H4R。因此，在计划的项目中，我们验证了H4R参与急性右旋糖硫酸钠(DSS)诱导的结肠炎的假设，这是一种IBD的小鼠模型，可以作为有效的治疗靶点。为了支持这一假设，我们已经在初步研究中表明，在这个模型中，H4R的缺失导致了疾病的实质性改善。在该项目中，将研究H4R在DSS诱导的结肠炎模型中潜在的细胞机制。第一个具体目的是深入研究H4R对急性结肠炎临床和免疫学参数的影响。第二个目的是阐明H4R在嗜酸性粒细胞和/或肥大细胞上的功能性表达是否在结肠炎中起作用。第三个目的是研究在造血细胞或非造血细胞上表达的H4R在结肠炎中是否起关键作用。这些研究为开发治疗IBD的潜在新药奠定了基础。

Inflammatory bowel diseases (IBD) represent a growing medical and health economical challenge, with the number of patients constantly rising over the past decades. In addition to the inflammatory symptoms, IBD patients have a higher risk to develop tumors and psychiatric disorders. Yet, treatment of IBD consists of treating the inflammatory symptoms only, and although in many cases expensive drugs are administered, merely in about half of the patients symptoms are ameliorated. Consequently, there is an urgent need for new treatment options. Starting point for the project applied for are studies that showed increased concentrations of histamine, a pro-inflammatory mediator, and an increased activity of mast cells, the main producers of histamine, in the colon of IBD patients. It can, thus, be concluded that blocking the histamine effects will probably improve the inflammatory symptoms in IBD patients. Interfering at the histamine effect by blocking specific receptors is the mechanism of action of already well-established drugs used to successfully treat other diseases (allergies, acid-related gastrointestinal disorders). However, these drugs, which are specific for the histamine H1-receptor (H1R) and the H2R, have been found to be ineffective in the therapy of IBD. The receptor which is most probably involved in inflammatory diseases is the H4R. In the planed project we, thus, test the hypothesis that the H4R is involved in the acute dextransulphate sodium (DSS)-induced colitis, a mouse model for IBD, and can be used as effective therapeutic target. In support to this hypothesis we have already shown in preliminary studies that in this model the absence of the H4R leads to a substantial amelioration of the disease.In the project, the cellular mechanisms underlying the function of the H4R in DSS-induced colitis-model shall be studied. The first specific aim is to thoroughly study the impact of the H4R on clinical and immunological parameters of the acute colitis. The second aim is to elucidate the question whether the functional expression of the H4R on eosinophilic granulocytes and/or mast cells plays a role in colitis. The third aim is to study whether the H4R expressed on hematopoietic or on non-hematopoietic cells is crucial for colitis. These studies constitute the basis for the development of potential new drugs to treat IBD.