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

炎症性肠病（IBD）代表了日益增长的医疗和健康经济挑战，在过去几十年中患者数量不断增加。除了炎症症状外，IBD患者患肿瘤和精神疾病的风险更高。然而，IBD的治疗仅包括治疗炎性症状，并且尽管在许多情况下施用昂贵的药物，但仅在约一半的患者中症状得到改善。因此，迫切需要新的治疗方案。申请项目的起点是研究表明，炎症性肠病患者结肠中组胺（一种促炎介质）浓度增加，肥大细胞（组胺的主要生产者）活性增加。因此，可以得出结论，阻断组胺作用可能会改善IBD患者的炎症症状。通过阻断特异性受体来干扰组胺效应是已被公认的用于成功治疗其他疾病（过敏、酸相关胃肠道疾病）的药物的作用机制。然而，已经发现这些对组胺H1-受体（H1 R）和H2 R具有特异性的药物在IBD的治疗中无效。最可能参与炎性疾病的受体是H4 R。因此，在计划中的项目中，我们验证了H4 R参与了急性葡聚糖硫酸钠（DSS）诱导的结肠炎（IBD小鼠模型）的假设，并可用作有效的治疗靶点。为了支持这一假设，我们已经在初步研究中表明，在该模型中，H4 R的缺乏导致疾病的实质性改善。在该项目中，将研究DSS诱导的结肠炎模型中H4 R功能的细胞机制。第一个具体目标是彻底研究H4 R对急性结肠炎的临床和免疫学参数的影响。第二个目的是阐明的问题是否H4 R的功能性表达的嗜酸性粒细胞和/或肥大细胞在结肠炎中发挥作用。第三个目的是研究在造血细胞或非造血细胞上表达的H4 R是否对结肠炎至关重要。这些研究构成了开发治疗IBD的潜在新药的基础。

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.