Mast cell regulated innate immunity in otitis media; pro-inflammatory and immunosuppressive effects of mast cells in otitis media

中耳炎是一个主要的健康问题，造成大量的发病率和大量的卫生保健支出。这种疾病的病因和治疗方法仍不完全清楚。肥大细胞是正常中耳中唯一的常驻白细胞。我们观察到，在肥大细胞缺失的情况下，中耳炎的消退明显延迟。这些数据提示肥大细胞可能在中耳的先天和同源防御中发挥重要作用，并可能参与中耳炎的发病机制。在其他部位，肥大细胞最近被证明不仅具有促炎作用，而且具有免疫抑制作用。我们提出了一系列采用转基因小鼠的综合实验来验证这些假设，并阐明肥大细胞在中耳中的作用机制。TNF缺失的肥大细胞将用于重建肥大细胞缺失小鼠的中耳肥大细胞群，继续我们之前对TNF缺失小鼠的研究。分析这些小鼠细菌性中耳炎的病程。为了检测肥大细胞的免疫抑制功能，我们将IL-10 k/o小鼠诱导细菌性中耳炎。分析中耳黏膜炎症反应及促炎因子IL-1α、IL-6、TNF的表达水平。这些实验将在用来自IL-10 k/o小鼠的肥大细胞重组的肥大细胞缺陷小鼠中重复，以分析所观察到的效果是否依赖于肥大细胞。

Otitis media is a major health problem causing substantial morbidity and resulting in substantial health care expenditures. The causes and treatment of this disorder remain incompletely understood. Mast cells are the only resident leukocytes in the normal middle ear. We observed that in the absence of mast cells, the resolution of otitis media is significantly delayed. These data suggest that the mast cell may play an important role in the innate and cognate defense of the middle ear, and may contribute to otitis media pathogenesis. At other sites, mast cells have recently been demonstrated not only to act pro-inflammatory but also immunosuppressive. We propose a series of integrated experiments employing genetically modified mice to validate these hypotheses and to elucidate the mechanism(s) by which mast cells operate in the middle ear. Mast cells deficient in TNF will be used to reconstitute the middle ear mast cell populations of mast cell deficient mice in continuation of our previous studies in TNF deficient mice. The course of bacterial otitis media in these mice will be analyzed. To examine the immunosuppressive function of mast cells, bacterial otitis media will be induced in IL-10 k/o mice. Inflammatory reactions in the middle ear mucosa as well as the expression levels of the pro-inflammatory cytokines IL-1α, IL-6 and TNF will be analyzed. These experiments will be repeated in mast cell deficient mice reconstituted with mast cells derived from IL-10 k/o mice to analyze if the observed effects are mast cell dependent.