MUCOSAL DYSFUNCTION IN REFRACTORY RHINOSINUSITIS

在这个项目的前一个资助期，我们对难治性慢性鼻窦炎患者的呼吸道进行了广泛的评估，结果发现了一个意想不到的发现：与健康对照组相比，患有这种疾病的患者在组胺局部刺激时表现出鼻黏膜分泌低反应。这一现象的重要性被同时观察到的鼻液细胞学记录的同一患者过度的粘膜炎症所强调。常年性变应性鼻炎、慢性炎症、鼻黏膜炎症与黏膜高反应性有关。我们现在提出分泌性粘膜低反应性在难治性鼻-鼻窦炎患者中发挥着重要的病理生理作用，因为它可能导致环境伤害(如过敏原、刺激物和感染)的动态平衡和保护机制减弱。因此，这个项目的竞争性更新旨在确定导致分泌反应性降低的粘膜功能成分，并调查这一现象的病理生理学重要性。使用刺激鼻腔的技术，刺激剂对不同的粘膜结构有特定的作用，我们的第一个目的是检验腺体器官是所观察到的粘膜功能障碍的主要原因的假设。在我们的第二个目标中，我们将测试分泌性粘膜低反应性是否是在实验条件下暴露于过敏、病毒和神经源性炎症诱导剂后恶化结果的风险因素，以及不良治疗结果的风险因素。我们的第三个目标将解决这样的假设，即分泌性粘膜低反应性表现出家族易感性。这将通过将难治性鼻窦炎患者的兄弟姐妹与(A)我们健康对照组的兄弟姐妹的粘膜反应性进行比较来测试这一点，(B)囊性纤维化患者，他们总是患有难治性鼻窦炎，并具有良好的遗传缺陷，以及(C)囊性纤维化患者，他们是CFTR突变的必然携带者。这个项目是整个项目拨款项目的一个组成部分，该项目的主要假设仍然是上皮细胞/粘膜功能障碍在慢性鼻-鼻窦炎的发病机制中起着核心作用。这项研究为这种疾病的病理生理学机制提供了一种新的假说，主要集中在一种已确定的分泌性粘膜功能障碍上。建立这样一个机制可能会带来治疗这一重大但管理不善的健康问题的新方法。

Our extensive evaluation of the airways of patients with refractory chronic rhinosinusitis during the previous funding period of this project resulted in an unexpected finding: in comparison to healthy controls, patients with this condition exhibited nasal mucosal secretory hyporesponsiveness upon localized provocation with histamine. The importance of this phenomenon is accentuated by the concomitant observation that the same patients had excessive mucosal inflammation documented in nasal fluid cytology. In the case of perennial allergic rhinitis, anther chronic inflammatory condition, nasal mucosal inflammation would be associated with mucosal hyperreponsiveness. We now propose that secretory mucosal hyporesponsiveness plays a central pathophysiologic role in patients with refractory rhinosinusitis as it may lead to diminished homeostatic and protective mechanisms against environmental insults such as allergens, irritants and infections. The competitive renewal of this project is, thus, designed to identify the functional elements of the mucosa that contribute to reduced secretory responsiveness and to investigate the pathophysiologic importance of this phenomenon. Using the technique of nasal provocation with stimulants that have specific actions on various mucosal structures, our first aim is to test the hypothesis that the glandular apparatus is mainly responsible for the observed mucosal dysfunction. In our second aim, we will test whether secretory mucosal hyporesponsiveness is a risk factor for worse outcomes after exposure to inducers of allergic, viral and neurogenic inflammation under experimental conditions, as well as a risk factor for poor treatment outcomes. Our third aim will address the hypothesis that secretory mucosal hyporesponsiveness exhibits familial predisposition. This will be tested by comparing the mucosal responsiveness of the siblings of patients with refractory rhinosinusitis to (a) the siblings of our health control group (b) patients with cystic fibrosis, who invariably suffer from refractory rhinosinusitis and have a well characterized genetic defect, and (c) the patients of patients with cystic fibrosis who are obligate carriers of CFTR mutations. This project is an integral part of the overall Program Project Grant the main hypothesis of which remains that epithelial cell/mucosal dysfunction play a central role in the pathogenesis of chronic rhinosinusitis. This project offers a novel hypothesis on the pathophysiologic mechanism of this condition by focusing around an identified secretory mucosal dysfunction. Establishing such a mechanism may lead to new approaches for the treatment of this major, yet poorly managed, health problem.