MUCOSAL DYSFUNCTION IN REFRACTORY RHINOSINUSITIS

在本项目的前期资助期内，我们对难治性慢性鼻窦炎患者的气道进行了广泛的评估，得出了一个意想不到的发现：与健康对照相比，患有这种疾病的患者在局部组胺刺激下表现出鼻黏膜分泌性低下。这一现象的重要性被同时观察到的患者在鼻液细胞学中有过度的粘膜炎症所强调。常年性变应性鼻炎是另一种慢性炎症，鼻黏膜炎症与粘膜高反应性有关。我们现在提出，分泌性粘膜反应性低下在难治性鼻窦炎患者中起着核心的病理生理作用，因为它可能导致体内平衡和保护机制的减弱，以抵御环境损害，如过敏原、刺激物和感染。因此，该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元素，并研究这一现象的病理生理学重要性。使用对各种粘膜结构具有特定作用的刺激剂鼻腔刺激技术，我们的第一个目的是验证腺体装置主要负责观察到的粘膜功能障碍的假设。在我们的第二个目标中，我们将测试在实验条件下，暴露于过敏、病毒和神经源性炎症诱导剂后，分泌性粘膜反应性低下是否是不良预后的危险因素，以及不良治疗结果的危险因素。我们的第三个目标将解决分泌性粘膜低反应性表现出家族易感性的假设。这将通过比较难治性鼻窦炎患者的兄弟姐妹与(a)健康对照组的兄弟姐妹(b)始终患有难治性鼻窦炎并具有明确特征的遗传缺陷的囊性纤维化患者的粘膜反应性来验证，以及(c)囊性纤维化患者的患者是CFTR突变的专性携带者。该项目是整个计划项目拨款的组成部分，其主要假设仍然是上皮细胞/粘膜功能障碍在慢性鼻窦炎的发病机制中起核心作用。本项目通过关注已确定的分泌性粘膜功能障碍，为这种情况的病理生理机制提供了一个新的假设。建立这样一种机制可能会为治疗这一重大但管理不善的健康问题带来新的方法。

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.