VIRAL MODULATION OF EPITHELIAL FUNCTION

这个项目资助的重点是慢性鼻窦炎的假设，这种疾病影响了大约15%的美国人，是由于上皮细胞功能障碍。这种功能障碍可能是由固有的遗传缺陷、环境影响或最可能的是两者的结合引起的。该项目通过测试病毒感染是否是慢性鼻窦炎发生和恶化的重要环境刺激因素，通过触发上皮细胞功能的改变，特别是增加促炎细胞因子的产生，包括IL-8、GM-CSF、RANTES和eotaxin，来支持这一假设。为了研究病毒感染与慢性鼻窦炎之间的关系，我们将在鼻窦内窥镜手术后对受试者进行前瞻性监测，以确定与同一受试者在疾病活动不那么严重的时期获得的分泌物相比，经历鼻窦炎加重的受试者的鼻和鼻窦分泌物是否显示出更高的病毒感染发生率。鉴于一氧化氮（NO）具有抗病毒作用并抑制上皮细胞因子的产生，我们也将验证鼻窦上皮在病毒感染期间无法通过酶诱导NO合成酶（iNOS）增加NO的产生是慢性鼻窦炎的危险因素这一假设。我们将研究鼻病毒在培养的上皮细胞中诱导iNOS的机制，并确定在实验鼻病毒感染期间，与正常受试者相比，慢性鼻窦炎受试者是否表现出较低的上皮iNOS诱导表达，以及上皮细胞因子的产生和炎症的增加。鼻内糖皮质激素目前被提倡作为一种适当的治疗方法来减少鼻窦手术后患者的疾病复发。然而，尽管这种鉴定被广泛使用，但在窦损伤后招募的受试者中，糖皮质激素与安慰剂的疗效和机制验证了基于体外数据的假设，即局部糖皮质激素会降低受试者中GM-CSF、RANTES和eotaxin的上皮表达以及组织嗜酸性粒细胞，但对上皮表达IL-8或嗜中性粒细胞炎症几乎没有影响。我们认为这样的结果只会产生部分治疗效果。这些研究应该为慢性鼻窦炎的发病机制提供重要的见解，并可能导致改进治疗这一主要健康问题的疗法的发展。

This Program Grant focuses on the hypothesis that chronic rhinosinusitis, a disease affects approximately 15% of Americans, is due to epithelial cell dysfunction. This dysfunction may arise from an inherent genetic defect(s), environmental influences, or most likely, a combination of the two. This project contributes to this hypothesis by testing whether viral infection is an important environmental stimulus in the development and exacerbation of chronic rhinosinusitis by triggering alterations in epithelial cell function, particularly increased production of pro- inflammatory cytokines, including IL-8, GM-CSF, RANTES and eotaxin. To examine the relationship between viral infection and chronic rhinosinusitis we will monitor subjects prospectively following endoscopic sinus surgery to determine if nasal and sinus secretions from subjects experiencing exacerbations of rhinosinusitis show a higher incidence of viral infection, detected by PCR, compared to secretions obtained from the same subjects during periods when disease activity is less severe. Given that nitric oxide (NO), is antiviral and inhibits epithelial cytokine production, we also will test the hypothesis that an inability of the sinus epithelium to increase production of NO, via the enzyme inducible NO synthase (iNOS), during viral infections is a risk factor for chronic rhinosinusitis. We will examine the mechanism of induction of iNOS by rhinovirus in cultured epithelial cells and will determine if subjects with chronic rhinosinusitis show lower induction of epithelial iNOS expression, and increased epithelial cytokine production and inflammation, compared to normal subjects during experimental rhinovirus infections. Intranasal glucocorticoids are currently advocated as an appropriate therapy to reduce disease recurrence in patients after sinus surgery. Despite widespread use for this identification, however, the efficacy, and mechanisms glucocorticoids versus placebo in subjects recruited after sinus injury to test the hypothesis, which is based upon in vitro data, that topical glucocorticoids will reduce epithelial expression of GM-CSF, RANTES, and eotaxin, and tissue eosinophilia in subjects but will have little effect on epithelial expression of IL-8 or on neutrophilic inflammation. We suggest that such an outcome will result in only a partial therapeutic effect. These studies should provide important insights into the pathogenesis of chronic rhinosinusitis and may lead to the development of improved therapies for the treatment of this major health problem.