VIRAL MODULATION OF EPITHELIAL FUNCTION

这个项目的重点是假设慢性鼻-鼻窦炎，一种影响大约15%的美国人的疾病，是由于上皮细胞功能障碍造成的。这种功能障碍可能源于先天遗传缺陷(S)、环境影响，或者最有可能的是两者的结合。该项目通过测试病毒感染是否是慢性鼻-鼻窦炎发展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和嗜酸性粒细胞趋化因子，对这一假说做出了贡献。为了研究病毒感染和慢性鼻窦炎之间的关系，我们将对内窥镜鼻窦手术后的受试者进行前瞻性监测，以确定与疾病活动不那么严重的时期相同受试者的分泌物相比，经历鼻窦炎恶化的受试者的鼻腔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)是抗病毒的，并抑制上皮细胞因子的产生，我们还将测试一种假设，即在病毒感染期间，鼻窦上皮无法通过酶诱导的一氧化氮合酶(INOS)增加NO的产生，这是慢性鼻窦炎的风险因素。我们将研究鼻病毒对培养上皮细胞诱导性一氧化氮合酶的机制，并将确定在实验性鼻病毒感染期间，慢性鼻窦炎受试者是否表现出比正常受试者更低的上皮性iNOS表达，以及更多的上皮性细胞因子产生和炎症。鼻腔内糖皮质激素目前被认为是减少鼻窦手术后疾病复发的一种合适的治疗方法。然而，尽管这种鉴定被广泛使用，但在鼻窦损伤后招募的受试者中，糖皮质激素与安慰剂相比的有效性和机制验证了这一假设，该假说基于体外数据，即局部应用糖皮质激素将减少受试者上皮细胞GM-CSF、RANTES和嗜酸性粒细胞趋化因子的表达，并减少组织嗜酸性粒细胞增多，但对上皮细胞IL-8的表达或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.