Impaired intestinal barrier function and airway inflammation in cystic fibrosis

描述(申请人提供)：美国约有30,000名囊性纤维化(CF)患者，每年另有1,000人被诊断出来。肠道是CF的主要器官之一，尽管进行了积极的治疗，但营养不良在这种疾病中很常见。营养不良是CF患者死亡率的强烈预测因素，其直接原因是过度破坏性肺部炎症导致的呼吸道衰竭。长期的研究目标是了解CF的肠道功能障碍，以便确定新的治疗方向，以提高生活质量和寿命。这项应用的目的是确定肠功能受损在多大程度上导致CF肺的过度免疫反应。该项目的中心假设是，CF的肠道固有防御功能受损，包括碱性磷酸酶(IAP)活性降低，肠道屏障功能受损，以及小肠细菌过度生长，导致了肺的过度免疫活动，这是该病的特征。IAP是先天防御的一部分，对肠道屏障功能很重要。此外，脂多糖(脂多糖或内毒素)是IAP的天然底物。经IAP去磷酸化后，内毒素被解毒。CF小肠细菌过度生长是很常见的，这会增加进入循环的内毒素数量。因此，有人认为，由于IAP缺乏，肠道通透性增加，肠道细菌过度生长，更多来自肠道的生物活性内毒素可以进入循环，到达较远的位置，如呼吸道。当发生感染时，肠源性循环内毒素会加重CF肺的炎症。将使用一只负责CFT基因敲除小鼠(CFTR基因敲除小鼠)的定向破坏。CF小鼠的小肠有几个变化，这使它成为人类CF疾病的优秀模型。CF小鼠的呼吸道免疫活性也显著提高。该项目提出了两个具体目标：(1)确定CF小鼠肠道粘膜屏障功能受损的程度；(2)确定改善CF肠道表型的治疗方法在多大程度上也改善了CF小鼠的屏障功能并降低了呼吸道免疫活性。 相关性：致命的遗传病囊性纤维化(CF)在美国影响着大约30,000人，每年有1000多人被诊断出来。胃肠系统功能不良是呼吸功能下降的一个重要因素，而呼吸功能下降是导致CF死亡的最终原因。拟议项目的成功完成有望带来新的治疗方法，以改善CF患者的肠道功能、生活质量和寿命。

DESCRIPTION (provided by applicant): There are about 30,000 cystic fibrosis (CF) patients in the US and another 1,000 individuals are diagnosed annually. The intestinal tract is one of the major organs affected in CF and despite vigorous therapy, malnutrition is common in this disease. Poor nutrition is a strong predictor of mortality in CF patients, whose proximate cause is airway failure due to excessive destructive lung inflammation. The long term research goal is to understand intestinal dysfunction in CF in order to identify new therapeutic directions that improve quality of life and longevity. The objective of this application is to determine the extent to which impaired intestinal function contributes to the excessive immune response in the CF lung. The central hypothesis of this project is that impaired intestinal innate defenses in CF, including decreased alkaline phosphatase (IAP) activity, compromised gut barrier function, and small intestinal bacterial overgrowth, contribute to the excessive immune activity of the lung, which is characteristic of this disease. IAP is part of the innate defenses and is important to intestinal barrier function. Also, lipopolysaccharide (LPS or endotoxin) is a natural substrate of IAP. After dephosphorylation by IAP, LPS is detoxified. Bacterial overgrowth of the CF small intestine is common, which will increase the amount of endotoxin available to enter the circulation. Thus, it is proposed that due to IAP deficiency, increased gut permeability, and intestinal bacterial overgrowth, more bioactive endotoxin from the gut can enter the circulation and reach distant sites like the airways. Gut-derived circulating endotoxin will exacerbate inflammation in the CF lung when infection occurs. A mouse with a targeted disruption of the gene responsible for CF (Cftr knockout mouse) will be used. The CF mouse has several changes in the small intestine that make it an excellent model for human CF disease. The CF mouse also has significantly elevated airway immune activity. Two Specific Aims are proposed for this project: (1) Determine the extent to which the mucosal barrier function of the intestine is impaired in the CF mouse; and (2) Determine the extent to which treatments that ameliorate the CF intestinal phenotype also improve barrier function and decrease airway immune activity in the CF mouse. RELEVANCE: The fatal genetic disease cystic fibrosis (CF) affects about 30,000 people in the US and 1,000 more are diagnosed annually. Poor functioning of the gastrointestinal system is an important factor in the decline in respiratory function which is the eventual cause of death in CF. Successful completion of the proposed project is expected to lead to new therapeutic approaches to improve intestinal function, quality of life, and longevity of CF patients.