Impaired intestinal barrier function and airway inflammation in cystic fibrosis

描述（由申请人提供）：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。肠道是CF的主要受累器官之一，尽管治疗有力，但营养不良在此病中很常见。营养不良是CF患者死亡率的重要预测因素，其直接原因是过度破坏性肺部炎症导致的气道衰竭。长期的研究目标是了解CF的肠道功能障碍，以确定新的治疗方向，提高生活质量和寿命。本应用的目的是确定肠功能受损在多大程度上导致CF肺过度免疫反应。该项目的中心假设是CF的肠道先天防御受损，包括碱性磷酸酶（IAP）活性降低、肠道屏障功能受损和小肠细菌过度生长，导致肺部过度免疫活性，这是该疾病的特征。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（LPS或内毒素）是IAP的天然底物。通过IAP去磷酸化后，LPS被解毒。CF小肠细菌过度生长是常见的，这将增加可进入循环的内毒素的数量。因此，我们提出，由于IAP缺乏、肠道通透性增加和肠道细菌过度生长，来自肠道的更多生物活性内毒素可以进入循环并到达遥远的部位，如气道。肠源性循环内毒素会加重CF肺部的炎症。将使用有针对性地破坏CF基因的小鼠（Cftr敲除小鼠）。CF小鼠的小肠发生了一些变化，使其成为人类CF疾病的优秀模型。CF小鼠的气道免疫活性也显著升高。本项目提出了两个具体目标：(1)确定CF小鼠肠道黏膜屏障功能受损的程度；(2)确定改善CF肠道表型的治疗在多大程度上也能改善CF小鼠的屏障功能和降低气道免疫活性。

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.