Innate Immune Defect and Neutrophilic Inflammation in Cystic Fibrosis

摘要 囊性纤维化是最常见和最致命的遗传性疾病之一，影响约1/3,000名活产儿 在美国。负责的基因突变与编码CF的基因相关联 跨膜电导调节器(CFTR)，cAMP激活的氯离子通道。虽然这种疾病 几乎累及所有器官和系统，其肺部并发症的发病率和死亡率最高。这个 突出的肺部病理特征是慢性细菌感染、持续性中性粒细胞炎症和 化脓性小气道阻塞，其中持续性肺部炎症是肺结构的原因 损伤和功能丧失。尽管Cf分子缺陷是在30年前发现的，但这种联系 CFTR氯通道缺陷与破坏性肺部炎症之间的关系尚未明确。这样的一个 知识差距阻碍了任何有效治疗CF的知情发展。目前的建议是 解决这一领域的突出问题。我们的主要假设是CFTR功能丧失在 骨髓来源的先天免疫细胞分子修饰和功能失活的能力受损 炎症激动剂，导致CF肺过度刺激和中性粒细胞炎症。为了测试这一点 假设，我们提出了三个具体的目标：目标1：确定谱系特异性CFTR功能丧失在 中性粒细胞和单核/巨噬细胞不同程度地导致肺内持续性中性粒细胞炎症； 目的2：确定CF型肺中性粒细胞炎症是由于中性粒细胞过度募集、减少 细胞凋亡和/或低效的胞吐作用；目标3：定义中性粒细胞和巨噬细胞 中性粒细胞趋化因子的化学修饰和功能失活。 这项研究的完成将为研究慢性肺病的发病机制提供新的见解。新知识 所获得的结果将指导合理设计干预措施，以有效治疗这种毁灭性的疾病。

ABSTRACT Cystic fibrosis (CF) is one of the most common and deadly genetic disorders, affecting ~1/3,000 live births in the United States. The responsible genetic mutations are linked to the gene that encodes CF Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride channel. Although this disease affects almost all organs and systems, its lung complications claim the most morbidity and mortality. The prominent lung pathology is marked by chronic bacterial infection, persistent neutrophilic inflammation, and purulent small airway obstruction, of which persistent lung inflammation is responsible for lung structure damage and function loss. Even though the CF molecular defect was discovered three decades ago, the link between the CFTR chloride channel defect and the destructive lung inflammation has not been defined. Such a knowledge gap impedes any informed development of effective therapies for CF. The current proposal is to address this outstanding problem in the field. Our overarching hypothesis is that CFTR loss-of-function in marrow-derived innate immune cells compromises their ability to molecularly modify and functionally deactivate inflammatory agonists, leading to excessive stimulation and neutrophilic inflammation in CF lungs. To test this hypothesis, we propose three specific aims: Aim 1: Determine that lineage-specific CFTR loss-of-function in neutrophils and monocytes/macrophages leads to persistent neutrophilic inflammation in the lung differentially; Aim 2: Determine that CF lung neutrophilic inflammation is due to neutrophil excessive recruitment, reduced apoptosis, and/or inefficient efferocytosis; Aim 3: Define that CF neutrophils and macrophages are compromised in chemical modification and functional deactivation of neutrophil chemotactic factors. Completion of this research will provide novel insights into CF lung disease pathogenesis. The new knowledge obtained will guide the rational design of interventions for effective treatment of this devastating disease.