Lipid Mediators and Dysregulated Inflammation in CF

描述（由申请人提供）：慢性肺病仍然是囊性纤维化（CF）发病率和死亡率的主要原因。尽管通过鉴定负责基因CFTR提供了分子见解，但对CF中肺部疾病的发病机制的清楚理解仍然难以捉摸。CF肺的特征在于失调的炎症反应和慢性气道感染，最终结果是气道的进行性支气管扩张破坏。CF中的气道炎症反应是持续的嗜中性粒细胞;反过来，活化的中性粒细胞的产物是CF中肺破坏的主要原因。脂氧素（LX）是抗炎花生四烯酸代谢产物，在炎症过程中产生。二十二碳三烯（DT）是二十二碳六烯酸代谢产物，具有组成性和炎症过程中产生的类似生物活性。在各种模型中，LX和DT已显示出预防嗜中性粒细胞介导的损伤并促进嗜中性粒细胞介导的炎症的消退。我们已经发现，在CF患者的气道中，以及在Cftr缺陷小鼠中，LX浓度受到抑制。我们还发现，在慢性气道炎症和CF感染的小鼠模型中施用代谢稳定的LX类似物可抑制嗜酸性炎症并显著减轻疾病严重程度。我们进一步发现，与Cftr充足的同窝出生小鼠不同，Cftr缺陷小鼠在气道的任何细菌攻击之前的基线时DT的肺表达不足。这些数据有力地表明了以下假设：（a）在CF肺中LX和DT介导的抗炎活性存在病理生理学上重要的缺陷;和（B）LX和DT类似物具有预防和/或改善CF中致病性炎症反应的治疗潜力。在这些研究中，我们的目标是：（a）确定LX在CF相关肺部感染和炎症小鼠模型中治疗作用的分子机制;（B）确定CF中LX缺乏的分子机制;（c）确定DT在CF相关肺部炎症中的作用。

DESCRIPTION (provided by applicant): Chronic pulmonary disease remains the major cause of morbidity and mortality in cystic fibrosis (CF). Despite the molecular insights afforded by identification of the responsible gene, CFTR, a clear understanding of the pathogenesis of lung disease in CF remains elusive. The CF lung is characterized by dysregulated inflammatory responses and chronic airway infection, the end result being progressive bronchiectatic destruction of the airways. The airway inflammatory response in CF is persistently neutrophilic; in turn, the products of activated neutrophils are largely responsible for lung destruction in CF. Lipoxins (LX) are anti-inflammatory arachidonic acid metabolites, generated during inflammation. Docosatrienes (DT) are docosahexaenoic acid metabolites with similar bioactivities generated constitutively as well as during inflammation. In a variety of models, LX and DT have been shown to prevent neutrophilmediated damage and promote the resolution of neutrophil-mediated inflammation. We have found that LX concentrations are suppressed in the airways of patients with CF, as well as in Cftr-deficient mice. We have also found that administration of a metabolically stable LX analog in a mouse model of the chronic airway inflammation and infection of CF suppresses neutrophilic inflammation and markedly attenuates disease severity. We have further found that, unlike Cftr-sufficient littermates, Cftr-deficient mice are deficient in pulmonary expression of DT, at baseline, prior to any bacterial challenge of the airway. This data strongly suggest the following hypotheses: (a) there is a pathophysiologically important defect in LX-and DT mediated anti-inflammatory activity in the CF lung; and (b) LX and DT analogues have therapeutic potential for preventing and/or ameliorating pathogenic inflammatory responses in CF. In these studies we aim to: (a) define the molecular mechanisms underlying the therapeutic effects of LX in mouse models of CF-related pulmonary infection and inflammation; (b) determine the molecular mechanisms responsible for LX deficiency in CF; and (c) define the role of DT in CF-related pulmonary inflammation.