Lipid Mediators and Dysregulated Inflammation in CF

描述(申请人提供)：慢性肺部疾病仍然是囊性纤维化(CF)发病率和死亡率的主要原因。尽管对致病基因cftr的鉴定提供了分子方面的见解，但对cf的肺部疾病的发病机制仍缺乏清晰的认识。慢性阻塞性肺疾病的特点是炎症反应失调和慢性呼吸道感染，最终导致呼吸道的进行性支气管扩张性破坏。慢性支气管炎的呼吸道炎症反应是持续的中性粒细胞；反过来，活化的中性粒细胞的产物在很大程度上导致了慢性支气管炎的肺破坏。脂蛋白(LX)是一种抗炎的花生四烯酸代谢产物，在炎症过程中产生。二十二碳三烯(DT)是二十二碳六烯酸的代谢物，具有相似的生物活性。在各种模型中，LX和DT已被证明可以防止中性粒细胞介导的损伤，并促进中性粒细胞介导的炎症的消退。我们已经发现，在CF患者的呼吸道中，LX浓度受到抑制，在CFTR缺陷小鼠中也是如此。我们还发现，在慢性呼吸道炎症和CF感染的小鼠模型中，给予代谢稳定的LX类似物可以抑制中性粒细胞炎症，并显著减轻疾病严重程度。我们进一步发现，与CFTR充足的窝产仔不同，CFTR缺乏的小鼠在呼吸道受到任何细菌攻击之前，在基线时肺组织中DT的表达是不足的。这一数据强烈提示以下假设：(A)LX和DT介导的CF肺内抗炎活性存在重要的病理生理学缺陷；以及(B)LX和DT类似物具有预防和/或改善CF病理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模型中的治疗作用的分子机制；(B)确定CF中LX缺乏的分子机制；以及(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.