Lipid Mediators and Dysregulated Inflammation in CF

描述（由申请人提供）：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。尽管通过鉴定相关基因CFTR提供了分子见解，但对CF肺部疾病的发病机制的清晰理解仍然难以捉摸。CF肺的特点是炎症反应失调和慢性气道感染，最终结果是气道的进行性支气管扩张破坏。CF患者气道炎症反应持续呈中性粒细胞性；反过来，活化的中性粒细胞的产物在很大程度上负责CF的肺破坏。脂毒素（LX）是炎症期间产生的抗炎花生四烯酸代谢物。二十二碳三烯（DT）是二十二碳六烯酸代谢物，具有相似的生物活性，在组成和炎症过程中产生。在各种模型中，LX和DT已被证明可以预防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。我们发现LX浓度在CF患者和cftr缺陷小鼠的气道中受到抑制。我们还发现，在慢性气道炎症和CF感染的小鼠模型中给予代谢稳定的LX类似物可抑制中性粒细胞炎症并显着减轻疾病严重程度。我们进一步发现，与cftr充足的窝鼠不同，在任何细菌攻击气道之前，cftr缺陷小鼠的肺DT表达在基线时是缺乏的。这些数据有力地提出了以下假设：(a) CF肺中lx和DT介导的抗炎活性存在病理生理上的重要缺陷；(b) LX和DT类似物具有预防和/或改善CF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)定义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.