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.
|Gu, YuanYuan; Harley, Isaac T W; Henderson, Lindsay B et al. (2009) Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 458:1039-42|
|Machado, Fabiana S; Esper, Lisia; Dias, Alexandra et al. (2008) Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6. J Exp Med 205:1077-86|
|Petasis, Nicos A; Keledjian, Raquel; Sun, Yee-Ping et al. (2008) Design and synthesis of benzo-lipoxin A4 analogs with enhanced stability and potent anti-inflammatory properties. Bioorg Med Chem Lett 18:1382-7|
|Karp, Christopher L; Flick, Leah M; Yang, Rong et al. (2005) Cystic fibrosis and lipoxins. Prostaglandins Leukot Essent Fatty Acids 73:263-70|
|Petasis, Nicos A; Akritopoulou-Zanze, Irini; Fokin, Valery V et al. (2005) Design, synthesis and bioactions of novel stable mimetics of lipoxins and aspirin-triggered lipoxins. Prostaglandins Leukot Essent Fatty Acids 73:301-21|