Karp Christopher L, Flick Leah M, Park Kiwon W, Softic Samir, Greer Todd M, Keledjian Raquel, Yang Rong, Uddin Jasim, Guggino William B, Atabani Sowsan F, Belkaid Yasmine, Xu Yan, Whitsett Jeffrey A, Accurso Frank J, Wills-Karp Marsha, Petasis Nicos A
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Nat Immunol. 2004 Apr;5(4):388-92. doi: 10.1038/ni1056. Epub 2004 Mar 21.
In cystic fibrosis, dysregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways. The underlying mechanisms have remained unclear. Lipoxins are anti-inflammatory lipid mediators that modulate neutrophilic inflammation. We report here that lipoxin concentrations in airway fluid were significantly suppressed in patients with cystic fibrosis compared to patients with other inflammatory lung conditions. We also show that administration of a metabolically stable lipoxin analog in a mouse model of the chronic airway inflammation and infection associated with cystic fibrosis suppressed neutrophilic inflammation, decreased pulmonary bacterial burden and attenuated disease severity. These findings suggest that there is a pathophysiologically important defect in lipoxin-mediated anti-inflammatory activity in the cystic fibrosis lung and that lipoxins have therapeutic potential in this lethal autosomal disease.
在囊性纤维化中，中性粒细胞炎症失调和慢性感染会导致气道的进行性破坏。其潜在机制仍不清楚。脂氧素是调节中性粒细胞炎症的抗炎脂质介质。我们在此报告，与其他炎症性肺部疾病患者相比，囊性纤维化患者气道液中的脂氧素浓度显著降低。我们还表明，在与囊性纤维化相关的慢性气道炎症和感染的小鼠模型中，给予代谢稳定的脂氧素类似物可抑制中性粒细胞炎症，降低肺部细菌负荷，并减轻疾病严重程度。这些发现表明，囊性纤维化肺部中脂氧素介导的抗炎活性存在病理生理学上的重要缺陷，并且脂氧素在这种致命的常染色体疾病中具有治疗潜力。
