Human resistin, a neutrophil-derived metabolic and inflammatory mediator correlates with decreased lung function and NETosis in cystic fibrosis airway disease

Abstract Resistin, a protein initially cloned from mouse adipocytes, is a strong antagonist of insulin signaling. In humans, it is located in both the azurophil and specific granules of PMNs and as a result can be elevated in metabolic and PMN-driven inflammatory disorders. Cystic fibrosis (CF) combines PMN-dominated airway inflammation with profound metabolic anomalies, but the presence of resistin in CF patients has not been studied thus far. Methods: We measured resistin levels using an ELISA on platelet-free plasma and airway fluid from CF patients and measured the presence of neutrophil extracellular traps (NETs) a marker of neutrophil activation in CF airway fluid. Results: Resistin levels in platelet-free plasma were significantly higher in CF subjects than in HC subjects. Resistin levels in expectorated CF sputum were 2 to 3 orders (100-500 fold) of magnitude higher than in plasma. Interestingly, we found a strong negative correlation between sputum resistin and lung function (Spearman Rho=-0.81, P<10-4). Similarly resistin was also shown to positively correlate with NETs in CF sputum. Conclusions: Resistin levels are abnormal in CF plasma and strikingly elevated in CF airway fluid during chronic disease. These results show, as also suggested by prior studies, that extracellular resistin is associated with PMN-driven CF airway inflammation, including NET release. Mechanistic studies looking at the precise impact of resistin on metabolism and inflammation in CF are warranted.