Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8–driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF.

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Background The relationship between anti-inflammatory lipoxins and pro-inflammatory leukotrienes may be important in the pathobiology of asthma and its severity. Objective To investigate whether exhaled breath condensate (EBC) lipoxin and leukotriene measurements can non-invasively characterize the asthmatic diathesis and its severity. Methods We measured lipoxin A4 (LXA4) and leukotriene B4 (LTB4) levels in EBC collected from asthmatics of different severities and from healthy controls. Results EBC LXA4 and LTB4 levels are elevated in asthmatics as compared to healthy controls (LXA4 31.40 vs. 2.41 pg/ml EBC respectively, p < 0.001; LTB4 45.62 vs. 3.82 pg/ml EBC, p < 0.001). While both eicosanoids are elevated in asthmatics, the ratio LXA4 to LTB4 decreases with increasing asthma severity. It is 41% lower in severe versus moderate asthmatics (0.52 vs. 0.88, p = 0.034). EBC LXA4 levels correlate with the degree of airflow obstruction measured by FEV1 (r = 0.28, p = 0.018). A cut-off value of 7 pg LXA4/ml EBC provides 90% sensitivity and 92% specificity for the diagnosis of asthma (AUC 0.96, p < 0.001). A cut-off value of 11 pg LTB4/ml EBC provides 100% sensitivity and 100% specificity for the diagnosis of asthma (AUC 1, p < 0.001). Conclusions Pro-resolving and pro-inflammatory eicosanoids are generated in airways of all asthmatics. The proportion of pro-resolving compounds declines with asthma severity. These findings support the role for EBC eicosanoid measurements in the non-invasive diagnosis of asthma and suggest that pro-resolving eicosanoid pathways are dys-regulated in severe asthma.

This is a report on the significant increase in urinary LTE4 and 9alpha, 11beta-PGF2 concentrations during anaphylaxis. Urinary LTE4 and 9alpha, 11beta-PGF2 concentrations may be a reliable marker of endogenous production of inflammatory mediators associated with anaphylaxis.

Rationale: Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.Methods: Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.Measurements and Main Results: 8-Isoprostane levels in sputum supernatants were inversely related to LXA 4 in severe asthma (r = 20.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA 4 and 15-epi-LXA 4 biosynthesis by peripheral blood leukocytes. LXA 4 and 15-epi-LXA 4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA 4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited plateletactivating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA 4 100 nM], 78.3% inhibition [15-epi-LXA 4 100 nM]) and 15-epi-LXA 4 markedly inhibited tumor necrosis factora-induced increases in bronchial contraction.Conclusions: LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).

Peripheral platelets were activated more in patients with stable AERD compared with those in patients with stable ATA, patients with idiopathic chronic eosinophilic pneumonia, and control subjects. Platelet activation was involved in cysteinyl leukotriene overproduction and persistent airflow limitations in patients with AERD.

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