Lipoxin A4 and interleukin-8 levels in cystic fibrosis sputum after antibiotherapy

Chiron, R.; Grumbach, Y; Quynh, Nga Vu Thi; Verrière, Valia; Urbach, V.

doi:10.1016/j.jcf.2008.04.002

Cited by 22 publications

(23 citation statements)

References 27 publications

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“…Consistent with the notion that P. aeruginosa actively manipulates the inflammatory environment in the airway, other studies have demonstrated that i.v. antibiotic treatments increase LXA 4 levels, while decreasing proinflammatory chemokine concentrations in BALF of patients with CF (28). As a result, P. aeruginosa may be uniquely poised to exploit both pro-and antiinflammatory strategies to thwart host defense mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Flitter

Hvorecny

Ono

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Flitter

Hvorecny

Ono

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In order to test the hypothesis that eicosanoid class switching is defective in CF, giving rise to a failure to resolve acute inflammation, we compared eicosanoids temporally associated with the ''switch'' from propagation to resolution, LTB 4 and LXA 4 , respectively. In addition, with the expectation that the phase of inflammation would be affected by the infectious context [29], we conducted subgroup analysis based on the presence or absence of microbial pathogens detected in the BAL fluid. By comparing relative mediator concentrations, expressed as a LXA 4 /LTB 4 ratio, we demonstrate that the balance in eicosanoid biosynthesis weighs heavily in favour of LXA 4 production over LTB 4 production in control BAL when compared to CF BAL ( fig.…”

Section: Discussionmentioning

confidence: 99%

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

et al. 2014

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Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A 4 (LXA 4 ) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the ''class switch'' of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease.Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA 4 to leukotriene B 4 (LTB 4 ) is depressed in CF BAL (p,0.01), even in the absence of infection (p,0.001).Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p,0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA 4 /LTB 4 ratio (p50.01, r50.66) and with percentage macrophage composition of the BAL fluid (p,0.001, r50.82), which were absent in CF.Impoverished 15-LO2 expression and depression of the LXA 4 /LTB 4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung. @ERSpublications Reduced 15-LO2 expression in the lower airways of children with CF, associated with a depressed LXA 4 /LTB 4 ratio http://ow.ly/tzZWa This article has supplementary material available from

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“…Several studies have shown that markers of inflammation are elevated in the sputum of individuals with CF, including neutrophil elastase and IL-8 (2, 3); while markers of inflammation resolution, such as lipoxin A4, are decreased (4). Individuals with CF also display abnormalities of fatty acid (FA) metabolism, most notably characterized by decreased linoleic acid (LA) and docosahexaenoic acid (DHA) levels (5, 6).…”

Section: Introductionmentioning

confidence: 99%

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study

O'Connor

Thomsen

Brown

et al. 2016

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Background Airway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA). Methods This is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6 to 18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites. Results Seventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo. Conclusions Urine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further investigation.

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Lipoxin A4 and interleukin-8 levels in cystic fibrosis sputum after antibiotherapy

Cited by 22 publications

References 27 publications

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study

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Lipoxin A4 and interleukin-8 levels in cystic fibrosis sputum after antibiotherapy

Cited by 22 publications

References 27 publications

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4ratio in children with cystic fibrosis

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study

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Reduced 15-lipoxygenase 2 and lipoxin A₄/leukotriene B₄ratio in children with cystic fibrosis