Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway

Abstract

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.

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

“…In humans, the ratio of proresolving LXA 4 to proinflammatory LTB 4 is balanced when inflammation is properly controlled (7,18), whereas this balance is skewed toward LTB 4 in certain chronic inflammatory diseases (40)(41)(42). Although the mechanisms of excess LTB 4 production in these diseases remain to be elucidated, it is possible that defective RvD1 levels or activity play a role through the mechanisms elucidated in this report.…”

High-dose oral N -acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis

“…The recognition of neutrophilic inflammation as a major driving force in the progression of CF airway disease has led several groups to propose novel antiinflammatory approaches, including modulators of lipid mediator production (39,40). So far, none of these approaches has proven safe and efficient in the long term.…”

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

“…9 Although the mode of inheritance defines CF as a single-gene disorder, its variable course indicates that non-inherited and inherited factors shape the manifestation of the monogenic disease, which has been acknowledged by several research groups with an investigation of CF-modifying genes. The disease is characterized by a proinflammatory state, 10 which has been described in-vitro in cell systems, [11][12][13][14][15][16] using a murine model 17 and was confirmed mostly, [18][19][20][21] albeit not exclusively, 22,23 in ex-vivo material studied from CF patients. Consequently, several studied candidate genes were derived from the field of immunity, immunology and host defense such as the cytokines IL8, [24][25][26] IL1B 25,26 and TGFB1.…”