Characterization of LPS-induced lung inflammation incftr^−/−mice and the effect of docosahexaenoic acid

Abstract

The mechanism by which Pseudomonas causes excessive inflammation in the cystic fibrosis lung is unclear. We have reported that arachidonic acid is increased and docosahexaenoic acid (DHA) decreased in lung, pancreas, and ileum from cftr-/- mice. Oral DHA corrected this defect and reversed the pathology. To determine which mediators regulate inflammation in lungs from cftr-/- mice and whether inhibition occurs with DHA, cftr-/- and wild-type (WT) mice were exposed to aerosolized Pseudomonas lipopolysaccharide (LPS). After 2 days of LPS, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2, and KC levels in bronchoalveolar lavage fluid were increased in cftr-/- compared with WT mice and not suppressed by pretreatment with oral DHA. Neutrophil levels were not different between cftr-/- and WT mice. After 3 days of aerosolized LPS, neutrophil concentration, TNF-alpha, and the eicosanoids 6-keto-PGF1alpha, PGF2alpha, PGE2, and thromboxane B2 were all increased in bronchoalveolar lavage fluid from cftr-/- mice compared with WT controls. Oral DHA had no significant effect on TNF-alpha levels in cftr-/- mice. In contrast, neutrophils and eicosanoids were decreased in cftr-/- but not in WT mice treated with DHA, indicating that the effects of DHA on these inflammatory parameters may be related to correction of the membrane lipid defect.

DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity

“…Studies in two different mouse models of CF ( 6,8 ) demonstrated normalization of LA and AA levels in lung, intestine, and pancreas after dietary supplementation with DHA. Furthermore, this treatment corrected the phenotypic manifestations of CF, decreasing ileal villus height, pancreatic duct diameter, and pulmonary infl ammation stimulated by lipopolysaccharide ( 6,25 ). Similarly, CF patients treated with DHA exhibited signifi cant decreases in plasma AA levels (26)(27)(28), accompanied in some cases by increased LA ( 29,30 ).…”

“…Therefore, we hypothesized that the effects of DHA and EPA on metabolism may be due to changes in the expression of these enzymes. To test this, we measured the expression of the four major enzymes in the n-3 and n-6 metabolic pathways ( ⌬ 5-and ⌬ 6-desaturases, plus elongases 2 and 5) by that DHA therapy reduces AA levels in CF patients and animal models ( 6,(25)(26)(27)(28)(29)(30).…”

Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

“…There is an increase in arachidonic acid and a decrease in docosahexaenoic acid (DHA) in cftr 2/2 mice (Freedman et al 1999). Investigators have shown that oral administration of DHA to cftr 2/2 mice corrected the lipid imbalance and reversed the observed pathological manifestations (Freedman et al 2002;Beharry et al 2007). There have been a handful of studies of DHA supplementation in CF patients (Van Biervliet et al 2008;Aldamiz-Echevarria et al 2009).…”

Cell culture models demonstrate that CFTR dysfunction leads to defective fatty acid composition and metabolism

“…Although CF serum does not display large changes in AA levels, AA levels are increased in tissues from CF patients (8) and in CFTR knock-out mice (9). CF is associated with an excessive host inflammatory response independent of infection (10,11), with these changes in fatty acids levels being postulated to play a role in this altered innate immune response (9,12). However, reported fatty acid alterations in CF mouse tissues have been variable (13), and cultured human CF cell lines have not to date shown the fatty acid changes characteristic of CF tissues and serum (14).…”