Omega‐3 fatty acids suppress the enhanced production of 5‐Iipoxygenase products from polymorph neutrophil granulocytes in cystic fibrosis

Abstract

Pulmonary damage in cystic br osis (CF) is associated with chronic inflammation mediated in part by proinflammatory 5-lipoxygenase products (5-LOP, leukotrienes and 5-hydroxyeicosatetraenoic acid) from polymorph neutrophil granulocytes (PMN). The authors studied 5-LOP formation of PMN from CF patients and in vitro effects of added eicosapentaenoic acid (EPA) and fish oil. Circulating PMN were isolated from 10 CF patients without acute infections and 10 control persons of the same age (4-20 years). Total 5-LOP liberation from PMN of CF patients was significantly increased over controls after incubation with the calcium ionophore A23 (1 mumol L-1) without arachidonic acid (AA) (380 +/- 24 vs. 294 +/- 28 pmol mL-1) and with 10 mumol L-1 AA (1303 +/- 104 vs. 1015 +/- 104 pmol mL-1), and there were nonsignificant trends to high values after incubation with 5 mumol L-1 platelet activating factor (PAF, 134% of controls) and 1 mumol L-1 formyl-methionylleucyl-phenylalanine (FMLP, 125%). The addition of 100 micrograms mL-1 fish oil to PMN of CF patients challenged with A23 completely suppressed synthesis of proinflammatory 5-LOP of the 4-series, while inactive 5-LOP metabolites of the 5-series were produced. Added EPA (10 mumol L-1) also suppressed 4-series 5-LOP and significantly reduced leukotriene B4 concentration by 48% from 39.9 +/- 3.2 to 20.6 +/- 11.4 pmol L-1, again with a concomittant increase of inactive 5-series metabolites. The authors conclude that the turnover of endogenous and exogenous AA is enhanced in CF, possibly due to stimulated phospholipase A2 activity. The relatively small effect of the receptor dependent stimuli PAF and FMLP may be caused by a down-regulation of PMN receptors in CF. Supplementation of long-chain omega-3-fatty acids may be beneficial for reducing excessive inflammation in CF patients and should be further evaluated.

Molecular Species Compositions of Lung and Pancreas Phospholipids in the cftrtm1HGU/tm1HGU Cystic Fibrosis Mouse

“…In addition, because of the significant differences in phospholipid compositions and metabolism between mice and people, detailed analysis of compositions of phospholipid molecular species from human cells expressing mutant CFTR is essential to evaluate the potential clinical relevance of any of the results found in mouse models of CF. Administration of 22:6 n-3 to children with CF has great potential benefit as an anti-inflammatory therapy (28), but the possibility that this intervention may correct a basic defect of CFTR function requires more careful study both in mice and in patients with CF. …”

RBx 7796: A novel inhibitor of 5-lipoxygenase

“…Some of these molecules were effective in acute infl ammation models but failed to offer protection in chronic models of infl ammation in experimental animals and in clinic [16,26,30,31]. Reports exist to suggest that long chain fatty acids [32,33] and molecules like α-Tocopherol [34] with long carbon chain can inhibit 5-lipoxygenase, albeit, with weak II-potency. Through extensive medicinal chemistry efforts, we have discovered RBx 7796 (Clafrinast) -a distinct chemical entity from N-hydroxyurea, that inhibits 5-lipoxygenase enzyme in a competitive manner and exhibits effi cacy in several experimental animal models of airway infl ammation.…”

Neutrophil generation of inflammatory precursors is not modulated by docosahexaenoic acid

“…Arachidonic acid-5, 6,8,9,11,12,14, H(n) (180-240 Ci/ mmol), 4,7,10,13,16,19-DHA-1-14 C (40-60 mCi/mmol), fatty acid-free bovine serum albumin (BSA), lipopolysaccharide from Pseudomonas aeruginosa (LPS), Histopaque 1077 and various classes of products not otherwise specified were purchased from Sigma Chemical Company (St. Louis, MO, USA). RPMI 1640, fetal bovine serum (FBS), penicillin and streptomycin were obtained from Hyclone Europe Ltd. Dextran T-70 was obtained from Pharmacia Pfizer Italy.…”

“…CF is also associated with an imbalance in the ratio of essential PUFA owing to decreased levels of linoleic and docosahexaenoic acid (n3C22:6; DHA) and to a variable excess of arachidonic acid (n6 C20:4; AA) [5,6]. Several lines of evidence suggest that these abnormalities of AA and DHA pathways are primary in CF [5][6][7][8] and many studies have suggested that supplementation with fish oils may be beneficial for reducing excessive inflammation in the disease [1,2,9,10]. Because AA competes with DHA for the same enzymes and for the site of esterification at the sn-2 position of phospholipids, it has been hypothesized that an increase in the content of DHA in the membrane can decrease the proinflammatory response triggered by AA cascade pathway, reducing the production of eicosanoids during inflammatory processes [1,[9][10][11].…”

“…Several lines of evidence suggest that these abnormalities of AA and DHA pathways are primary in CF [5][6][7][8] and many studies have suggested that supplementation with fish oils may be beneficial for reducing excessive inflammation in the disease [1,2,9,10]. Because AA competes with DHA for the same enzymes and for the site of esterification at the sn-2 position of phospholipids, it has been hypothesized that an increase in the content of DHA in the membrane can decrease the proinflammatory response triggered by AA cascade pathway, reducing the production of eicosanoids during inflammatory processes [1,[9][10][11]. The most favored hypothesis is that DHA brings about this effect by decreasing AA incorporation into membrane phospholipids and downregulating the release of AA-derived proinflammatory precursors [3,10,11].…”