Polyunsaturated fatty acids and uses thereof

Details Polyunsaturated fatty acids and uses thereof Polyunsaturated fatty acids and uses thereof

1996-05-28

1998-06-16

Reamer, James H.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

A61K 3120

Patent

active

057671567

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to polyunsaturated fatty acids, their use in stimulation of macrophages and neutrophils, and their use as therapeutic agents.
Macrophages play an important role in antimicrobial activity. Macrophage activation results in the killing of bacteria such as E. coli, S. typhimurium, L. monocytogenes, Legionella pneumophila, M. tuberculosis, M. Leprae, Staphylococci, Psuedomonas organisms, Cryptococcus neoformans, Chlamydia and Histoplasma capsulatum. Macrophages are also involved in anti-viral responses, e.g., against herpes simplex and alpha viruses. Macrophage activation is also a general feature of early parasite infection by parasites, e.g., Plasmodium, Trypanosoma, Leishmania, Helminths e.g., trematodes (Schistosoma) nematodes (Trichenella Tichinosis) etc. They are also thought to have potent anti-fungal activity, e.g., against Candida sp. When activated, macrophages are better able to resist infection by intracellular parasites which normally multiply within them, e.g., Leishmania, T. cruzi, and acquire the ability to eliminate already established parasites. The major effector functions of macrophages include: the generation of reactive oxygen intermediates (measured by lucigenin-dependent chemiluminescence and superoxide production), production of reactive nitrogen intermediates, limitation of intracellular iron availability, phagosomal acidification and phagosomal-lysosome fusion, production of defensins. These actions are cytotoxic for many bacteria, parasites and viruses. Stimulated macrophages also kill tumour cells although the mechanisms may not be the same as those involved in microbial killing.
Stimulation of neutrophils results in the generation of oxygen-derived reactive species with release of lysosomal enzymes and other granule proteins (Panettone, J. C. and Ward, P. A. 1992, Am J Pathol 107;396-418). The release of these mediators is coordinated with phagocytosis which leads to microbial killing. It is known that certain PUFA can activate superoxide production by human neutrophils (Badwey et al., 1981, J Biol Chem 256:12640-12643; Badwey et al 1984, J Biol Chem 259:7870-7877, Poulos et al., 1991, Immunol 73:102-108) and that a particular PUFA (docosahexanoeic acid, 22:6, (n-3)) can synergise the superoxide production induced by the bacterial peptide fMLP and the phorbol ester TPA.
While it is known that certain fatty acids can affect the activity of human neutrophils the effects of fatty acids, particularly PUFA, on monocytes and macrophages are less well defined. Dietary deficiency of 20:5n-3 leads to impaired adherence and spreading of macrophages (Lefkowith et al 1991, J. Biol. Chem. 226:1071-1076; Lefkowith et al 1991, J. Immunol. 149:1729-1735). Cultured murine peritoneal macrophages elicited with thioglycollate and cultured in the presence of polyunsaturated fatty acids show increased phagocytosis of unopsonized zymosan (Calder et al 1990, Biochem. J. 269(3):807). Dietary supplementation with fish oil (a mixture of n-3 fatty acids) has yielded conflicting results with respect to superoxide production with either reported enhancement (Berger et al 1992, J. Nutr., 123;225.223) or depressing (Fisher et al 1990 Am J. Clin Nutr 51:804-233) of superoxide production by macrophages or monocytes.
Cytokines such as tumour necrosis factor (TNF) and colony stimulating factors (CSFs) have also been shown to activate neutrophils. TNF stimulates enhanced phagocytosis (Shalaby et al, J Immunol 135:2069-2073), enhanced production of superoxide anions (Teujiimoto et al., 1986, Biochem. Biophys. Res Comm 137:1094-1100), release of lysozyme and hydrogen peroxide and causes neutrophil degranulation (Klebanoff et al., 1986 J Immunol 136:4220-4225). Neutrophils also show enchanced microbiocidal and tumourcidal activity when stimulated by TNF (Shalaby et al, 1985 J Immunol 135:2069-2073; Djeu et al., 1986 J Immunon 137:2960-2984; Blanchard et al., 1989 J Leukocyte Biol 45:538-454). The anti-tumour action of TNF may be mediated through the activation of neutrophils (Shau 1986, J Im

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