Pain, inflammation, and nutrition (Proceedings)

Inflammation

Inflammation is a reaction of the microcirculation characterized by movement of fluid and leukocytes from the blood into extravascular spaces. This is frequently an expression of the host's attempt to localize and eliminate metabolically altered cells, foreign particles, microorganisms or antigens. The clinical signs of inflammation were described in Classical times; the Greeks and Romans noted the association of redness (rubor), heat (callor), swelling (tumor) and pain (dolor) with acute injury to tissues. Further extension of the injury or the effects of the inflammatory response itself may lead to loss of function of the tissue or organ. These are the clinical signs with which we are most familiar and with which we associate response to injury.

Pain and inflammation

Inflammation is a vital reaction, but it also plays a central role in many of today's widespread diseases of Western cultures; osteoarthritis, periodontal disease, inflammatory bowel disease, cancer, brain aging/dementia. Chronic inflammatory diseases are often associated with chronic pain.

In 1979 the International Association for the Study of Pain (IASP) adopted the following definition of pain 'an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage'. This definition was subsequently considered elusive, and the following statement was added in order to make the position more clear: 'Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life'.1 This definition avoids tying pain to the stimulus. It has been suggested that in human medicine the variations in current treatments of pain syndromes reflects a lack of a unifying theory of pain. In 2007 a unifying theory of pain was proposed by clinicians at the Division of Inflammation and Pain Research, L.A Pain Clinic. This theory states; the origin of all pain is inflammation and the inflammatory response.1 This law unifies all pain syndromes as sharing a common origin of inflammation and suggests that therapies should include those aimed at resolution of inflammation.

Control of inflammation

Pus bonum et laudabile "good and commendable pus". Even the ancient Egyptians recognized the importance of a robust host defense. Since that time, with major progress in recent decades, the focus of research in inflammation was to elucidate the chemical mediators that evoke the cardinal signs of inflammation; heat, redness, swelling, pain and loss of function. Once these mediators were identified the emphasis shifted to producing inhibitors as a means of controlling inflammation during disease. This approach has been stymied by the sheer volume of local chemical mediators that have been identified. There are several hundred known mediators including; many protein based mediators (cytokine, chemokines, growth factors and inappropriately liberated enzymes), reactive oxygen species and other radiacal, and lipid mediators (platelet activating factor, eicosanoids, prostanoids and leukotrienes).2

Recent work has identified a promising alternative to controlling inflammation. Resolution of inflammation and the return of tissues to homeostasis are essential in health and disease. Efforts to identify molecular events governing termination of self-limited inflammation have uncovered pathways in resolving exudates that actively generate, from essential omega fatty acids, new families of local-acting mediators. These chemical mediator families, termed resolvins and protectins, are potent agonists that control the duration and magnitude of inflammation, joining the lipoxins as signals in the resolution phase of the inflammatory process.3 In addition, these compounds also display potent protective roles in neural systems, liver, lung, and eye. Given the potent actions of lipoxins, resolvins, and protectins in models of human disease, deficiencies in resolution pathways may be the common denominator for many of the chronic inflammatory diseases of Western culture.4,5 These newly described pathways offer exciting new potential for therapeutic control via resolution.

Basic fatty acid metabolism

All mammals synthesize fatty acids de novo up to palmitic acid (16:0), which may be elongated to stearic acid (18:0) and converted into oleic acid (18:1). Plants, unlike mammals, can insert additional double bonds into oleic acid and produce the polyunsaturated fatty acids (PUFA) linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3). Both LA and ALA are considered essential fatty acids (EFA) because animals cannot synthesize them from other series of fatty acids; thus, they must be supplied by the diet.

Dietary PUFA serve as substrates that may be metabolized to form important, biologically active compounds. To produce those metabolites, a number of cells contain a group of enzymes that desaturate (introducing a double bond between carbon atoms), elongate (increasing length of fatty acid chain) and oxygenate fatty acids.

All PUFA are categorized based on the position of the first double bond in the structure from the terminal end. The two most important PUFA series are the omega-6 series (the first double bond is located at the sixth carbon atom) and the omega-3 series (the first double bond is located at the third carbon atom). In the omega-6 series, linoleic acid can be desaturated to yield gamma-linolenic acid (GLA, 18:3n-6), which is elongated to dihomogammalinolenic acid (DGLA, 20:3n-6) and ultimately desaturated again to produce arachidonic acid (AA, 20:4n-6) in the animal.

Many marine plants, especially algae, elongate chains and add double bonds to ALA to yield omega-3 PUFA with 20 and 22 carbon atoms and five or six double bonds. Formation of these long-chain omega-3 PUFA by marine algae and their transfer through the food chain to fish account for the abundance of eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) in certain marine fish oils.

AA and EPA act as precursors for the synthesis of eicosanoids, a significant group of immunoregulatory molecules that function as local hormones and mediators of inflammation. The amounts and types of eicosanoids synthesized are determined by the availability of the PUFA precursor and by the activities of the enzyme system to synthesize them. In most conditions the principal precursor for these compounds is AA, although EPA competes with AA for the same enzyme systems. The eicosanoids produced from AA appear to be more inflammatory than those formed from EPA. Ingestion of oils containing omega-3 PUFA results in a decrease in membrane AA levels since omega-3 PUFA replace AA in the substrate pool and also produces an accompanying decrease in the capacity to synthesize eicosanoids from AA. In contrast, eicosanoids derived from EPA promote less inflammatory activity and may alter vascular function. Inflammatory eicosanoids produced from AA may be depressed when animals consume foods with high levels of omega-3 fatty acids.

Nutrition and inflammation

Beneficial actions of polyunsaturated fatty acids were noted many years ago but the underlying mechanisms for these effects are poorly understood. It is clear that arachidonic acid is transformed into many potent bioactive compounds such as prostaglandins, leukotrienes and lipoxins. The departure of fatty acids from simply playing structural roles in cell membranes and/or as energy stores came largely from the recognition of the rapid transformation of arachidonic acid to these potent eicosanoids by both cyclooxygenase and lipoxygenase mechanisms. Many of the classic prostaglandins and leukotriene mediators are pro-inflammatory and play a decisive role in inflammation and/or in systems where prostaglandins are key physiologic regulators.

The molecular mechanisms underlying the beneficial actions of polyunsaturated fatty acids remain an area of active research. Investigators have recently identified a variety of novel oxygenated products generated by enzymatic processes from the precursor omega-3 fatty acids EPA and DHA. These new compounds possess potent actions in the resolution of inflammation and may also have neuroprotective properties. The term resolvin (resolution phase interaction products) has been proposed for some of these compounds since they display both potent anti-inflammatory and immunoregulatory properties, reducing neutrophil traffic and the magnitude of the inflammatory response. The term protectin (or neuroprotectin) has been proposed for another class of these compounds with protective actions in neural and retinal tissues.

Resolvins are derived from both EPA (E series) and DHA (D series). Both the D and E classes of resolvins appear as biosynthetic products involving cell-to-cell interaction with vascular endothelial cells and are potent regulators of leukocyte infiltration. Specifically, resolvin E1 (RvE1) has been shown to dramatically reduce dermal inflammation, peritonitis, colitis, periodontitis, dendritic cell migration and interleukin (IL)-12 production. Resolvins of the D series block tumor necrosis factor-alpha activity and act as potent regulators to limit leukocyte infiltration into inflamed brain, skin and peritoneum.

Among the essential fatty acids, DHA is concentrated in the central nervous system, neurons and retina where it is thought to regulate membrane fluidity and ion fluxes. The term docosaniods has been proposed to describe products generated from DHA. DHA-derived docosatrienes have neuroprotective action in retinal cells and can improve the sequelae associated with stroke and dementia. The terms protectin or neuroprotectin describe these compounds which are rapidly generated from DHA and released locally into tissues. The effects of protectins on neural pain receptors and pathways are unknown. There is emerging evidence that resolvins and docosanoid compounds may also have immunoregulatory actions by influencing antigen-presenting cells and T-cell traffic.

Fatty acid supplementation has been used for many years to help manage patients with a variety of inflammatory diseases and associated pain. The underlying mechanisms for the beneficial effects of fatty acid supplementation have been poorly understood. Resolvins and protectins, which are generated from EPA and DHA, are 'switched-on' in the resolution phase of an inflammatory response, thus acting as 'braking-signals' in inflammation and reducing leukocyte-mediated injury in several different tissues. The discovery of resolvins and pretectins offers molecular mechanisms that could underlie some of the beneficial actions of dietary fatty acid supplementation observed in many clinical settings. These same actions should be explored further in pain management.

New horizons: nutrigenomics

The most important new area of investigation in animal nutrition is the concept of nutrigenomics. Nutrigenomics is the science investigating how individual dietary substances (nutrients) or their metabolites interact with the animal's genome to regulate the structure or expression of genes to alleviate or stop a disease process. Nutrigenomics is rapidly gaining in public interest. For example, the cover story in Time magazine in January 2005 had the following quote: "It isn't what you eat that will kill you, and it isn't just your DNA that will save you – it is how they interact." With the recent completion of the human and canine genome projects, cloning of the first dog and popularity of the topic in the lay press, we will see animal owners asking about applications of nutrigenomics in themselves and their pets. As described earlier, use of specific fatty acids in foods designed to help manage osteoarthritis in dogs was the first effort to combine the science of nutrigenomics with clinical proof of product efficacy. Nutrigenomics is not just a fancy word or future concept; it can be linked to clinical results that will improve the quality of life for animals and their owners. The impact of aging can be also be seen in gene expression profiles from healthy older dogs. Older dogs show increased expression of genes for inflammation and muscle wasting and decreased expression of genes for cartilage protection. This gene expression in healthy older dogs can be modified with appropriate nutritional management. Nutrigenomics may hold the key to better understanding of the interaction between nutrition, inflammation and pain management.

References

1 Omoigui S: The biochemical origin of pain – Proposing a new law of pain: The origin of all pain is inflammation and the inflammatory response. Part 1 of 3 – A unifying law of pain. Medical Hypotheses (2007) 69, 70–82.

2. Serhan C: Novel Ω-3 derived local mediators in anti-inflammation and resolution. Pharmacology & Therapeutics (2005) 105, 7-21.

3. Serhan C: Resolution Phase of Inflammation: Novel Endogenous Anti-Inflammatory and Proresolving Lipid Mediators and Pathways. Annu Rev Immunol (2007) 25:101–37.

4. Schwab JM, Serhan CN. Lipoxins and new lipid mediators in the resolution of inflammation. Curr Opin Pharm 2006;6:414-420.

5. Serhan CN. Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes and neuroprotectins. Curr Opin Clin Nutr Metab Care 2005;8:115-121.

6. Arita M, Clish CB, Serhan CN. The contributions of aspirin and microbial oxygenase to the biosynthesis of anti-inflammatory resolvins: novel oxygenase products from omega-3 polyunsaturated fatty acids. Biochem Biophys Res Commun 2005;338:149-157

7 Bannenberg GL, Chiang N, Ariel A, et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol 2005;174:4345-4355.