ARE YOU ANTI- OR PRO-INFLAMMATION?
Inflammation is a normal defense mechanism that protects the host from infection and other insults; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. It is typified by redness, swelling, heat, pain and loss of function, and involves interactions amongst many cell types and the production of a number of chemical mediators. But is inflammation positive for animal health? Should we favor it or prevent it?
Where an inflammatory response does occur, it is normally well regulated in order that it does not cause excessive damage to the host. It is self-limiting and resolves rapidly. This self-regulation involves the activation of negative feedback mechanisms such as the secretion of anti-inflammatory mediators, inhibition of pro-inflammatory signaling cascades, shedding of receptors for inflammatory mediators, and activation of regulatory cells. As such, when controlled properly, regulated inflammatory responses are essential to remain healthy and maintain homeostasis.
Pathological inflammation involves a loss of tolerance and/or of regulatory processes. Where this becomes excessive, irreparable damage to host tissues and disease can occur. Irrespective of the cause of the inflammation, the response involves four major events:
An increased blood supply to the site of inflammation;
Increased capillary permeability caused by retraction of endothelial cells. This permits larger molecules, not normally capable of traversing the endothelium, to do so and thus delivers soluble mediators to the site of inflammation;
Leukocyte migration from the capillaries into the surrounding tissue.
Release of mediators from leukocytes at the site of inflammation. These may include lipid mediators (e.g., prostaglandins (PGs), leukotrienes (LTs)), peptide mediators (e.g., cytokines), reactive oxygen species (e.g., superoxide), amino acid derivatives (e.g., histamine), and enzymes (e.g., matrix proteases). These mediators normally would play a role in host defense, but when produced inappropriately or in an unregulated fashion they can cause damage to host tissues. Several of these mediators may act to amplify the inflammatory process acting, for example, as chemo-attractants. Some of the inflammatory mediators may escape the inflammatory site into the circulation and from there they can exert systemic effects. For example, the cytokine interleukin (IL)-6 induces hepatic synthesis of the acute phase protein C-reactive protein, while the cytokine tumor necrosis factor (TNF)-α leads to metabolic effects within skeletal muscle, adipose tissue and bone.
Long chain fatty acids influence inflammation through a variety of mechanisms. These mechanisms are associated with changes in fatty acid composition of cell membranes. The modification of cell membranes composition in long chain fatty acids can alter membrane fluidity, the emission of signals, and the production of lipid mediators.
Cells involved in the inflammatory response are typically rich in arachidonic acid from Omega-6 category. When we are looking at the composition of the membranes of blood cells (e.g., neutrophils, lymphocytes, monocytes) from humans consuming typical Western diets, we found out that they contain about 10 to 20% of arachidonic acid and only 1% EPA and about 2% DHA.
Arachidonic acid, EPA and DHA are both directly involved in the regulation of the inflammatory mechanisms. These three components are at the origin of the synthesis of lipid mediators namely a group called eicosanoids (cf figure 1)
Eicosanoids are key mediators and regulators of inflammation and immunity and are generated from 20 carbon PUFAs (eicosa means 20 in Greek). Eicosanoids, which include prostaglandins, thromboxanes, leukotrienes are generated mainly from arachidonic acid. These Eicosanoids are involved in modulating the intensity and duration of inflammatory responses. Because of the relatively high amount of arachidonic acid in membrane phospholipids of cells involved in inflammation, this fatty acid is typically the major precursor for eicosanoid mediators. In general, arachidonic acid-derived eicosanoids (e.g., PGE2 and LTB4) act in a pro-inflammatory way.
EPA and DHA are converted as well to newly discovered components called “resolvins” and “protectins” through pathways involving cyclooxygenase and lipoxygenase enzymes. As their names say, these mediators are anti-inflammatory and inflammation resolving. For example, resolvin E1, resolvin D1 and protectin D1 all inhibit trans-endothelial migration of neutrophils, so preventing neutrophilic infiltration at sites of inflammation. Resolvin D1 inhibits as well the production of interleukine-1β, and protectin D1 inhibits TNF. The role of resolvins and protectins may be very important because resolution of inflammation is important in shutting off the ongoing inflammatory process and in limiting tissue damage.
Both Omega-6s and Omega-3s are substrate of the COX (cyclooxygenase) and LOX (lipoxygenase) enzymes. COX and LOX are needed for the production of the PG, LT, resolvins and protectins. Therefore, if the quantity of EPA and DHA in the cells membranes increase in comparison to arachidonic acid, it will redirect the utilization of Cox and Lox towards the production of anti-inflammatory and inflammation resolving mediators that will result in the reduction of the inflammation.
Animal studies have shown a direct relationship between arachidonic acid content of inflammatory cell phospholipids and ability of those cells to produce PGE2. Increased membrane content of EPA and DHA (and decreased arachidonic acid content) results in a changed pattern of production of eicosanoids and resolvins.
Therefore, we see here a strategy to control the inflammation mechanisms by modulating the balance between Omega-6s and Omega-3s present in the membranes of the cells.
This modulation can be modified through diet. In the experimentation below (figure 2) done in human, the level of EPA can increase from 1 to 3% and DHA can double to reach 4%.
It is well documented that the production of PGE2 and LT4 production by inflammatory cells can be significantly decreased by the dietary supplementation of Omega-3 for a period of weeks to months. Other studies confirmed as well an increase of LT4 from macrophage of mice fed with fish oil.
The importance of Omega-3s in human nutrition has been popularized for several decades already through infant formula (milk powder) or Omega-3 gellules. More recently, animal nutritionists enriched diets with Omega-3 to propose to consumers some Omega-3 enriched eggs and meat. But it is critical to consider as well the benefits of Omega-3 for the health of animals themselves. All the recent studies presented above underlined the positive effects of Omega-3 in the control of inflammation. Intensive farming is often source of inflammation for animals and the utilization of Omega-3 could be a solution to mitigate this inflammation and higher animal performance both in Swine, Poultry, Ruminants and possibly Auquaculture.