Regardless of how old you are, how big or small you happen to be, or what your daily routine looks like, we have ALL experienced the pain of inflammation at one time or another. From acute to chronic inflammation, millions of people worldwide have known the irritations, discomforts, and even agonies of this physiological response and are often subject to its very negative side effects. With billions of dollars being spent on research and development for remedies to fight inflammation, it is no wonder that a great deal of the world’s population include anti-inflammatories as part of their daily regime. But one may ask, since it is such a prevalent condition, where does inflammation come from and how can we stop it? We will attempt to answer this question and others as we dive deep into the subject of INFLAMMATION.
WHAT IS INFLAMMATION?
The inflammatory response is just that… it is a biological response by each cell of each tissue involved in the presence of damage, irritation, dangerous stimuli, or the presence of pathogens. It is the way cells communicate with the rest of the body by using chemoattractants, blood vessels and capillaries, and the immune system. Its main purpose is to attract attention to the area of injury or invasion, eliminate necrotic cells and the biological carnage created by the damage, and then proceed with the proper tissue repair mechanism. Inflammation has all sorts of “wonderful” signs that can be seen or felt. When a part of the body is red, swollen, warm, or even loses some of its function, this can be a classic sign of inflammation. The most typical sign however, is pain and irritation. Pain is the natural biological response that tells the brain that there is a problem in a certain area that requires attention. That attention of course, is the inflammation response.
When the inflammation response is initiated, especially in acute inflammation, immune cells (mast cells, macrophages, Kupffer cells, etc.) that are either already close by or reside in the involved tissue undergo a unique type of activation. The receptors on the surface of these immune cells do a sort of “handshake” with molecules released caused by damage or infection. This sets off the alarm within the immune cell and causes it to release inflammatory mediators, (more on this later). These inflammatory molecules’ main job is to induce vasodilation, which in turn increases blood flow to the area of concern. Blood vessels and capillaries become leaky and allow fluid and solutes from the bloodstream into the tissue. This of course, is what causes the redness, swelling, and warmth. With this intricate biological process comes the involvement of an array of different molecules of various shapes, sizes, and functions. So, the question now becomes… what are they?
THE KEY PLAYERS
Since there are too many molecules that are involved in the inflammation response to identify and chart in this text, we will take a brief look at some of the key characters that play a common role in the cascade of events that lead to inflammation and pain.
Histamine – this monoamine comes from mast cells and basophils, is typically stored in compartmentalized granules and is released after certain stimuli to an effected area. Histamine release results in vein and capillary permeability and arteriole dilation.
Nitric Oxide – NO is a blood soluble gas that is released from tissue cells and macrophages and is one of the body’s most potent vasodilators and muscle cell relaxers. NO is also responsible in the cascade of events in leukocyte attraction and recruitment.
Enzymes – enzymes are catalysts whose main role is to drastically speed up reaction rate. Some of the enzymes involved in the inflammation response are:
- Tryptase: primarily stored in mast cells, tryptase is a proteolytic enzyme secreted upon activation of these mast cells and has a wide variety of functions in the immune system-triggering cascade1.
- Cyclooxygenase: COX-1 and 2 are isozymes that catalyze the conversion of arachidonic acid to prostanoids2 and in the case of inflammation, the E-series prostaglandins.
- Lipooxygenase: LOX has many isozymes and is mainly involved in the conversion of arachidonic acid to pro-inflammatory eicosanoids such as the family of leukotrienes3.
- Phospholipase A2: PLA2 is the enzyme responsible for the removal of a fatty acid from its glyceryl backbone within a triglyceride. This liberated fatty acid now becomes the substrate (primarily arachidonic acid) for pro-inflammatory molecules4.
Cytokines – these functional proteins are instrumental to the inflammation response. Some of the main players are gamma interferon (IFN-γ), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α). These immunoproteins affect a wide variety of cells and induce inflammation by activating macrophages, initiating the production of more cytokines, and regulating endothelial genes involved in inflammation, just to name a few.
Eicosanoids – these signaling molecules are created by the enzymatic rearrangement of some of our favorite fatty acids such as arachidonic acid and other PUFA’s. The end product of such reactions includes leukotriene B, C, and D, 5-Hydroxyeicosatetraenoic acid (5-HETE), and of course the prostaglandins. All of these lipid-soluble molecules are the main culprits behind fever, vasodilation, and pain5,6.
So, when damage occurs, dangerous stimuli abounds, or when pathogens are present, these signaling molecules are immediately released and the cascade of events of the inflammation response ensues.
MEDICINAL & NATURAL REMEDIES
For hundreds, even thousands of years, humans have sought out myriads of different ways to alleviate the pain and discomfort of inflammation using drugs and holistic medications. Many of these have been used successfully and have much research performed on them. Of these remedies, the two main categories of anti-inflammatories are steroids and non-steroidal anti-inflammatories (NSAIDS).
The steroids that are involved in the impediment of the inflammation response include medications such as the glucocorticoids. These corticosteroids are one of the most powerful agents of all anti-inflammatories, regardless of the root cause of the inflammation. They do this by aiding in the production of a unique protein that directly inhibits the actions of phospholipase A2 (as mentioned earlier), so not only do glucocorticoids suppress the immune response involved in the inflammation response, but they also block the synthesis of the two main products of inflammation… prostaglandins and leukotrienes7.
Non-steroidal anti-inflammatory drugs are a class of molecules that directly inhibit the enzymes involved in the production of pro-inflammatory eicosanoids – more specifically cyclooxygenase and lipoxygenase. Although there are dozens of classes of NSAIDS, the ones we are all familiar with are aspirin, acetaminophen (Tylenol), ibuprofen, Celebrex®, etc. Their actions on relieving pain and inflammation are typically quicker than the majority of corticosteroids.
The reason why most of the natural remedies for inflammation come from dietary supplements are due to the fact that many plants are natural sources of these NSAIDS and contain terpenes and alkaloids that act in a similar pharmacological manner as NSAIDS or steroids. For example, the herb Devil’s Claw has been shown in studies to act as a COX-2 inhibitor8, thus inhibiting the production of the E-series prostaglandins. The popular herb turmeric contains curcuminoids and has demonstrated to have anti-inflammatory effects by inhibiting an array of mediators including phospholipase A2, LOX, COX-2, leukotrienes, thromboxane, prostaglandins, nitric oxide, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, IL-12, and TNF-α9.
CURRENT RESEARCH & TECHNOLOGY
As science and medicine advance, it is interesting to sit back and watch how new and exciting remedies are uncovered to help battle this widespread problem. One such example is that studies have shown that magnesium deficiency, of all things, induces such an inflammatory response that results in leukocyte and macrophage activation (recall from earlier), release of inflammatory cytokines and acute-phase proteins, and excessive production of free radicals10. Talk about a surprise attack from not taking your magnesium. Feverfew (Tanacetum parthenium L.) is an herb found in many vitamin stores and has been used for centuries to treat many different ailments. Just recently, it has been known to combat inflammation that is involved in migraine headaches and rheumatoid arthritis by inhibiting pro-inflammatory cytokine-mediated signaling, as well as blocking the synthesis of prostaglandins11 as discussed earlier.
So, we can see as technology and research expands, so does the control we begin to have over this often-debilitating condition. Hooray for R&D!
Of all the intricate players and steps involved in the process of the inflammation response, it would cause one to marvel at its design – as negative as its effects are. The molecules that are made, the enzymes that make them, the cells that house them, the circulatory system that facilitates the flow of traffic, all lead to the reality that although science and technology have come so far as to understand and treat this biological phenomenon, we still most likely have not even scratched the surface.
Chad Brey, a California State University, Northridge alumnus, has since worked as a chemist for various analytical and research facilities such as Amgen, Baxter, and Nusil Technology. Since 1997 he has worked in the dietary supplement industry for companies such as Earthwise Nutrition (formerly known as Great Earth Vitamins) and has earned a number of certificates as an IACET-certified dietary supplement specialist. Chad has written dozens of technical articles on the specifics of how certain dietary supplements work. Chad has formulated and developed small and large molecules in research and development laboratories since 2003 and continues to consult others in R&D today.
1. Caughey, George H. (2016-05-05). Mast cell proteases as pharmacological targets. European Journal of Pharmacology. Pharmacological modulation of Mast cells and Basophils. 778: 44–55.
2. Litalien C, Beaulieu P (2011). Chapter 117 – Molecular Mechanisms of Drug Actions: From Receptors to Effectors. In Fuhrman BP, Zimmerman JJ. Pediatric Critical Care (4th ed.). Philadelphia, PA: Elsevier Saunders. pp. 1553–1568.
3. Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB (1986). Arachidonic acid metabolism. Annu. Rev. Biochem. 55: 69–102.
4. Grace Y. Sun et al., Phospholipases A2 and Inflammatory Responses in the Central Nervous System. Neuromolecular Med. 2010 Jun; 12(2): 133–148.
5. Larry R. Engelking, Eicosanoids I. Textbook of Veterinary Physiological Chemistry (Third Edition), 2015.
6. Dennis EA, Norris PC, Eicosanoid storm in infection and inflammation. Nat Rev Immunol. 2015 Aug;15(8):511-23.
7. Goppelt-Struebe M, Wolter D, Resch K (Dec 1989). Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerase. British Journal of Pharmacology. 98 (4): 1287–95.
8. Zhang L, Feng L, Jia Q, Xu J, Wang R, Wang Z, Wu Y, Li Y (2011). Effects of β-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro. Bioorg. Med. Chem. 19 (16): 4882–6.
9. Chainani-Wu N., Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003 Feb;9(1):161-8.
10. Forrest H Nielsen, Magnesium deficiency and increased inflammation: current perspectives. J Inflamm Res. 2018; 11: 25–34.
11. Anil Pareek et al., Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. 2011 Jan-Jun; 5(9): 103–110.