The term inflammation is derived from Latin and means to set on fire.
The classic signs of redness, swelling, and pain reflect the molecular turbulence of the tissues involved.
When inflammation occurs, the body's response is to prepare for the worst and respond accordingly. In fact, much of the damage done from an injury is on account of the body's response, not the actual injury.
Human neuronal chemistry treats both lack of food and injury as mortal enemies.
To deal with these perceived dangers, the body evolved complicated systems to store excess calories as fat to prevent starvation. It also gave inflammation the role of sealing off the area to limit damage.
On the molecular level, inflammation is a complex series of chemical events within vascular tissue (blood vessels). The players involved are blood cells, which have sophisticated cascading mechanisms.
Inflammation is the body’s response to harmful stimuli. It is an attempt to wall off the problem until it can rid itself of the offending agent.
Inflammation is classified as either acute or chronic.
Acute inflammation is the body’s initial response to the harmful stimuli. During this phase of inflammation, there is an increased movement of plasma and leukocyte cells from the blood to the injured tissues. Acute inflammation is characterized by swelling, redness, pain, heat, and loss of function
Prolonged inflammation or chronic inflammation is the continual destruction and repair of tissue. During this phase, there is a progressive shift in the type of cells (monocytes, macrophages), which migrate to the site of inflammation. Chronic inflammation is characterized by simultaneous destruction and healing of tissue.
There are three powerful inflammatory agents, prostaglandins, thromboxanes and leukotrienes. These chemical mediators stimulate the body’s inflammatory response.
Prostaglandins and leukotrienes are the enablers of inflammation.
Prostaglandins are also known as prostanoids..
Prostaglandins cause inflammatory cell migration to injured joints.
Leukotrienes are responsible for mucus production during asthma attacks and inflammation in joints.
Thromboxanes are involved with clot formation.
Arachidonic acid, a fatty acid chain of 20 carbons, is the starting point in the formation of the three inflammatory enablers.
Arachidonic acid can also be converted into cholesterol and then on to any of the steroid hormones.
Arachidonic acid stands at the crossroads of health. The fate and destination of arachidonic acid determines the manner in which the body reponds to stress and inflammation.
Both leukotrienes and prostaglandins are directly formed from arachidonic acid, while thromboxane must go through prostaglandin.
Inflammatory agents retain the 20-carbon skeleton of their parent compound (arachidonic acid). For that reason the entire family of compounds are known as eicosanoids (eicosa is Greek for the number 20).
The pathways that arachidonic acid molecule follow are complex. It involves the enzyme cyclooxygenase, an enzyme that exists in two forms and which catalyzes the reaction of arachidonic acid into prostaglandin. The function of these enzymes is to regulate the inflammatory response
Besides the cyclooxygenase enzyme system, another enzyme, (5-lipoxygenase) can convert arachidonic acid when the body is in need of leukotrienes.
Leukotrienes are found in the synovial fluid of joints.
Prostaglandins are eicosanoid mediators, derived from arachidonic acid. Prostaglandins are produced in nearly all body tissues when their cells are damaged.
Prostanoids function as hormones but unlike hormones, only act at the site where they are produced.
Prostaglandins act as short-lived and short-range hormones.
The first of the prostaglandin compounds or prostanoids to be identified and studied was prostaglandin, so named because it was first isolated from the prostate glands of sheep.
Prostaglandin was found to have a broad range of activities with roles in inflammation, cell division, migration and muscle tone.
Prostaglandin was only the first of many such substances to be isolated and described.
Another compound was found to be particularly potent in causing the contraction of the smooth muscle tissue that sheaths blood vessels and the bronchial passages to the lungs.
This compound turned out not to be a single factor but rather a mixture of closely related molecules and were called leukotrienes.
They were so named because of their ability to stimulate leukocytes (while blood cells).
Prostaglandins and leukotrienes are neither steroids (steroids requires a tetracyclic nucleus) nor proteins, which are made up of amino acid chains.
Prostaglandins are instead lipids, long chain fatty acids tails and a small hydrophobic head.
Prostaglandins and leukotrienes incite inflammation following exercise.
Reducing their production is one of the goals of this program, which can be achieved by reducing the amount of linoleic acid in the diet..
Leukotrienes are eicosanoid compounds, derived from the body’s store of arachidonic acid.
Leukotrienes are responsible for the effects of asthma and allergies.
Leukotrienes cause the contraction of the smooth muscle tissue that sheath and line the walls of blood vessels. They are also found in bronchial passages of the lungs.
Leukotrienes are produced by leukocytes (while blood cells). These 20 carbon long compounds bind to receptors on smooth muscles. Leukotrienes are powerful contractors of smooth muscle.
Contraction of smooth muscle in blood vessels produces vasoconstriction. Contraction of smooth muscle in the lungs produce bronchoconstriction. Leukotrienes thus play an important role in anaphylactic (allergic) reactions.
Leukotrienes are neither steroids nor proteins but instead are lipids. Lipids are made up of a long chain fatty acid tail and a small hydrophobic head.
Leukotriene formation begins with a peroxidation reaction catalyzed by 5-lipoxygenase with subsequent steps involving glutathione, a powerful antioxidant enzyme.
Lipoxygenase enzymes are found in both plant and animal cells. In plants, such as soybeans, the lipoxygenase enzyme is used for the synthesis of antimicrobial compounds. This may explain why soy products are so healthy.
Human lipoxygenase on the other hand, is an iron-based enzyme that catalyzes the oxidation of arachidonic acid and causes the anaphylactic effects described above.
Lipoxygenase is capable of binding arachidonic acid with molecular oxygen causing the formation of hydroperoxide radicals and eicosanoic acids.
Further dehydration of these radicals results in the production of four types of leukotrienes. The reactions occur in white blood cells, macrophages and platelets.
The inflammatory process begins when a cell becomes damaged and releases prostaglandins, specifically the E2 version or PGE2.
PGE2 prostaglandins belong to the eicosanoid family of compounds. PGE2 initiate a cascade of chemical reactions culminating in the migration of white blood cells (leukocytes) to the site of the injury. PGE2 formation depends on the activity of the arachidonate cyclooxygenase enzyme system.
The inhibition or blockage of this enzyme system decreases prostaglandin production causing less white cell migration.
Arachidonate cyclooxygenase is the enzyme system that catalyzes the synthesis of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase enzymes are divided into COX-1 and COX-2 forms.
Histamine, prostaglandins, thromboxane and leukotrienes are four classes of inflammatory compounds. They each provoke a strong and different biological response from the body.
1. Histamines are derived from the amino acid histidine and are released from white blood cells. Histamines produce vasodilation and increase the permeability of capillaries, thereby promoting the movement of substances out of blood vessels and into the site of the injury. Antihistamine oppose these actions
2. Prostaglandins or Prostanoids are hormone-like substances that are actively synthesized at the site of injury. The effect of these mediators of inflammation is to intensify pain.
3. Thromboxanes are factors that initiate blood clotting in order to seal wounds.
4. Leukotrienes are very powerful agents that constrict blood vessels.
Actions of NSAIDs
The drugs in this class have three major effects.
1. Anti-inflammatory: modification of inflammatory reactions.
2. Analgesic: repression of pain.
3. Antipyretic: lowers a raised temperature.
The primary action of NSAIDs and the effects they produce are all related to the inhibition of the enzyme arachidonate cyclooxygenase (COX), in both its two forms COX-1 and COX-2.
Inhibition of cyclooxygenase enzymes lowers the production of pro-inflammatory compounds (prostaglandins, leukotrienes and thromboxanes). Prostanoid repression reduces swelling.
Analgesic drugs should never be used as a chronic or habitual remedy. Their ability to repress pain is counterproductive to health since they also hinder the body’s ability to heal itself.
NSAIDs produce analgesia, antipyretic and anti-inflammatory activity and include aspirin, ibuprofen (Advil and Motrin), indomethacin (Indocin) and naproxen (Aleve).
Non- steroidal anti-inflammatory drugs are the most often used drugs to reduce the symptoms of arthritis.
NSAIDs act without alleviating the underlying disease process (some in fact may exacerbate the problem).
Gastrointestinal disturbances, skin reactions and kidney effects have been found among chronic users of all types of NSAIDs.
The newest class of NSAIDs on the market are the selective inhibitors of the cyclooxygenase 2 enzyme. For want of a better term, I refer to this group of anti-inflammatory agents as coxibs.
Repression of Inflammation
Humans are exposed to many stresses during their daily lives. The stress induced by exercise, although a healthy stress, is not without its share of harmful effects.
Exercise produces an enormous increase in the production of free radicals. Free radicals initiate inflammation by attacking and altering healthy structures. The attacks render these
locations future foci for an inflammatory response.
Inflammation is the body’s response to irritation, injury or infection. Inflammation is characterized by the three cardinal signs of heat, redness, and swelling, usually accompanied by pain at the injury site. Swelling is due to increased leakage of fluid from the blood vessels involved, while heat and redness are caused by the capillary dilation required to convey more blood to the site.
In order to repress inflammation, a compound must interfere with the normal cascade of enzyme reactions that produce the mediators of inflammation, the prostanoids.
The central purpose of all NSAIDs is to repress inflammation in joints, tendons and ligaments. Reducing the redness, swelling and heat that characterize inflammation, improves an athlete’s mobility and lessens their pain. This is the typical manner that doctors advise athletes to manage inflammation.
The Athlete’s Diet is a non-pharmaceutical approach to managing inflammation and pain. Anti-inflammatory drugs should be only be used sparingly and certainly not at the first sign of pain. Analgesic drugs should never be used as a chronic or habitual remedy. Their ability to repress pain is counterproductive to health since they also hinder the body’s ability to heal itself. It relies on the antioxidant and anti-inflammatory pigments of plants to minimize pain and chronic inflammation.
Prostaglandins, leukotrienes and thromboxanes are referred
to as eicosanoids, due their derivation from arachidonic acid,
the 20-carbon chain fatty acid precursor. ‘Eico’ is derived from Greek for the number twenty.
The amount of arachidonic acid that is converted into a prostanoid determines how strong the inflammatory response will be. The more available arachidonic acid, the more that becomes converted. Maintaining arachidonic acid in its embedded form, as part of the phospholipids in the membrane, minimizes this conversion and represses inflammation.
The mediators of inflammation are better repressed when the ratio of omega-3 fatty acids to omega-6 oils remain in balance. Imbalance causes illness.
The Athlete’s Diet recommends olive oil and omega-3 supplements. This will alter a poor lipid profile and improve the omega fatty acid ratio.
Chemistry of Prostaglandins
Prostaglandins represent a class of substances that function like hormones but are not. They function locally and depend on the conversion of arachidonic acid to one of a series of compounds.
They are collectively known as prostanoids. The first of the prostaglandin compounds (also called prostanoids) to be identified and studied was prostaglandin, so named because it was first isolated from the prostate glands of sheep. Prostaglandin was only the first of many such substances to be isolated and described.
Prostaglandin was found to have a broad range of activities, with roles in inflammation, cell division, cell migration and muscle tone.
Prostanoids cause inflammatory cell migration to injured joints and other injured sites.
The enzyme cyclooxygenase converts arachidonic acid to the precursor prostaglandin. Prostaglandins are therefore chemically synthesized from arachidonic acid when a high ratio of omega-6 to omega-3 exists.
Arachidonic acid is derived from omega 6 fatty acids (linoleic). Omega 6 fatty acids are consumed in a diet rich in polyunsaturated oils.
The purpose of an anti-inflammatory diet is to reduce the conversion of arachidonic acid into an inflammatory mediator. This is done by limiting the amount of free arachidonic acid and increasing the amount bound to the cell’s membrane.
This is accomplished by increasing omega-3 fatty acids in the diet and limiting its linoleic acid content.
Linoleic acid is an 18-carbon fatty acid found in vegetable oils.
Linoleic acid serves as the precursor to arachidonic acid.
Arachidonic acid is a twenty-carbon fatty acid that is stored in cellular membranes as part of is phospholipid structure. They are often floating or embedded in the membrane and are easily and quickly dislodged.
The destiny of arachidonic acid is critical to recovery from exercise. It is very important to athletes that they regulate the fat content of their diet in order to influence the molecular destiny of arachidonic acid.
When high amounts of linoleic acid (the 18-carbon precursor) is present, arachidonic acid is dislodged from its embedded site.
Arachidonic acid is released through the action of phospholipase A2.
The subscript 2 denotes the number of double bonds in the fat chain and also indicates that it leads to the formation of the 2 series of prostaglandins.
The 2 series of prostaglandins are the pro-inflammatory prostanoids.