What Are Mediators?
You’d Think a “Mediator” Would Be The Good Guy …
If you check the common, day-to-day definition of “Mediation”, you'll find something along the lines of “a way of resolving disputes between two or more parties”. However, in medical terms, “Mediators” is a fancy name for the chemicals that are released by mast cells upon degranulation.
You will often hear that mast cells release histamine and that is what causes the mastocytosis symptoms.
Well, this is partially true.
Potent as histamine is, it would need to be many, many times more potent to account for the variety and intensity of all the symptoms you experience.
Mediators, Mediators Everywhere …
Truth be told, there are actually many more chemical mediators, other than histamine, which are released during degranulation.
How many, do you ask? Well, make sure you're seated before you proceed. Here's what my hero, Dr. Afrin, has to say about numbers:
Here's the link he refers you to, if you're curious:
This makes the rest of this post a bit futile, but let's discuss what is known and what we, as common mortals, maybe able to deal with.
The most studied mediators, and therefore the more discussed in the medical literature are the following:
Preformed mediators (Which are already stored in the mast-cell granules):
- heparin (active as anticoagulant)
Newly formed lipid mediators (which are created at the time of degranulation):
- prostaglandin D2
- leukotriene C4
- platelet-activating factor (PAF)
- Eosinophil chemotactic factor
A bio-active amine causing vasodilation, erythema, edema, pruritus, urticaria, bronchoconstriction, increased gastric acid, intestinal cramping, further degranulation of mast cells, leukocyte activation.
It is a potent mediator of inflammation causing attraction of other immune cells including white blood cells which eat dead bacteria cells, causes nerves to fire, makes blood vessels porous allowing white blood cells to the tissues to find and remove bacteria and diseased cells. It also influences body temperature.
Initiates the production of a hormone called bradykinin, that contributes to swelling, anaphylaxis and inflammatory symptoms. This production of bradykinin causes swelling, low blood pressure (from fluid loss) and white blood cells sticking together (which stimulates the immune system). Prolonged high release of heparin leads to bone density loss, leading to osteoporosis /osteopenia in otherwise low risk patients.
Heparin inhibits localized clotting, thus causing bleeding.
Degrades HDL (good) cholesterol, which compromises its protective role. Leads to clinically high LDL (bad) cholesterol in patients who have good diets. Tryptase is a measure of mast cell numbers not disease severity
Dr. Theoharides calls it meat tenderizer. Enough said …
Serotonin is stored in and released from human mast cells. It is also released from activated platelets.
Serotonin has several roles and effects in the body
- Regulates bowel movements by increasing smooth muscle tone .
- Controls appetite (higher concentration of serotonin makes you hungrier )
- Regulates insulin and growth factor release – so suppresses insulin release from the pancreas
- Regulates the breathing rate (higher concentration of serotonin increases your breathing rate )
- Regulates the heart rate (higher concentration of serotonin increases your heart rate )
- Constricts blood vessels(called vasoconstriction), which means the heart has to pump harder (increased cardiac output ). This increases blood pressure
- Upregulates any mood – anxiety, depression, happiness, anger – making these moods more intense .
- Controls sleep, pain and memory
- Has a role in building and degenerating bone
- In platelets, serotonin has a role in maintaining our bodily system's balance or in returning these systems to functioning within a normal range (homeostatis) and blood clotting
Mast cells release serotonin as a function of their normal activity. Mast cells in mastocytosis patients release serotonin twice a day. The normal rate is once a day.
Causes death of endothelial cells and causes release of IL8, which also activates other mast-cells, causing a chain reaction of degranulation. This highlights one mechanism by which one mast cell being activated leads to further degranulation, releasing chemical contents from other mast cells.
This is noted by patients as a snowball effect: having one reaction makes another more likely. They notice they are becoming more sensitive to triggers. This is known medically as “second phase reactions”, caused by anaphylaxotin produced as part of the activation of the complement system.
Chymase is also known to convert angiotensin I to angiotensin II and thus plays a role in hypertension and atherosclerosis. Inhibition of coagulation locally, bronchoconstriction, osteoporosis
This also coverts angiotensin I to angiotensin II.
Cause bronchoconstriction, increased vascular permeability and contractability
Cause pruritus, pain, rhinorrhea, hypotension, flushing, osteoporosis
Cause wheal and flare, pain, pruritus
Tumor necrosis factor
Causes recruitment of inflammatory cells
Multiple, Combined and Mast Cell-Specific Effect
Each mediator doesn't cause just one problem. Each mediator has an entire array, a unique array, of effects – direct effects, indirect effects, local effects, and remote effects – so when you do all the multiplying implicit in all of this biology math, you begin to understand why this disease could present with such extreme variety of symptoms.
The amount and type of mediators released by a mast cell appears to depend on the specific stimulus applied. In addition, different types of mast cells exist, and distinct systemic effects may be caused by different mast cell types.