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Posted by on May 10, 2013 in The Basics |

What Are Mediators?

What Are Mediators?

Do you have any questions about mediators? Then please head for the “Why Is It All So Confusing?” forum and we'll try and help.

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:

I refer interested colleagues and interested patients to a website called “COPE With Cytokines”, built and maintained by German biologist Horst Ibelgaufts. Even the COPE list is not a complete list of all known mast cell mediators and receptors, but I refer people interested in this topic to the COPE list because it nevertheless is the “most complete” list I have yet found in one place. Again, I know it’s not a complete list, but if you want to go to just one place to get the best visceral impact as to the full scope of what these cells are capable of doing, this is the site to go to, and when you navigate through this site to get to the entry for “mast cells,” you’ll see a very, very long list of mediators and receptors these cells can express.

Here's the link he refers you to, if you're curious:

Horst Ibelgauft’s COPE

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):

  • histamine
  • heparin (active as anticoagulant)
  • tryptase
  • serotonin

Newly formed lipid mediators (which are created at the time of degranulation):

  • thromboxane
  • prostaglandin D2
  • leukotriene C4
  • platelet-activating factor (PAF)
  • cytokines
  • Eosinophil chemotactic factor

Histamine

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.

Heparin

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.

Tryptase

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

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.

Chymase

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

Renin

This also coverts angiotensin I to angiotensin II.

Leukotrienes

Cause bronchoconstriction, increased vascular permeability and contractability

Prostaglandin D2

Cause pruritus, pain, rhinorrhea, hypotension, flushing, osteoporosis

Platelet-activating factor

Cause wheal and flare, pain, pruritus

Tumor necrosis factor

Causes recruitment of inflammatory cells

Interleukins

Attract neutrophils

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.