Platelet-activating factor
Encyclopedia
Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine) is a potent phospholipid
activator and mediator of many leukocyte functions, including platelet
aggregation and degranulation, inflammation
, and anaphylaxis
. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.
It is produced in response to specific stimuli by a variety of cell types, including neutrophils, basophils, injured tissue, monocytes/macrophages, platelet
s, and endothelial cells.
.
It causes platelets to aggregate and blood vessels to dilate. Thus, it is important to the process of hemostasis
. At a concentration of 10-12 mol/L, PAF causes life threatening inflammation of the airways to induce asthma
like symptoms.
Toxin
s such as fragments of destroyed bacteria induce the synthesis of PAF, which causes a drop in blood pressure
and reduced volume of blood pumped by the heart, which leads to shock and possibly death.
in the early 1970s. Its structure was elucidated by Constantinos A. Demopoulos in 1979.
(LPC) and acetyl CoA by the enzyme LPC acetyltransferase (LPCAT). It is also derived from 2-acetyl monoalkylglycerol ether by phosphocholine transferase.
It is degraded (thereby terminating its capacity to act as a signaling molecule) by a group of enzymes called PAF acetylhydrolase
s (PAFAHs), which are related to phospholipase A2
.
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
activator and mediator of many leukocyte functions, including platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
aggregation and degranulation, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, and anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.
It is produced in response to specific stimuli by a variety of cell types, including neutrophils, basophils, injured tissue, monocytes/macrophages, platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s, and endothelial cells.
Chemistry
Several molecular species of platelet-activating factor that vary in the length of the O-alkyl side-chain have been identified.- Its alkyl group is connected by an etherEtherEthers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
linkage at the C1 carbon to a 16-carbon chain. - The acyl group at the C2 carbon is an acetateAcetateAn acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
unit (as opposed to a fatty acidFatty acidIn chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
) whose short length increases the solubility of PAF, allowing it to function as a soluble signal messenger. - The C3 has a phosphocholinePhosphocholinePhosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
head group, just like standard phosphatidylcholinePhosphatidylcholinePhosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
.
Function
It is an important mediator of bronchoconstrictionBronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....
.
It causes platelets to aggregate and blood vessels to dilate. Thus, it is important to the process of hemostasis
Hemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...
. At a concentration of 10-12 mol/L, PAF causes life threatening inflammation of the airways to induce asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
like symptoms.
Toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
s such as fragments of destroyed bacteria induce the synthesis of PAF, which causes a drop in blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and reduced volume of blood pumped by the heart, which leads to shock and possibly death.
History
It was discovered by French immunologist Jacques BenvenisteJacques Benveniste
Jacques Benveniste was a French immunologist. In 1979 he published a well-known paper on the structure of platelet-activating factor and its relationship with histamine...
in the early 1970s. Its structure was elucidated by Constantinos A. Demopoulos in 1979.
Biosynthesis and degradation
PAF is biosynthesized from lysophosphatidylcholineLysophosphatidylcholine
Lysophosphatidylcholines , also called lysolecithins, are a class of chemical compounds which are derived from phosphatidylcholines. They result from partial hydrolysis of phosphatidylcholines, which removes one of the fatty acid groups. The hydrolysis is generally the result of the enzymatic...
(LPC) and acetyl CoA by the enzyme LPC acetyltransferase (LPCAT). It is also derived from 2-acetyl monoalkylglycerol ether by phosphocholine transferase.
It is degraded (thereby terminating its capacity to act as a signaling molecule) by a group of enzymes called PAF acetylhydrolase
PAF acetylhydrolase
PAF acetylhydrolase is an enzyme that catabolizes platelet-activating factor....
s (PAFAHs), which are related to phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
.
Antagonists
- SM-12502 is a PAF antagonistReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, which is metabolized in the liver by the enzyme CYP2A6CYP2A6Cytochrome P450 2A6 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine and cotinine. It is also involved in the metabolism of several...
. - RupatadineRupatadineRupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia, S. A...
is an antihistamineAntihistamineAn H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
and PAF antagonist used to treat allergies.