Friday 22 March 2013

Acute Inflammation: Soluble Mediators

Soluble mediators, also known as chemical mediators, are the switches that cause the inflammatory response to be turned on and off. These substances are messengers that act on blood vessels and cells and control their actions. Their four main functions are to cause arteriolar dilation, increase vascular permeability, act as chemoattractants for leukocytes and to stimulate pain. There are three varieties of soluble mediators: circulating chemical mediators, those released from cells, and receptors on the surface of cells. In this post, we'll take a look at each type of chemical mediator as well as how they work together in the inflammatory response.

Circulating Soluble Mediators

These mediators are present in the plasma as precursors and have to be activated before they will work. There are three groups of these proteins that are inter-related: the complement, kinin and clotting systems. Together these are known as the plasma proteases. Each system has a series of proteins which become activated in sequence to generate a large number of chemical mediators which act to greatly increase the acute inflammatory response.

Complement Cascade

This is a sequence of molecular events that occur in the vascular system. It causes inactive plasma proteins which are produced by the liver to be activated after a tissue has been injured. The cascade triggers the formation of many molecules which have proinflammatory, chemotactic, opsonising (allowing foreign substances to be phagocytosed), permeability and microbicidal effects.

The cascade eventually causes the formation of a membrane attack complex (MAC). The MAC forms a tube like structure which perforates the cell membranes of foreign cells and some host cells. This allows water, small molecules and ions to pass into the cell via osmosis and cause lysis. 

The video below shows an interesting illustration of this process.

 

The Kinin Pathway

Like the clotting cascade, the kinin pathway is activated by factor XII (also known as Hageman Factor) which is triggered by contact with basement membranes or endotoxins. The kinin pathway consists of proteins which are split from their precursors by enzymes known as kallikreins which may be derived from tissue or plasma. There are several kinins but bradykinin is the major product of the system. Bradykinin causes vasodilation, pain, increased vascular permeability and smooth muscle contraction. Bradykinin  can be broken down by kinase to control its effects. 

A substance called prekallikrein enhances the activation of Hageman factor and amplifies the system.


The Coagulation Pathway

 This was discussed in detail in this post. The end-product of this pathway is fibrin which essential in the inflammatory response as it acts as a mechanism for inflammatory cells to use to assist migration. It serves to localise the agents which cause inflammation and also assists in healing by increasing the proliferation of fibroblasts and collagen production. 

Fibrin degradation products (FDPs) also have several actions:
  • they are chemoattractants for neutrophils,
  • they increase vascular permeability, 
  • smooth muscle contraction
  • inhibit the action of thrombin on fibrinogen
  • Inhibits platelet activation and adhesion.

 Cell-Derived Chemical Mediators

These mediators may exist pre-formed in granules or the cells may be stimulated to synthesise the chemical mediators.

 
Preformed Chemical Mediators

There are two groups of preformed chemical mediators: vasoactive amines and neuropeptides.

Vasoactive Amines:

These are histamine and serotonin which are released by mast cells, basophils and platelets. They cause arteriolar dilation, extravascular smooth muscle contraction, venule permeability by rounding up endothelial cells, and pain. Several factors cause the release of these substances including physical injury, immune reactions, fragments of the complement cascade, neuropeptides, cytokines, and histamine-releasing proteins from leukocytes. Histamine is also a chemoattractant for eosinophils.  

They are rapidly degraded and histamine receptors become refractory after 30 minutes.

Neuropeptides:

Neuropeptides have a similar role to vasoactive amines and are small peptides found in the central and peripheral nervous systems. An example is Substance P which function to transmit pain signals, regulate blood pressure, stimulate secretion by immune cells and increase vascular permeability. 

Induced Chemical Mediators

These require cells to be induced to make them. There are 5 groups of these mediators: Cytokines, Eiconasoids and platelet activating factors, Nitric Oxide, Oxygen Derived Free Radicals, and Heat Shock Proteins.

Cytokines

This group includes tumour necrosis factor (TNF), interleukins, interferons and chemokines. These substances are able to activate leukocytes which produce more cytokines and amplify the response. They may act locally or at long distances. The major cytokines that mediate inflammation include interleukins, and Tumour Necrosis Factor. They are stimulated by bacterial endotoxins and immune complexes, physical injury and other inflammatory stimuli. Their most important actions are:
  • endothelial activation
  • leukocyte activation
  • fibroblast recruitment
  • priming of neutrophils.  
Other cytokines that are involved in acute inflammation include interferons and chemokines.

The interleukins and TNF work together in the acute phase response. When gram negative bacteria activate macrophages interleukins and TNF are released. This has several effects which may:
  • act on the liver and cause it to produce acute phase proteins (which can be detected clinically)
  • act on the precursor cells in the bone marrow to increase the production of neutrophils and may cause increased phagocytosis by neutrohils. 
  • act on the brain to induce fever, decrease appetite and increase the desire to sleep.
  • At very high levels, these substances have systemic effects leading to shock.

Eiconasoids: 

These are derived from polyunsaturated fatty acids within cell membranes. During the metabolism of eiconasoids, cyclooxygenase and lipoxygenase convert arachidonic acid into four types of eiconasoids: prostaglandins, thromboxanes, leukotrienes, and hydroxyacids.

These substances have a variety of effects on the body including vasodilation, chemotaxis of neutrophils and increased vascular permeability. 

Corticosteroids prevent the first step (phospholipase) of this metabolism and prevent the formation of leukotrienes and prostaglandins. Non-steroidal anti-inflammatories (NSAIDs) inhibit cyclooxygenase and prevent the formation of prostaglandins. 

Nitric Oxide

This is produced by endothelial cells, macrophages and neurons and causes vascular smooth muscle relaxation and vasodilation. It also reduces platelet aggregation and adhesion, inhibits mast-cell induced inflammation, regulates the recruitment of leukocytes and facilitates microbial killing.

Oxygen Derived Free Radicals

These are released from leukocytes during the inflammatory process. Low level release can increase the expression of cytokines and leukocyte adhesion molecules and amplify the inflammatory response. High levels can cause damage to the body.


Heat Shock Proteins

These cells may be induced by infection with intracellular pathogens. They may be referred to as "molecular chaperones" as they modify the destiny and function of other proteins. They prevent the premature and senseless interaction between molecules and assist in the folding and unfolding of proteins. 

Receptors on the Surfaces of Cells

 The receptors on the surfaces of cells involved in acute inflammation belong to a family called the 'pattern recognition receptors' (PRR). These receptors detect the molecular patterns that are characteristic of certain types of microbial infections by recognising the patterns of molecules that are contained in the DNA of pathogens. Activation of PRRs results in an increase in the production of inflammatory mediators, increased phagocytosis, in addition to an increased Th1 lymphocyte response and an increase in the number of chemokine receptors and chemoattractants. 

 There are many pattern recognition receptors, however a classic example is the TLR4 (Toll-like Receptor 4). This receptor only binds to the lipopolysaccharide of bacteria and results in the production of cytokines and reactive oxygen intermediates which activate leukocytes which then kill the microbes. 
   

So in summary, there are three categories of soluble mediators: plasma-derived mediators, cell-derived mediators, and receptors on the surfaces of cells. These categories are inter-related and work together to cause acute inflammation. 

That's all for now, please let me know if you have any questions :)

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