- Nitric oxide
- Interstitial space
- Oxygen species
- Signaling molecules
- For a view of the known receptors/functions where Prostaglandins are involved, click here
In its Acute form, it is the adaptive immune response originated in the vascular tissue to injury or infection, and whose main objectives are to assist the body’s repair mechanisms, preventing the spreading of infectious agents and removing damaged tissue.
Injury may be caused by:
- Mechanical trauma
- Exposure to significant differential temperatures (hot or cold surfaces)
- Irritant chemical agents
Infection may come from:
Acute inflammation manifests with:
- Redness and heat, as a result of increased blood flow to the area
- Swelling, product of the accumulation of fluid at the injury site
- Pain, as swelling compresses nearby nerve endings
- Impairment or loss of function to the affected area
In very broad terms, it is :
- Characterized by local hemodynamic and microvascular changes with leukocyte accumulation, the acute inflammatory response is consistently marked by microvascular leakage and the accumulation of neutrophils .
Vasodilation, (mediated by histamine, prostacyclin (PGI2), and nitric oxide (NO), and increased Vascular Perfusion, (mediated by histamine and leukotrienes C4, D4, and E4) are combined to set favorable conditions for the inflammatory infiltrate to enter the injured area. The combination and synchronicity in which they occur cause local capillaries to dilate and become more permeable, increasing significantly blood flow to the area and allowing proteins and plasma fluid to enter the interstitial space.
• Neutrophiclic Leukocytes (Neutrophils) are the first kind of white blood cells to enter the inflamed tissue; their function is to destroy bacteria by releasing lisosomal enzymes. This process is mediated by
- Selectins which are molecules on leukocytes surface that provide loose binding enabling “rolling” on injured tissue
- ICAM-1 , provides firm adhesion to the endothelium
- CD31 mediates the extravasation from capillaries and into damaged tissue
- C3b and IgG ; both coat foreign cells to facilitate the binding of leukocyte receptors to effectively facilitate phagocytosis.
- Myeloperoxidase and lysozyme generate toxic Reactive Oxygen Species ROS that effectively eliminate bacteria once phagocytosis has occurred.
• Lymphocytes enter later than Neutrophils and accumulate also in the injured area. They are responsible for the manufacturing and release of a host of different antibody molecules ( contributing to chemical recognition of foreign cells), cytokines and growth factors that regulate and orchestrate other immune cells action.
Simultaneously upon the inflammatory response, there is a series of reparative processes, namely:
- Parenchymal regeneration: functional cells start dividing (reproducing) to replace dead ones. Depending on conditions, a process called fibrosis ,instead of regeneration, takes place where fibroblasts and endothelial cells migrate to the site of the injury and produce granulation tissue.
Other healing-associated growth factors produced by platelets include basic fibroblast growth factor, insulin-like growth factor 1, platelet-derived epidermal growth factor, and vascular endothelial growth
- Angiogenesis: the physiological process through which new blood vessels form from pre-existing ones.
- Production of extracellular matrix material, thus providing structural support and integrating (by physical/communicational means) connective tisssue.
Platelets release a multitude of growth factors including platelet-derived growth factor (PDGF ) and TGF beta , which stimulates the deposition of extracellular matrix .
- Scar formation, formed of the same collagen as the affected tissue, see fibrosis .
Arachidonic acid biochemical cascade in inflammation
Now, let us take a look at the chemokine side of inflammation :
Arachidonic acid , a chemokine mediating the inflammatory response, is a polyunsaturated fatty acid and it is a constituent of the cell plasma membrane. Along with Diacylglycerol or phospholipids present out of the plasma membrane, trigger the following biochemical cascade:
Brief Biochemistry Introduction:
Essential Fatty Acids : There are two essential fatty acids, made both of an 18 Carbon structure, which the body can not biosynthesize itself and must be supplied by nutrition:
1) Alpha-linolenic Acid, which displays its 1st double bond on Carbon 3 counting from right to left, hence called an Omega-3 FA. Sources: Flaxseed oil, beans, vegetables, and whole grains.
2) Linoleic acid, whose 1st double bond is found in carbon 6, hence, an Omega-6 FA. Sources: leafy vegetables, seeds, nuts, grains, and vegetable oils of corn, safflower, soybean, cottonseed, sesame, sunflower.
The enzymes available in our bodies have the limitation that are only capable of adding new double bonds within 10 carbons of the carboxylic acid end of a fatty acid, this being the reason that linoleic and alpha linolenic acid are indispensable and must be imported from nutrition. Any long chain omega-3 fatty acid has to originate from an omega-3 fatty acid from our diet and any omega-6 fatty acid has to be synthesized from an exogenous omega-6.
Through the action of fatty acid desaturases 1 and 2 ( FADS2, and FADS1) and the elongase HELO1 enzymes, Linoleic acid is converted into a 20 Carbon molecule called Arachidonic Acid.
Now, when all the indispensable concepts have been introduced, it is time to take a look at a very important biochemical cascade (not the only one, though) that takes place once a cellular membrane has been injured:
- Made by the oxidation of arachidonic acid, they are critically important signaling molecules with remarkable bioactive abilities. Produced in very small amounts by almost all cells, display short half lives in the seconds and minutes range, and their action is confined to the local area where synthesized. In fact, they act as autocrine and paracrine lipid mediators to maintain local homeostasis in the body.
- Most important of these compounds are:
- Eicosanoids are not found preformed in tissues. They are generated de novo from phospholipids. They are implicated in the control of many physiological processes, as mediators and modulators of inflammatory reactions.
- PGs and thromboxane A2 (TXA2), collectively termed Prostanoids, are formed when arachidonic acid (AA), a 20-carbon unsaturated fatty acid, is released from the plasma membrane by phospholipases and metabolized by the sequential actions of PGG/H synthase or by cyclooxygenase (COX) and their respective synthases.
- There are 4 principal bioactive PGs generated in vivo: prostaglandin E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2), and prostaglandin F2α (PGF2α). PG production is kept at very low levels in tissues under normal conditions and increases significantly under inflammatory conditions, before the recruitment of leukocytes and the infiltration of immune cells.
- PGE2 and prostacyclin are the most important. These products are both potent vasodilator and hyperalgesic agents and since they have been detected at sites of inflammation it is believed that they contribute to the erythema, oedema and pain which are characteristic of the inflammatory response. Prostaglandin E2 is also a powerful pyrogenic substance. The selective inhibition of cyclo-oxygenase by non-steroid aspirin-like drugs confirms the inflammatory phenotype generated by the action of both.
- For a view of the known receptors/functions where Prostaglandins are involved, click here .