Vascular Events

Inflammation is the body's alarm for damage or infections. It can start from tissue damage like a cut or broken bone. It can also start with an infection that gets into the tissue. There are four cardinal symptoms of inflammation with Pain, Redness, Heat and Swelling. The Endothelial cells that make up the blood vessels regulate what can move out of the blood and into the tissue. The endothelial cells are very active cells with many functions from regulating the blood as a liquid in healthy conditions to initiating clotting in injury. They also play a key role in inflammation and trafficking immune system cells out into the tissues. If we look at the four key signs of inflammation, we can link them to key actions of the blood vessels.

When injury or infection occurs, the blood vessels in that area will dilate allowing more blood and immune cells to flow into that area. The blood is red, and it has a much higher temperature than the skin. The increased blood flow will lead to redness and heat. The increased cellular activity in the area of damage will contribute to the increased heat. Blood vessels will also increase their permeability. The endothelial cells will shrink to increase the gap between them. This allows for the flow of blood, fluids, immune cells, antibodies and complement proteins to flow out of the blood vessel into the tissue. This flow out of the blood into the tissue leads to swelling also called edema. The swelling will increase pressure on the pain receptors in the area leading to pain. The overall influx of fluids and immune cells cause swelling which can immobilize joints leading to loss of function. Every sign we associate with inflammation comes from the increased blood flow to the injury by the opening up of endothelial linings.

What causes these vascular events to occur? The initial reaction is caused by neurogenic and myogenic responses to injury. The nerves and muscles respond first. Then the many inflammatory cytokines and mediators that are released by the sentry cells in the local area will contribute to inflammation. They can even start inflammation if an infection with no injury. Local Sentry and Mast Cell release things like Histamine, Prostaglandins, Leukotrienes, Tumor Necrosis Factor alpha (TNFa), Interleukin 1 (IL-1), C3a and C5a. Inflammation is broken down into 2 categories based on where it starts. I have gone through so many immunology courses and they always focus on inflammation of cytokines released from immune cells, but never focus on inflammation of tissue damage.

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Arachidonic Acid Pathway

The response of inflammation from cellular damage pathways can happen from physical trauma like a cut, break or burn. It can also happen from pathogens that release toxins. Bacteria will release toxins that cause cell damage. Even immune cells like the neutrophils, when they fight the bacteria, will release their enzymes that can damage cells. This is why chronic inflammation leads to tissue damage and fibrosis (scar tissue). Chronic Inflammation can also lead to tumor genesis.

All cells have a membrane made up of phospholipids. When they get damaged, these phospholipids can be knocked loose into the tissue. These phospholipids break down into Arachidonic Acid. These free phospholipids will be changed by an enzyme called Phospholipase A2 (PLA2). The PLA2 will break down the phospholipid into Arachidonic Acid (AA). The AA will be further broken down by two other enzymes that create two further pathways. Steroids like Prednisone will block Phospholipase A2 and thus block all the pathways of Arachidonic Acid. This is what makes it a powerful anti-inflammatory drug.

The first the Arachidonic Acid can take is the Cyclooxygenase (COX) enzyme pathway which breaks down the AA into Prostaglandins. The COX enzyme is the key target for Aspirin and all over the counter Non Steroidal Anti Inflammatory Drugs (NSAIDS) like Ibuprofen. This blocks all the downstream effects of the prostaglandins. These prostaglandins will be used by the blood vessels to regulate vascular flow. In healthy tissues, the blood vessels will convert the Prostaglandins to Prostacyclin (PGI2) to keep vessels dilated and flowing. In injury, the blood vessels will convert the Prostaglandins to Thromboxane A2 (TXA2) to do vasoconstriction to slow blood flow. The reset of the prostaglandins will go on to produce fever and pain. PGE2 is the key prostaglandin of pain and fever. This is how taking over the counter pain relievers help reduce pain by blocking this entire COX pathway. Prostaglandins might play a role in pain and inflammation, but they also play a role in protection of the stomach lining from stomach acid. This is why taking NSAIDS will cause problems with the stomach. It blocks the prostaglandins that protect the stomach from the acid.

There are also 2 forms of the COX enzyme with COX1 and COX2. They both have different effects and some drugs focus on affecting one more than the other. Most over the counter pain relievers block both. COX1 specific inhibitors will affect platelets and blood clotting. This has led to the use of Aspirin for prevention of blood clots. It also raises the risk of bleeding events. That has led to development of COX2 specific inhibitors. COX2 is linked to PGE2 and its role in pain and fever. This has led to COX2 specific inhibitors that only target this part of the pathway. This allows the COX1 intact for normal blood clotting. It still blocks the protective prostaglandins that protect the stomach. Most over-the-counter pain medications block both of these pathways.

The second pathway the Arachidonic Acid can take is the Lipoxygenase (LOX) enzyme pathway which breaks down AA into Leukotrienes. The key leukotriene in inflammation is leukotriene B4 (LB4). This acts as a strong attractant for neutrophils and leads to swelling. The LB4 is produced by the AA pathway, but it is also produced by Mast Cells after they degranulate. Many of these inflammatory cytokines will be released by Mast Cells from pathogens. The rest of the Leukotrienes with LC4, LD4 and LE4 all play a role in bronchoconstriction. They are targets of medications in Asthma and other breathing disorders.

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Cellular Events

The other side of inflammation comes from the cells of the immune system responding to an infection and releasing proinflammatory cytokines. This begins with the sentry cells like mast cells and macrophages. They are the first responders to an infection. They release inflammatory substances that will go to the endothelial cells and begin vasodilation and increase permeability. The mast cells will release Histamine while the macrophage will release TNFa and IL-1 or Interferons. The other inflammatory mediators that can act upon the endothelial cells are the C3a and C5a of the complement system. The complement system is a group of proteins that can be activated by pathogens or antibodies to create inflammation.

When the endothelial cells receive these cytokines and inflammatory mediators, the vessels will dilate and increase their permeability. The endothelial cells shrink to allow the flow of blood and proteins into the tissues, but are not large enough for immune cells to pass through. The immune cells require a process called diapedesis which actively moves the immune cells from the blood into the tissue. This is called extravasation. The process of diapedesis goes through several stages. First the selectins will be expressed by the endothelial cells and the immune cells such as neutrophils. The selectins on the immune cell will catch with the selectins on the endothelial cells causing them to slow down and roll along the side of the blood vessel wall. This is called rolling adhesion. The cytokines like IL-8 (CXCL8) will cause the endothelial cells and immune cells to express integrins like LFA-1 and VLA-4 on the immune cells. The endothelial cells will express ICAM-1 and VCAM-1 which will bind to the integrins of the immune cells. That will cause tight binding and the full stop of the immune cell. Next the PECAM ligand will bind to the CD-31 on the immune cell and pull it through the small opening.

The first stages of immune cell driven inflammation is regulated by preformed elements released by granules from inside of the cells. This starts with the activation of Mast Cells and their degranulation releasing Histamine. The Histamine will act upon the endothelial cells causing them to release the contents of their granules called Weibel Palade Bodies. They contain P selectins which will be expressed by the endothelial cells. The initial activation of the endothelial cells with histamine and P selectins starts within seconds and lasts for the first hour or two. After that, the sentry cells like macrophages will process antigens and begin expressing proinflammatory cytokines like TNF-a and IL-1. These cytokines are not expressed immediately as they actually take time to be produced. The endothelial cells will release their P selectins as part of their Weibel Palade Bodies initially. Then they will express the E selectins later in response to the TNFa and IL-1.

The acute phase reaction is part of inflammation and starts when the sentry cells begin releasing cytokines like TNF-a, IL-1, and IL-6. The IL-6 will go to the liver and begin the production of critical proteins necessary in the immune response. One of them will be the production of all the complement proteins. Next will be the creation of C reactive Protein (CRP). The increased production of ferritin for binding and storing iron is a critical acute phase reactant that plays a big role in chronic inflammation and Anemia of Chronic Disease. The CRP protein will bind to phosphocholine that is expressed by damaged or dying cells. CRP will bind to these receptors and trigger the classical complement pathway. The measure of CRP is a key indicator for inflammation. Other key immune proteins will also be produced like mannose binding lectin (MBL) for the complement system.

The acute phase reaction will include the fever caused by the TNFa and IL-1 in the hypothalamus. These are all the effects of cellular inflammation from the first activation of Mast Cells releasing quick acting inflammatory signals. It acts on the Endothelial cells that will reinforce the neurogenic and myogenic reactions caused by injury. It can initiate the inflammatory process in case of infection. This brings more immune cells into the tissue. The Antigen Presenting Cells in the tissue will process antigens and release more cytokines to enhance the inflammatory process. Other elements like complement can come into the space and trigger from pathogens. The activation of complement can further enhance inflammation. Damage to cells will call into action the Arachidonic Acid pathway and even more inflammatory mediators like Prostaglandins and Leukotrienes. The inflammation process is a coordinated and multi system response to damage or infection.

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