Necrosis and apoptosis

Definitions & Key takeaways

Necrosis is a type of cell death that occurs when cells are damaged by external factors like an infection, as well as internal factors like tissue ischemia. There are six types of necrosis: coagulative and gangrenous necrosis, which happen to hypoxic tissues; liquefactive necrosis, which happens because of hydrolytic enzymes; caseous necrosis - like in tuberculosis; fat necrosis, which happens when fatty acids spill outside adipose cells, like during trauma, and finally fibrinoid necrosis - which is caused by fibrin deposits, like in malignant hypertension.

Apoptosis, on the other hand, is a programmed cell death that occurs when the body needs to get rid of damaged or unnecessary cells. Apoptosis occurs due to intrinsic and extrinsic pathways. With apoptosis, white blood cells come in and clean up the dead tissue, so this is a neat way for cells to die.

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Generally speaking, cells have two ways to die. One way is by apoptosis, which is a form of programmed cell death.
The second way is by necrosis, which is when cells die due to injury or disease. Overall, apoptosis occurs much more often than necrosis.
One example is when our old skin cells undergo apoptosis and get replaced by new skin cells. Another example is in our hands and feet during fetal development.
Initially, human hands and feet look like ducks' feet, with webs of skin connecting the fingers, but the cells in the webbing undergo apoptosis, and that allows us to form individual digits that allow us to pick our nose and play the piano.
In contrast, necrosis occurs less frequently. An example of necrosis is when a blood vessel that feeds an area of the body, say, the big toe, becomes blocked and can't deliver oxygen and nutrients to the cells like usual.
It causes ischemia, and the cells die. As a result, the tissues of the toe will turn a nasty shade of black, signaling necrosis.
In apoptosis, there are two activating mechanisms, the intrinsic pathway, also called the mitochondrial pathway, and the extrinsic pathway, also called the death receptor pathway.
The intrinsic pathway occurs when a cell is exposed to stress, like radiation, hypoxia, or low oxygen, a high intracellular concentration of calcium ions, or oxidative stress, which is where reactive molecules with unpaired electrons, called free radicals, steal electrons from nearby molecules.
These stressors cause two intracellular proteins, backs and back, to move the cytosol to the mitochondria. Once in the mitochondria, backs and back pierce the outer mitochondrial membrane, making it porous and leaky.
This allows two additional proteins called Smax and cytochrome C, to spill into the cytosol. Smax binds the proteins that normally inhibit apoptosis and deactivates them.
Meanwhile, cytochrome C binds to both ATP, the main form of intracellular energy, as well as an enzyme called Apath1. Together, cytochrome C and Apath1 combine to form a large protein complex called apoptosome.
The AAP1 portion of the apoptosome then cleaves an enzyme called procapsase 9 into its active form, capsase 9. Capsase 9 then goes on to activate capsase 3, and capsase 3 goes on to activate other capsases, like a chain event.
Eventually, this capsa cascade leads a cell to commit apoptosis. That's because these capsaics cleave the proteins that make up the cell's nucleus, organelles, and cytoskeleton, a bit like a ninja sabotaging a bridge by removing its nuts and bolts.
This destroys the cytoskeleton, as well as the proteins that anchor the cytoskeleton to the cell membrane. As a result, the cell membrane starts to develop blebs, or bulges in the cell membrane.
The blebs are structurally weak, so they start to break off from the cell membrane, eventually forming small apoptotic bodies that are eaten by neighboring phagocytes.
At the same time, the apoptotic cell releases anti-inflammatory signals, thereby preventing the recruitment of other immune cells from the blood and preventing tissue inflammation.
So apoptosis is a neat process that conveniently recycles the organic contents of the dead cell. Now, when the signals from apoptosis come from outside the cell, it's called the extrinsic pathway.
One example is when a nearby macrophage recognizes an old cell, a pathogenic cell, or a cell that has completed its task.
In these situations, a macrophage can initiate apoptosis, by releasing tumor necrosis factor alpha, or TNF alpha, a cell signaling protein.
That binds to very appropriately named death receptors on the target cell membrane, one example being tumor necrosis factor receptor one.
The systostolic end of this receptor dives deep inside the cell, and it's called the death domain. When the TNF alpha binds to the tumor necrosis factor receptor one.
The death domain changes its shape and is able to bind to two proteins. One is called fast associated protein with death domain or FADD, and the other is called tumor necrosis factor receptor type 1 associated death domain protein, or TRADD.
So, the death receptor, FADD and TRADD come together to form a multi-complex protein called, wait for it, the death-inducing signal complex or DC.
Once everything is together, DC cleaves procapsase 8 into capsase 8, which in turn activates capsase 3, and capsase 3 goes on to activate other capsases.
This initiates the capsase cascade that commits the cell to apoptosis. After that, the process of apoptosis unfolds, just like the intrinsic pathway.
Now, in addition to macrophages, if a cytotoxic T cell detects that a cell is expressing foreign antigens, the T cell will express a protein on its membrane called fast ligand, which binds to a death receptor on the target cell called the first apoptosis signal receptor, or FA receptor.
Similar to the death domain of tumor necrosis factor receptor one. The fast receptor protein also has its very own death domain that can bind to FADD to form disc.
As before, DC activates procapsase 8 into capsase 8, and that triggers the capsase cascade, which leads to apoptosis. Alright, let's switch gears and take a look at necrosis, which can be triggered by external factors like an infection, or extremely hot or cold temperatures, as well as internal factors like tissue ischemia.
Now, there are 3 main types of necrosis called primary, secondary, and regulated necrosis. Primary necrosis, also known as accidental necrosis or oncotic necrosis, typically occurs when ischemia disrupts the normal functioning of mitochondria.
As a result, the cell is unable to synthesize ATP causing all ATP dependent cellular processes to stop working, including the ionic pumps that regulate the flow of ions in and out of the cell.
Without functioning ion pumps, sodium starts to flow into the cell, and it's followed by water. This causes the cell to swell up like a balloon.
This process of cell swelling is called oncosis. Soon, the cell bursts and spills its internal contents and small molecules, called damage associated molecular patterns, into the surroundings.
These molecules trigger the inflammatory response and attract nearby immune cells to release substances like proteases, which are enzymes that degrade proteins, and reactive oxygen species, which are unstable molecules that can damage other cells.
If this inflammatory process occurs among enough cells, it can destroy the tissue, and if it happens on a massive level, it can lead to organ dysfunction.
Now, it turns out that primary necrosis comes in a few different flavors. First, there's coagulative necrosis, which occurs when a tissue becomes hypoxic, has low levels of oxygen, most commonly due to ischemia.
Hypoxia causes structural proteins to bend out of shape, like twisting a paper clip so that it can no longer work. Hypoxia also affects lysosomal enzymes, which become ineffective at getting rid of the affected proteins.
So, although the cells die, they retain some structure and don't get completely destroyed. From a macroscopic level, the dead tissue becomes a gel-like substance, and has a pale wedge shape, with the apex oriented toward the obstruction.
That's because a blood vessel typically serves a region of tissue that typically fans out, and all of that tissue becomes hypoxic, and then undergoes coagulative necrosis.
Occasionally, blood re-enters the area of necrosed tissue, like if a blocked blood vessel opens back up. And when that happens, it gives the tissue a dark red color, and it's called a red infarct.
Coagulative necrosis can occur in any cell of the body, but it occurs most often when there's low oxygen to the heart, kidneys, or spleen tissue.
Next, there's liquefactive necrosis, that occurs when hydrolytic enzymes completely digest the dead cells into a creamy substance full of dead immune cells.
Think of a cream-filled doughnut. Liquefactive necrosis is most commonly seen in the brain, however, it can also happen to pancreatic cells, or within an abscess located anywhere in the body.
The brain has resident macrophages called microglial cells, that contain hydrolytic enzymes. These enzymes completely destroy damaged brain cells, basically liquefying the dead brain tissue.
Similarly, the pancreas has various enzymes like trypsin that are designed to digest food, but sometimes get activated in chronic inflammation due to gallstones or alcohol consumption, and destroy the pancreatic tissue itself.
Finally, in abscesses, neutrophils use their proteolytic enzymes to liquefy tissue, which results in pus. Next, there's gangrenous necrosis, and it also occurs due to hypoxia.
So that's why some consider it a form of coagulative necrosis. Gangrenous necrosis typically affects the lower limbs and gastrointestinal tract, and it causes the tissue to get dried up like a mummy, sometimes called dry gangrene, but if the dry gangrene gets infected, then liquefactive necrosis can occur, and then it's called wet gangrene.
Next, there's Cassius necrosis, and it's a bit of a mix between coagulative and liquefactive necrosis. Typically, it's the result of a fungal or mycobacterial infection, classically Mycobacterium tuberculosis, which causes tuberculosis.
The dead cells disintegrate, but are not fully digested, which leaves the tissue with a cottage cheese consistency. Next, there's fat necrosis, which most commonly occurs when there's trauma to fatty organs that have a lot of adipose cells, like the pancreas or the breasts.
Trauma to the pancreas or the breasts rupture the adipose cell membranes, which makes them spill their fatty acids into extracellular space.
There, the fatty acids combine with calcium, which leads to dystrophic calcifications in the tissue, that look like bits of chalk in the tissue.
Now, in addition, the pancreas can also undergo fat necrosis as a result of inflammation, called pancreatitis. With pancreatitis, the pancreatic cells spill lipase around the pancreas.
Lipase helps digest fats, so it causes fatty acids to spill out of the fatty retroperitoneal tissue, that's adjacent to the pancreas.
Finally, there's fibrinoid necrosis, which is almost always found in malignant hypertension and vasculitis. With hypertension, a constant high BP damages the muscular wall of the small arteries, so fibrin, a protein involved in the clotting of blood, starts to infiltrate and damage the walls of the damaged blood vessels.
Similarly, in vasculitis, there's an inflammatory reaction in the blood vessel walls that causes destruction. Now, let's take a look at secondary necrosis, which occurs when there are no phagocytes to clean up the mess of an apoptotic cell.
As a result, the cell membrane of an apoptotic cell loses integrity, and releases internal contents into the surroundings.
In contrast to primary necrosis, where damage associated molecular patterns induce a strong inflammatory response, during secondary necrosis, apoptotic cells release modified damaged associated molecular patterns that typically result in chronic inflammation.
Finally, there are regulated or programmed types of necrosis, such as necroptosis, pyrotosis, and feroptosis. Regulated necrosis is defined as genetically controlled cell death, characterized by hallmarks of primary necrosis, such as cellular swelling and leakage of intracellular contents.
Regulated necrosis triggers a stronger immune response when compared to apoptosis. But weaker when compared to primary necrosis.
All right, as a quick recap, apoptosis is a commonly occurring form of programmed cell death, whereas necrosis is a less common process, where cells die due to injury or disease.
Appotosis occurs due to intrinsic and extrinsic pathways. With apoptosis, white blood cells come in and clean up the dead tissue, so this is a neat way for cells to die.
Necrosis occurs because of external factors like an infection, as well as internal factors like tissue ischemia. There are 3 main types of necrosis, and they include primary, secondary, and regulated necrosis.
Primary necrosis includes 6 types of necroses. Coagulative and gangrenous necrosis, which happened to hypoxic tissues, liquefactive necrosis, which happens because of hydrolytic enzymes, cassius necrosis, like in tuberculosis, fat necrosis, which happens when fatty acids spill outside adipose cells, like during trauma, and finally, fibrinoid necrosis, which is caused by fibrine deposits, like in malignant hypertension.
On the flip side, secondary necrosis occurs when there are no phagocytes to clean up the mess of an apoptotic cell, while regulated necrosis refers to a genetically controlled cell death, characterized by cellular swelling, and leakage of intracellular components.