Apoptotic and Necrotic Processes

Both apoptosis and necrosis can be seen as part of a spectrum of shared biochemical events that both
result in some form of cellular death.

Apoptosis, or programmed cell death (PCD), causes cells to shrink, develop blebs (bubble-like spots) on
the cell membrane, undergo degradation of genetic and protein materials in the nucleus, and have their
mitochondria break down, thus releasing cytochrome. The fragments are each wrapped in their own
membrane, with other chemicals (such as ATP and UTP) released freely. These chemicals lead
macrophages — cell-eating bodies — to find and eliminate the dead cells and their fragments. This "eat
me" message is triggered by a phospholipid normally inert in a cell's membrane, and the macrophages in
turn release cytokines that inhibit inflammatory responses.

In contrast, necrotic cells swell or may form vacuoles on their surface, with interior structures either
distending or shrinking rapidly, destroying the cell's processes and chemical structures. The unregulated
release of cytochrome and the cell membrane's phospholipid (called phosphatidylserine) causes
immediate reactions in surrounding tissues, leading to swelling (inflammation) and edema; it also often
triggers other cell deaths through apoptosis. Unlike apoptosis, necrotic cells are not targeted by
macrophages for cleaning of their cellular debris, so the effects of the cell rupture can spread quickly and
throughout the body for long periods of time.

Energy Input

Apoptosis is energy-dependent, meaning it requires input from a cell for cell death to occur, leading to
the term "cell suicide." Necrosis does not require any energy input from a cell, as external factors or
localized infections are what trigger necrosis.

Caspases

For the apoptotic pathways that cause cell suicide, the primary molecular signals are inactive
proenzymes called caspases. Necrosis sometimes makes uses of caspases, but to a much lesser degree,
and often the process makes no use of them, as a cell itself is destroyed in an uncontrolled fashion
during necrotic events. For example, necrosis is the process behind dying, or necrotic, tissue that
surrounds, say, a venomous spider bite.

Research has identified as many as 13 caspases, broadly categorized as initiators, effectors, or

executioners (the ones that directly trigger cell death), and inflammatory. Despite what it may sound
like, inflammatory caspases actually inhibit inflammation. As necrosis lacks the inflammatory caspase
input, inflammation is always present in necrotic cell death.

Apoptotic and Necrotic Symptoms

Necrosis following a bite from a brown recluse spider.

magnifyNecrosis following a bite from a brown recluse spider.

Because apoptosis is a normal part of an organism's cellular balance, there are no noticeable symptoms
related to the process. In contrast, necrosis is an uncontrolled change in an organism's cell balance, so it
is always harmful, resulting in noticeable, negative symptoms.

Necrosis is accompanied in its early stages by inflammation, as components (including cell structures,
cytoplasm, and DNA/RNA) of the ruptured or damaged cells are released. To an organism, this
unregulated flow of proteins, chemicals, and genetic material triggers emergency responses, such as
inflammation to protect surrounding tissues, as well as an increase in white blood cells, macrophages,
and T cell production to fight off infection. These reactions are often accompanied by a metabolic boost
and fever, which can lead to fatigue and an overall weakened immune system.

If left untreated, necrotic tissues will lose vascularity, meaning they will lose blood flow, and thus start
dying. When this happens, the necrosis is called gangrene, a condition where tissue ultimately dies and
must be removed to stop necrosis from expanding.

When Apoptosis is Unhealthy

Apoptosis becomes abnormal only when the cellular processes that keep the body in balance either
cause too many cell deaths or cause too few. Many autoimmune diseases, such as muscular dystrophy
and Alzheimer's, are believed to be related to excessive apoptosis, causing muscle or nerve cells to die
before their time. Cells that grow without control, meaning apoptosis is not happening often enough,
usually lead to tumors, which themselves can become cancerous.

General Causes of Apoptosis and Necrosis

There are three mechanisms that cause cell death:

Self-generated signals in a cell, which may arise from age, infection, irregular mitosis (cell division), or
other causes. This mechanism is known as the intrinsic or mitochondrial pathway, whereas the following
two types of cell death are extrinsic pathways.

The triggering of death activators, receptors on a cell's surface that respond to external signals such as
hormones or other chemical messengers.

External triggering by reactive oxygen species, such as free radicals, which are dangerous to the body.

In general, apoptosis is part of life, the continuation of the cellular cycle initiated by mitosis. However,
apoptosis can be triggered by a variety of harmful stimuli, such as heat, radiation, lack of oxygen
(hypoxia), drugs and trauma, among others. In these cases, apoptosis rids the body of damaged cells or
cells that can no longer perform normally and helps heal damaged areas. Higher degrees of damage
from the same stimuli can lead to necrosis. For example, a mild burn can cause a small blister that heals
in a week, but a third-degree burn will cause necrosis in the affected area.

Apoptosis can also be caused by hormonal and chemical changes in the body, a process most often seen
in embryonic development. Both the immune and nervous systems develop with a large over-production
of cells that are reduced before birth through selective processes carried out by apoptosis. For example,
fetuses develop hands and feet without individual digits; once a chemical messenger is released, the
webbed tissue between the fingers and toes dies off, separating each digit. A similar process occurs with
sexual differentiation, as hormones guide fetal development to suppress or eliminate certain tissues and
structures in favor of developing others. On the other hand, if necrosis is present during fetal
development, some form of medical intervention is often required, and deformation or miscarriage may
occur.

Types of Necrosis and Their Causes

In necrosis, a cell's death is usually caused by a sudden and uncontrolled rupture based on two
mechanisms:

Interference with the cell's energy supply (blood, plasma, oxygen, etc.).

Direct damage to the cell membrane.

Necrosis is categorized in five ways, depending on the cause:

Bacterial or fungal infections may cause liquefactive necrosis. This is necrosis that includes the liquefied
mass of dead tissue known as "pus."

The necrosis that arises from denatured proteins that impede proper circulation is called coagulative
necrosis. This type is seen most often in the heart after an infarction, as well as in kidneys and adrenal
glands.

Fungal and mycobacterial infections, such as tuberculosis, can cause gaseous necrosis. This combination
of liquefactive and coagulative necrosis is caused by dead cells that are not completely digested by
microphages; they leave a granular residue that impedes circulation.

Necrosis that occurs only in fatty tissue is called fat necrosis. The most common form of this necrosis is
associated with pancreatitis, severe inflammation of the pancreas.

Deposits of antigens and antibodies combined with fibrin can adhere to and eventually block arteries
and destroy their structure. This is called fibrinoid necrosis.

Treatment

Apoptosis and necrosis are treated in very different ways, primarily based on the fact that one process is
often normal and the other is patently abnormal.

Although much of the apoptosis process is identified, the mechanisms and activation cascade is not yet
fully understood. Research into the pathways is widespread and expanding as the clinical findings have
direct applications to autoimmune diseases, such as Parkinson's, Huntington's, amyotrophic lateral
sclerosis, and HIV/AIDS, as well as nearly all types of cancer. Because apoptosis is a process of health and
disease, the more it is understood, the better the chances are of developing more effective and better-
targeted treatments. In all cases, untreated necrosis is dangerous and can lead to death.
In the case of autoimmune diseases, where apoptosis is causing too many cell deaths, treatment consists
of inhibiting the caspase triggers or reducing the external triggers that may be precipitating the
increased cell suicides. For cancer, the opposite is needed, so treatment to induce apoptosis in the
tumor cells, making the cells more vulnerable to drugs and radiation, is a key part of most therapies. A
promising new treatment involves the generic compound dichloroacetic acid (DCA), which has been
shown to be highly-effective in "reigniting" apoptosis in certain cancerous tumors.

The common treatments for necrosis are:

Antibiotics/NSAIDs: these fight the infectious and inflammatory nature of necrosis and are often the first
line of defense against its damage. In extreme cases, immunosuppressing drugs may be prescribed to
reduce the inflammatory response.

Debridement: removal of the dead tissue, from simple cleaning of the area to surgery, including
amputation. Fly larvae (maggots) are also used quite effectively in some forms of debridement.

Antioxidants: may be used to treat internal necrotic tissues, most often related to ischemia, the end
result of heart tissue losing vascularity after an infarction (heart attack).

Occurrence

With over 50 billion cells naturally dying in an adult human body each day, apoptosis is very common
and typically benign, if not entirely beneficial. Necrosis is relatively rare by comparison, and the degree
of cellular death depends greatly on whether effective treatments, such as antibiotics and anti-
inflammatory drugs, are applied.