Pathologic Reactions to Injury

Introduction:

Cells are in a constant state of action. From normal physiology to any external stimuli caused, they are in a constant mode of adaptation. This activity of maintaining homeostasis makes them viable. Some of the adaptive cellular responses are atrophy, hypertrophy, hyperplasia, and metaplasia. If the cells exceed the adaptive capacity, it causes cell injury. Cell injury could be both reversible and as well as irreversible in nature.

What Causes Cell Injury?

Cell injury can be due to a single gene defect or complex injury. Some of the causes are:

• Genetic Defects: Substitution seen in single amino acid of the hemoglobin S of sickle cell anemia.

• Infectious Agents: From submicroscopic organisms to tapeworms, which invade the human body through external mediums and cause cell damage.

• Immunologic Conditions: Loss of tolerance to self-antigen reactions. For example, anaphylaxis to drugs or foreign particles.

• Chemical Agents: Any concentrated substance disturbing the cellular osmolarity can damage the cell (for example, oxygen and sodium salts). Drugs of therapeutic use can also cause cell damage under favorable conditions. Other potentially toxic agents are carbon monoxide, insecticides, and air pollutants.

• Oxygen Deprivation: Conditions with oxygen depletion or hypoxia can cause cell death.

• Nutritional Deficiency: Malnourished body can develop conditions leading to cell death as well as excessive calories in the body can also lead to cell death and increased morbidity and mortality rate.

• Physical Agents: Exposure to radiation, high temperatures, electric shock, and change in atmospheric pressure can cause changes in cells.

• Aging: As the cells undergo aging, the regenerative properties take time and are seen in a diminished state.

What Is Reversible and Irreversible Cell Injury?

Both reversible and irreversible cell injury depends not only on the stress added but also on other factors like cellular vulnerability, differentiation, blood supply, and nutritional status.

• Reversible Cell Injury: Generalized swelling and fatty changes of cell organelles as a result of cellular injury followed by the regenerative process are called reversible cell injury.

• Irreversible Cell Injury: Irreversible cell death is also known as necrosis. It is followed by a sequence of morphological changes. It is caused by protein denaturation and organellar breakdown.

What Are the Types of Irreversible Cell Injury?

It is further divided into four types depending on the type of cell death:

• Coagulative Necrosis: After days of cell death, when its basic structural outline is preserved, it is known as coagulative necrosis. Seen mostly in hypoxic cell death of tissues.

• Liquefactive Necrosis: During any infection, white blood cells are released. As a result of phagocytic activity, liquefaction digests the dead cells.

• Caseous Necrosis: It forms a cheesy appearance in the necrotic area. Observed most commonly in tuberculous infections.

• Fat Necrosis: It causes fat destruction. Seen in acute pancreatitis.

What Are the Mechanisms of Cell Injury?

• ATP Depletion: ATP is the energy storehouse of a cell. Hence, the depletion of ATP molecules affects the homeostatic function. This results in the depletion of cellular osmolarity, transportation, protein synthesis, and metabolism pathway of the cell.

• Oxygen Depletion: Lack of oxygen supply leads to cell denaturation. However, activated free radical species are also responsible for cell death.

• Calcium Homeostasis Depletion: Cell injury leads to increased permeability of extracellular calcium ion influx into the cell membrane. This leads to loss of calcium homeostasis and eventually leads to cell death in tissues.

• Plasma Membrane Depletion: The toxins released can affect the permeability of the plasma cell membrane.

• Mitochondrial Depletion: Mitochondrial dysfunction directly affects the synthesis of ATP molecules. This causes the destruction of the proton gradient responsible for ATP production and the destruction of a protein called cytochrome c. Both of these mechanisms lead to apoptotic death.

What Is Ischemia?

It is a type of cell injury characterized by reduced or no blood flow in the vessels. This could be due to blocked vessels as a result leading to oxygen depravity or conditions like cyanosis and the absence of glycolysis in cells. Such conditions can also lead to cell death. This can happen anywhere in the body. For example, ischemia in calf arteries or critical limb ischemia (CLI) leads to pain, reduced pulse, and conditions like dry gangrene.

What Are the Cellular Adaptations Seen During Injury?

Adaptation responses change depending on the type of stimuli received. Like physiologic adaptation seen in pregnant women (for example, breast enlargement). Also, pathologic response was observed during cell injury. There are basically four types of cellular adaptations:

• Atrophy: It decreases cell size. This causes cell dysfunction, like loss of blood supply. It manifests as one age. Lack of diminished metabolic rate and loss of hormones are other aggravating factors.

• Hypertrophy: It is an increase in the size of cells leading to an increase in the size of organs. It could be due to hormonal dysfunction or a pathologic condition. For example, physiologic hypertrophy is seen in the uterus, and pathologic hypertrophy is seen in the heart due to hypertension or aortic valve disease.

• Hyperplasia: It is an increase in the number of cells of an organ or tissue. Seen commonly during the wound healing process. It can also constitute pathological hyperplasia. For example, the infection of Papillomavirus causes warts on the skin and, in extreme cases, endometrial cancers.

• Metaplasia: It is the change in cell type to another type. For example, in smokers, the normal ciliated columnar epithelium of the trachea and bronchi are replaced by stratified squamous epithelial cells.

What Is Pathologic Calcification?

It is the deposition of minerals like calcium, iron, magnesium, and other minerals in cells. It is seen as fine white granules or clump deposits. Eventually, these granules can turn into stone. Two types of calcification processes that can be observed are:

• Dystrophic Calcification: Deposition of minerals in dying or dead tissues. It is caused mainly due to organ dysfunction characterized by accumulated lipids. It could be due to previous cell injury also. For example, the calcified aortic valve of the heart.

• Metastatic Calcification: Deposition of minerals in any normal tissues. This could be due to increased hormonal secretion, bone disorders, vitamin disorders, and renal failure.

What Is Apoptosis?

Unlike necrosis, apoptosis is programmed cell death or cell suicide. There is no tissue inflammation noted. It leads to phagocytosis of apoptotic bodies. It leads to chromatin condensation. For example, apoptosis can be seen during the development of embryos in the formation of separate digits from webbed hands. It also fixes DNA damage caused by any virus. However, the abnormal proliferation of cancerous cells is not controlled by apoptosis.

What Are the Pathologic Reactions to Injury Seen During Aging?

Many aging factors trigger the injury due to diminished cellular function and reduced nutrient uptake. In senile patients, morphological changes have been noted, like irregular nuclei, pleomorphic vacuolated mitochondria, distorted Golgi bodies, diminished endoplasmic reticulum, and abnormally folded proteins. Human beings have a finite life span. They stop dividing and become senescent after fifty doublings. This is known as the Hayflick phenomenon. But in cases like progeria, those who age prematurely show only thirty-five doublings. Such genomic replication of cells is known by two mechanisms:

• Telomere Shortening: This is an incomplete replication of the ends of chromosomes. This determines the number of cell divisions. In normal somatic cells, telomerase shortens with progressive cell division. But in cancer cells, this telomeric activity is stopped and further gives way to proliferation.

• Clock Genes: There are certain genes that control aging. For example, the CLK-1 gene in Caenorhabditis Elegans nematode alters the growth rate and timing of the developmental process. In progeria, where patients show premature aging, they have a defective helicase in DNA unwinding protein which is responsible for replication and repair.

Such cellular events seen during aging could be due to both programmed events and environmental injury.

Conclusion:

Cell injury can be reversible and irreversible. The most common form is hypoxia.

Both reversible and irreversible injuries can be due to physiological and pathological factors.

The final outcome of such cellular function can be seen either as repair and regeneration or cell death.