Introduction

The cell undergoes a variety of changes in response to the injury. Some injuries may lead to the cell death. Injuries stimuli triggers the cellular adaptation process. The principal targets of cell injury are cell membranes, mitochondria, protein synthesis machinery and DNA. Control of the rate of cell death to the rate of cell division maintains physiological homeostasis. Cell death is a valuable process for living organisms because it removes injured or unwanted cells that utilizes valuable nutrients. In this article we are going to see the causes of cell injury, types of cell injury, mechanism of cell injury, cell adaptation and cell death in detail.

What is the cell injury?

Cell injury is defined as an alteration in cell structure or biochemical functioning, due to some stress that exceeds the ability of cell to compensate through normal physiologic adaptive mechanism.

Types of cell injury

There are two types of cell injury; reversible cell injury and irreversible cell injury.  The cell injury caused by mild stress is reversible cell injury. The injury caused by severe or persistent stress known as irreversible cell injury.

Reversible cell injury

In the early stage of mild forms of injury, the functional and morphologic changes are reversible if the damaging cause of injury is removed.

Irreversible cell injury

Due to the severe and persistent stress, the morphological and functional damages of the cell are not reversible. Which leads to the death of cell.

Causes of cell injury

Cell injury caused by two different ways, acquired causes and genetic causes.

Acquired causes

Acquired causes further classified as,

1. Oxygen deprivation (hypoxia) – Hypoxia is a deficiency of oxygen which causes cell injury by reducing aerobic oxidative respiration.
2. Cell injury caused by physical or chemical agents. It includes radiation, heat, cold, electricity, acids and poisonous gases.
3. Cell injury can be caused by microbial agents like bacteria, viruses, fungi, parasites, protozoa and rickettsia.
4. Immune system plays an important role in defense mechanism against infectious pathogens, but immune reaction may also cause cell injury.
5. Nutritional derangement also causes the cell injury. Nutritional deficiency causes the diseases like Marasmus, Kwashiorkor, Anemia. Nutritional excess causes obesity, atherosclerosis, heart diseases, hypertension.
6. Psychological factors: Various mental diseases like stress, anxiety, depression, overwork, frustration causes biochemical and morphological changes of cell. Bad habits like drug addiction, alcoholism, smoking results in cell injury.

Genetic causes

Genetic cases such as developmental defect, cytogenic defect, single gene defect (mendelian syndrome), disorders with multifactorial inheritation causes cell injury.

Pathogenesis of cell injury

The pathogenesis of cell injury depends on three factors

1. Time and duration of stimulus, small stimulus for long period or severe stimulus for short period.
2. Time and status of cell, for example cardiac cell sensitive to hypoxia and skeletal muscle cells are very well resistant to hypoxia.
3. Underlying intracellular changes, cell injury depends on cell organelle affected.

Mechanism of reversible cell injury

If hypoxia is for short period of time, the cell can be reversed to its normal condition. The hypoxia causes the mitochondrial dysfunction which leads to decrease in ATP production.

The decrease in ATP production results in,

• Failure of sodium-potassium pump
• Anaerobic glycolysis
• Decrease in protein synthesis

Failure of sodium-potassium pump

In a normal cell there is exchange of sodium to potassium with the help of ATP. In this exchange 3 sodium (Na⁺) moves out of the cell and 2 potassium (K⁺) enters inside the cell. Due to failure of sodium-potassium pump, this exchange rate reversed. As ions increases in the cell, water starts moving inside the cell which leads to cell swelling. This is the first morphological change in cell injury called hydropic change. Due to the cell swelling, inner cell organelles also start swelling.

Aerobic glycolysis

In aerobic glycolysis due to decrease in ATP production there is excess accumulation of lactic acids and inorganic phosphates from the hydrolysis of phosphate esters. This reduces the intracellular pH i.e. it becomes more acidic which decrease activity of many cellular enzymes.

Decrease in protein synthesis

Due to decrease in ATP production, the ribosomes which are attached on the surface of endoplasmic reticulum detached. This reduces the protein synthesis.

In reversible cell injury cell or cell organelles goes through some changes like,

• Defects in membrane permeability
• Decrease phospholipid synthesis
• Mitochondrial membrane damage
• Plasma membrane damage
• Reduced protein synthesis
• Injury to lysosomal membranes

Mechanism of irreversible cell injury

The long-term hypoxia results in irreversible damage of cellular structure and function. The irreversible cell injury alters the normal functions of cell which described as follows,

1. Severe membrane damage: The membrane prevents certain substances to directly enter inside the cell. Due to damage of plasma membrane, there is influx of calcium (Ca⁺) inside the cell. This calcium activates enzymes phospholipase, nuclease and protease. Which leads to cell death.
2. Severe mitochondrial damage: Excess intracellular calcium attaches to the mitochondria, which disables the functioning of mitochondria. The amorphous calcium salt is deposited in the mitochondrial matrix. This is known as amorphous flocculent densities.
3. Nuclear damage: The nuclear proteins are damaged by activate lysosomal enzymes such as protease, endonucleases, RNAase, DNAase. There are 3 types of irreversible nucleus damage.

• Pyknosis: Shrinkage of chromatin material makes nucleus dark basophilic.
• Karyorrhexis: The irreparably broken nuclear fragments of dying cell dispersed in the cytoplasm.
• Karyolysis: Destruction of chromatin material known as karyolysis which results in complete dissolution of nucleus.

Myelin figures: These are lamellated aggregates of phospholipids derived from damaged membranes of mitochondria or endoplasmic reticulum or cell membrane. Myelin figures are seen in both reversible and irreversible cell injury.

Cell death

Because of irreversible cell injury, cell cannot recover and dies. Cell death is of two types, necrosis and apoptosis.

Necrosis

Necrosis considered as uncontrolled pattern of cell injury and death. It is often causes due to the external factors such as injury, toxins and infection. The morphological changes that accompany necrosis are caused by lethally injured cells. Due to degradative enzymes on lethally injured cells, cells lose its membrane integrity and leak the cellular contents. Which consequently causes cell death and potent inflammation.

Apoptosis

It is a type of controlled and programmed cell death. It involves cell activating enzymes that break down cells own DNA, proteins and nuclei. It is characterized by cell shrinkage, membrane blebbing, and the controlled dismantling of cellular components. Apoptosis is essential for various physiological processes including development, immune response and removal of damaged or unwanted cells without causing inflammation to surrounding tissues.

Morphology of cell injury- Adaptive changes

Cells have ability to adapt to changes in their environment by altering their morphology and metabolic activity. These alterations can take the shape of hydropic, fatty or hyaline modifications. If the changes are permanent, it develops autolysis, necrosis or apoptosis. If a cell dies due to the injury, it results into gangrene or pathological calcification. Adaptive responses are part of the normal physiology of cell in attempt to limit the harmful effects of pathological stress. Common examples of adaptive changes are atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia.

Atrophy: Atrophy refers as a reduction in cell size. Atrophy simultaneously occurs in adjacent cells which leads to decrease in size of tissue or organ.

Hypertrophy: Hypertrophy refers as increase in cell size. Hypertrophy simultaneously occurs in adjacent cells which leads to increase in size of tissue or organ.

Hyperplasia: Hyperplasia means an increase in the number of cells within a tissue due to mitosis.

Metaplasia: It is a transient conversion of one cell type to another.

Dysplasia: In this there is a permanent conversion of one type of cell to another type of cell.

Cell swelling

Due to injury, there is mitochondrial dysfunction which leads to decrease in ATP production. It increases influx of water in the cell, which leads to cell swelling.

Intracellular accumulation

The normal cell accumulates abnormal number of various substances which may be harmful to the cell and cause injury. The site of this accumulation may be in the cytoplasm or nucleus.

Process and mechanism of intracellular accumulation

• Production of normal substances at normal or increased rate, but the metabolic rate to remove them is inadequate. For example, fatty change in the liver.
• Accumulation of abnormal endogenous substances due to defect in protein folding, packaging, transportation and inability to degrade abnormal protein. For example, accumulation of protein in liver cell.
• Accumulation of normal endogenous substance due to an inherited defect in enzyme, which required for metabolism of the substance. For example, lipid and glycogen storage disease.
• Accumulation of abnormal exogenous substance due to unavailability of enzymatic and transport mechanism. For example, silicosis and anthracosis.

Three categories of accumulation

1. Accumulation of constituents of normal cell metabolism.

• Fat
• Protein
• Carbohydrate

2. Accumulation of pigments

• Endogenous pigments
• Exogenous pigments

3. Accumulation of abnormal substances of abnormal cell metabolism

• Storage disease
• Inborn error of metabolism

Calcification

Calcification is the accumulation of calcium salts in tissue, blood vessels or organs. This accumulation makes them harden which disrupt body’s natural processes. Calcium is transported through the bloodstream. It is also available in every cell. Because of this calcification can occur in almost any part of the body.

Types of calcifications

• Small and large arteries
• Heart valves
• Brain (cranial calcification)
• Joints and tendons
• Soft tissues like breasts, muscles and fat
• Kidney, bladder and gallbladder

Some calcium accumulation is harmless, generally this accumulation is response of body to inflammation, injury or certain biological processes.

Causes of calcification

• Infections
• Calcium metabolism disorder
• Genetic or autoimmune disorder
• Persistent inflammation

Diagnosis of calcification

Calcification may diagnose through blood tests, X-rays or biopsy.

Enzyme leakage

Enzyme has covalent bonds with the cell membrane and within themselves. Normally enzymes are contained within cellular compartments. However, if there is any damage or injury these enzymes are released into the bloodstream in large quantity, this is called as enzyme leakage.

Cell death acidosis and alkalosis

Cell death is a natural process to remove unwanted and injured cells. The role of acidosis and alkalosis in cell death is largely related to their impact on cellular function and ability of cell to maintain stable internal environment.

When there is high level of acid in body tissues or body fluids called as acidosis. The high-level acid disrupts the normal cellular functions. The acidic environment alters the enzymatic activities, structure and function of proteins which ultimately results in cell damage and death.

When an individual has a high level of alkaline (base) in their tissues or fluids called as alkalosis. Alkalosis occurs due to excess bicarbonate ions or insufficient acid producing hydrogen ions. Like acidosis severe alkalosis can contribute to cell death. Alkalosis induced change in ion concentrations in cell leads to cell death.

Maintaining the body’s pH is necessary for survival and functioning of cell. The kidney and lungs are major organs to maintain acidosis and alkalosis in human body.

Electrolyte imbalance

There are many chemicals available in human body which helps to regulate important functions. These chemicals are called as electrolytes. When this electrolyte dissolved in water they gets separated into positive and negative ions. Human body’s nerve reactions and muscle functions are mainly depended on proper exchange of ions. Some common examples and their normal range in adults are:

• Calcium: 4.5-5.5 mEq/L
• Chloride: 97-107 mEq/L
• Potassium: 3.5-5.3 mEq/L
• Magnesium: 1.5-2.5 mEq/L
• Sodium: 136-145 mEq/L

Factor affecting electrolyte imbalance

• Vomiting, diarrhea, sweating, high fever.
• Kidney diseases
• Lack of nutrients
• Hormonal disorders
• Side effects of medications

Symptoms of electrolyte imbalance

• Muscle spasm
• Weakness
• Confusion
• Irregular heart beats
• Bone disorders
• Change in blood pressure
• Convulsions

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