Session 4: Cell Injury

Session 4: Cell Injury

• Felician Sikujua (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Define cell injury.

Identify causes of cell injury.

Explain different types of cell injury.

Identify biochemical mechanisms linked to cell injury.

Explain ischemia-reperfusion injury.

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Definitions of cell injury

Definitions of cell injury

Cell injury results when cells are stressed so severely that they are no longer able to adapt or cells are exposed to inherently damaging agents or cells suffer from intrinsic abnormalities (e.g., in DNA or proteins).

Variety of stresses a cell encounters as a result of changes in its internal and external environment.

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Overview of cell injury

Overview of cell injury

Different injurious stimuli affect many metabolic pathways and cellular organelles and exert their effects first at the molecular or biochemical level.

Cellular function may be lost long before cell death occurs and the morphologic changes of cell injury (or death) lag far behind both.

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Overview of cell injury cont…

Overview of cell injury cont…

The cellular derangements of reversible injury can be corrected, and if the injurious stimulus abates, the cell can return to normal.

Persistent or excessive injury, however, causes cells to pass the nebulous “point of no return” into irreversible injury and cell death.

Two phenomena consistently characterize irreversibility

The inability to correct mitochondrial dysfunction.

Profound disturbances in membrane function.

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Activity: Brainstorming

Activity: Brainstorming

What are the causes of cell injury?

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Causes of cell injury

Causes of cell injury

Oxygen deprivation (Hypoxia).

Physical agents.

Chemical agents.

Infectious agents (Biological agents).

Immunological reactions.

Genetic factors.

Nutrition imbalances.

Aging.

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Hypoxia

Hypoxia

Hypoxia is the commonest cause of the cell injury.

Hypoxia is caused by

Ischemia (the commonest cause of hypoxia).

Hypoxemia.

Decreased oxygen carrying capacity.

Hypoxia causes cell injury by reducing intracellular generation of ATP (by aerobic oxidative respiration) leading to the failure of many energy dependent cellular systems.

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Physical agents

Physical agents

These includes

Trauma like mechanical (e.g. road accidents).

Extremes of temperature.

Radiation (e.g. ultraviolet and ionising).

Electric shock.

Rapid changes in atmospheric pressure.

All have wide-ranging effects on cells including direct physical effects.

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Chemical agents

Chemical agents

Chemical poisons such as cyanide, arsenic, mercury.

Strong acids and alkalis.

Environmental pollutants: insecticides, pesticides.

Oxygen at high concentrations.

Hypertonic glucose and salt.

Social agents such as alcohol and narcotic drugs.

Therapeutic administration of drugs.

Some act directly but most of them by their metabolites.

Interfere cellular metabolism.

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Infectious agents

Infectious agents

These include

Bacteria.

Rickettsia & Chlamydia.

Prions.

Viruses.

Fungi.

Parasites (Protozoans, worms).

They damage cells directly or by their toxins.

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Immunologic reactions

Immunologic reactions

Although the immune system defends the body against pathogenic microbes, immune reactions can also result in cell and tissue injury.

Inflammatory mediators like interferons and interleukins stimulate reactions.

Examples are

Autoimmune reactions against one’s own tissues

Hypersensitivity diseases from allergic reactions against environmental substances in genetically susceptible individual.

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Genetic factors

Genetic factors

Genetic aberrations (abnormalities) can result in pathologic changes.

Genetic defects may cause cell injury as a consequence of deficiency of functional proteins or accumulation of damaged DNA or misfolded proteins.

This will trigger cell death when they are beyond repair.

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Nutritional imbalances

Nutritional imbalances

Due to a deficiency or an excess of nutrients.

Interfere normal metabolic pathways.

Nutritional deficiency diseases may be due to overall deficiency of nutrients (e.g. starvation), of protein calorie (e.g. marasmus, kwashiorkor), of minerals (e.g. anaemia), or of vitamins (e.g. scurvy).

Nutritional excess is a problem resulting in obesity, atherosclerosis, heart disease and hypertension.

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Aging

Aging

Cellular senescence leads to alterations in replicative and repair abilities of individual cells and tissues.

All of these changes result in a diminished ability to respond to damage and, eventually, the death of cells and of the organism.

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Types of cell injury

Types of cell injury

There are two (2) types of cell injury

Reversible cell injury.

Irreversible cell injury.

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Reversible cell injury

Reversible cell injury

In early stages or mild forms of injury, the functional and morphologic changes are reversible if the damaging stimulus is removed.

The injury has typically not progressed to severe membrane damage and nuclear dissolution.

Eventhough there may be significant structural and functional abnormalities.

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Reversible cell injury cont…

Reversible cell injury cont…

The two (2) main morphologic correlates of reversible cell injury are

Cellular swelling.

Fatty change.

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Cellular swelling

Cellular swelling

Results from failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis.

When cellular swelling affects many cells in an organ, the organ will

Have some pallor (as a result of compression of capillaries).

Increase in turgor.

Increase in weight.

Microscopic examination findings

Small, clear vacuoles within the cytoplasm.

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Cellular swelling cont…

Cellular swelling cont…

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Fatty change

Fatty change

Fatty change is principally encountered in cells participating in fat metabolism or depend on fat metabolism (e.g., hepatocytes, myocardial cells).

It is manifested by the appearance of lipid vacuoles in the cytoplasm.

Injured cells may also show increased eosinophilic staining in the cytoplasm.

Fatty change also called steatosis.

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Fatty change cont…

Fatty change cont…

Lipid vacuoles

(round and whitish)

Increased eosinophilic staining in the cytoplasm (pinkish)

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Intracellular changes in reversible cell injury

Intracellular changes in reversible cell injury

The intracellular changes (ultrastructure findings) associated with reversible injury include

Plasma membrane alterations such as blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments.

Mitochondrial swelling.

Appearance of phospholipid-rich amorphous densities (amorphous black substances) in the mitochondria.

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Intracellular changes in reversible cell injury cont…

Intracellular changes in reversible cell injury cont…

Dilation of the endoplasmic reticulum with detachment of ribosomes and dissociation of polysomes.

Nuclear alterations, with clumping of chromatin.

The cytoplasm may contain phospholipid masses, called myelin figures, which are derived from damaged cellular membranes.

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Intracellular changes in reversible cell injury cont…

Intracellular changes in reversible cell injury cont…

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Irreversible cell injury

Irreversible cell injury

Two phenomena consistently characterize irreversibility

The inability to correct mitochondrial dysfunction.

Causing lack of oxidative phosphorylation and ATP generation.

Profound disturbances in membrane function.

Injury to lysosomal membranes results in the enzymatic dissolution of the injured cell.

This is followed by necrosis type of cell death.

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Slide 27

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Mechanisms of cell injury

Mechanisms of cell injury

The biochemical mechanisms linking any given injury with the resulting cellular and tissue manifestations are:

Complex.

Interconnected.

Tightly interwoven with many intracellular metabolic pathways.

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Cellular targets for injurious stimuli

Cellular targets for injurious stimuli

Genetic apparatus of the cell (DNA).

Mitochondria (site for ATP production).

Protein synthesis (Ribosomes detachment from endoplasmic reticulum).

Cell membranes.

Plasma membrane

Organelle membrane (lysosomes, mitochondrial).

Cytoskeleton.

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General principles of cell injury responses

General principles of cell injury responses

The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity.

The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of the injured cell.

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components.

Multiple biochemical alterations may be triggered by any one injurious insult.

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Important biochemical mechanisms of cell injury

Important biochemical mechanisms of cell injury

ATP depletion.

Mitochondrial damage.

Increase calcium entry into the cell (Influx of calcium).

Reactive oxygen species accumulation.

Cell membrane damage.

Misfolded proteins and DNA damage.

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Other cellular alterations during cell injury

Other cellular alterations during cell injury

Abnormal deposits of materials in cells and tissues are the result of excessive intake or defective transport or catabolism.

Depositions of lipids.

Fatty change.

Cholesterol deposition.

Deposition of proteins.

Reabsorbed proteins in kidney tubules.

Immunoglobulins in plasma cells.

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Other cellular alterations during cell injury

Other cellular alterations during cell injury

• Deposition of glycogen

In glycogen storage disease.

• Deposition of pigments

Carbon, lipofuscin (breakdown product of lipid peroxidation).

Iron (due to overload, or in hemosiderosis).

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Other cellular alterations during cell injury

Other cellular alterations during cell injury

Pathologic calcifications.

Dystrophic calcification.

Deposition of calcium at sites of cell injury and necrosis.

• Metastatic calcification.

Deposition of calcium in normal tissues, caused by hypercalcemia (usually a consequence of parathyroid hormone excess).

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Ischemia-reperfusion injury

Ischemia-reperfusion injury

This occurs when there is restoration of blood flow to ischemic but viable tissues results, paradoxically, in the death of cells that are not otherwise irreversibly injured.

Thus reperfusion after ischemic state paradoxically deteriorates the already injured cell.

This is a clinically important process that may contribute significantly to tissue damage in myocardial and cerebral ischemia.

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Ischemia-reperfusion injury

Ischemia-reperfusion injury

Mechanisms that may account for the exacerbation of cell injury resulting from reperfusion into ischemic tissues:

New damage may be initiated during reoxygenation by increased generation of reactive oxygen species.

The inflammation that is induced by ischemic injury may increase with reperfusion.

Activation of the complement system may also contribute to ischemia-reperfusion injury.

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Key points

Key points

Hypoxia is the commonest cause of the cell injury.

Cell injury can reversible or irreversible.

The main morphological changes seen in reversible cell injury are cellular swelling and fatty change.

Profound mitochondrial dysfunction and membrane damage exacerbate irreversible cell injury.

ATP depletion is the most common biochemical mechanism of cell injury.

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Evaluation

Evaluation

What are the causes of cell injury?

What are the intercellular structural changes seen in reversible cell injury?

Mention mechanisms involved in cell injury

Define ischemic-reperfusion injury.

List four (4) structural changes of reversible cell injury.

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References

References

Kumar V.; Abbas A. K.; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, China. Pg. 1, 6-9.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India . Pg. 21, 27-43.

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