Session 6: Cell death

Session 6: Cell death

• Alex Simon (MD)

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Learning tasks

Learning tasks

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

Define necrosis.

Explain patterns of tissue necrosis.

Identify cellular changes in necrotic tissue.

Define apoptosis.

Identify examples of apoptosis in physiological and pathological situations.

Identify cellular changes in apoptotic cells.

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Introduction

Introduction

With continuing damage, the injury becomes irreversible, at which time the cell cannot recover and it dies.

There are two (2) types of cell death

Necrosis.

Apoptosis.

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Necrosis

Necrosis

Definition

Necrosis is the type of cell death that is associated with loss of membrane integrity and leakage of cellular contents culminating in dissolution of cells, largely resulting from the degradative action of enzymes on lethally injured cells.

The enzymes responsible for digestion of the cell may be derived from lysosomes of both the dying cells and inflammatory leukocytes.

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Necrosis cont…

Necrosis cont…

Ischemia, infections, toxins, and immune reactions cause necrosis type of cell death.

When damage to membranes is severe, enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell, resulting in necrosis.

Cellular contents also leak through the damaged plasma membrane into the extracellular space, where they elicit a host reaction (inflammation).

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Patterns of tissue necrosis

Patterns of tissue necrosis

These patterns are

Coagulative necrosis.

Liquefactive necrosis (colliquative necrosis).

Gangrenous necrosis (wet or dry gangrene).

Caseous necrosis.

Fat necrosis.

Fibrinoid necrosis.

Most of these patterns of necrosis have distinct gross appearance except fibrinoid necrosis.

Fibrinoid necrosis is seen only histologically.

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Coagulative necrosis

Coagulative necrosis

Coagulative necrosis is a most common type of necrosis in which the underlying tissue architecture is preserved for at least several days.

Hallmark of coagulative necrosis.

Injury denatures not only structural proteins but also enzymes, thereby blocking the proteolysis of the dead cells.

It is caused by the denaturing and coagulation of proteins within the cytoplasm.

The affected tissues take on a firm texture.

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Coagulative necrosis cont…

Coagulative necrosis cont…

Leukocytes are recruited to the site of necrosis, and the dead cells are digested by the action of lysosomal enzymes of the leukocytes.

The cellular debris is then removed by phagocytosis.

Microscopic examination shows loss of the nucleus but preservation of cellular shape.

The necrosed cells are swollen and appear more eosinophilic than the normal.

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Coagulative necrosis cont…

Coagulative necrosis cont…

Most often due to ischemic injury(infarct).

It is characteristic of infarcts (areas of ischemic necrosis) in all of the solid organs like heart, liver, spleen and kidney except the brain.

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Liquefactive necrosis

Liquefactive necrosis

Liquefactive necrosis is seen in focal bacterial or fungal infections.

Because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest (“liquefy”) the tissue.

For unknown reasons, hypoxic death of cells within the central nervous system often evokes liquefactive necrosis.

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Liquefactive necrosis cont…

Liquefactive necrosis cont…

Dead cells are completely digested, transforming the tissue into a liquid viscous mass.

Eventually, the digested tissue is removed by phagocytes.

If the process was initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus.

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Liquefactive necrosis cont…

Liquefactive necrosis cont…

Liquefaction necrosis results from cellular destruction by hydrolytic enzymes, leading to autolysis and heterolysis.

Liquefaction necrosis occurs in

Abscesses.

Brain infarcts.

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Gangrenous necrosis

Gangrenous necrosis

It is not a distinctive pattern of cell death.

It usually refers to the condition of a limb (lower leg) that has lost its blood supply and undergone coagulative necrosis involving multiple tissue layers.

This gives dry gangrene.

When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes

Resulting in wet gangrene.

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Gangrenous necrosis cont…

Gangrenous necrosis cont…

Gangrenous necrosis is a gross term used to describe dead tissue.

Common sites of involvement include

Lower limbs (commonest site).

Gallbladder.

GI tract.

Testes.

Dry gangrene has coagulative necrosis for the microscopic pattern.

Wet gangrene has liquefactive necrosis.

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Gangrenous necrosis cont…

Gangrenous necrosis cont…

dry gangrene (diabetic foot)

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Caseous necrosis

Caseous necrosis

Caseous necrosis is encountered most often in foci of tuberculous infection.

Caseous means “cheese-like,” referring to the soft, friable yellow-white appearance of the area of necrosis.

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Caseous necrosis cont…

Caseous necrosis cont…

The area of caseous necrosis is often enclosed with characteristic of a focus of inflammation known as a granuloma.

On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in the Haematoxylin & Eosin stained tissue.

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Fat necrosis

Fat necrosis

Fat necrosis can be caused by trauma to tissue with high fat content forming focal areas of fat destruction.

It commonly seen in

Pancreas.

Breast.

In acute pancreatitis, activated pancreatic lipases that have leaked out of and liquefy the membranes of fat cells in the peritoneum

These lipases split the triglyceride esters contained within fat cells.

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Fat necrosis cont…

Fat necrosis cont…

The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification).

Histologically, the foci of necrosis contain shadowy outlines of necrotic fat cells, basophilic calcium and an inflammatory reaction.

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Fibrinoid necrosis

Fibrinoid necrosis

It is a special form of necrosis in which complexes of antigens and antibodies are deposited in the walls of arteries.

Seen in polyarteritis nodosa, vasculitis.

The deposited immune complexes, together with fibrin produce a bright pink and amorphous appearance on Haematoxylin & Eosin stains called fibrinoid (fibrin-like).

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Fibrinoid necrosis cont…

Fibrinoid necrosis cont…

Deposition of fibrin-like material which has the staining properties of fibrin.

It is encountered in various examples of immunologic tissue injury.

Fibrinoid necrosis is detected only by histologic examination.

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Morphology of Necrosis

Morphology of Necrosis

Cytoplasmic changes.

Necrotic cells show increased eosinophilia.

Cell may have a more glassy, homogeneous appearance.

Myelin figures are seen.

Cytoplasm becomes vacuolated and appears “moth-eaten.”

Discontinuities in plasma and organelle membranes.

Marked dilation of mitochondria with large amorphous densities.

Disruption of lysosomes.

Intracytoplasmic myelin figures.

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Morphology of Necrosis cont…

Morphology of Necrosis cont…

Nuclear changes.

Assume one of three patterns due to breakdown of DNA and chromatin giving basophilic staining.

Pyknosis

Shrinkage of the nucleus.

Karyorrhexis

Pyknotic nucleus undergoes fragmentation.

Karyolysis

Fading of chromatin

Electron microscopy reveals profound nuclear changes culminating in nuclear dissolution.

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Apoptosis

Apoptosis

Definitions

A form of cell death in which programmed sequence of events lead to the elimination of cells without releasing harmful substances into the surrounding area.

Apoptosis is a pathway of cell death in which cells activate enzymes (caspases enzymes) that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.

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Apoptosis cont…

Apoptosis cont…

Apoptosis plays a crucial role in developing and maintaining health by eliminating old cells, unnecessary cells, and unhealthy cells.

Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off”).

In apoptosis, there is nuclear dissolution without complete loss of cell membrane integrity.

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Apoptosis cont…

Apoptosis cont…

Thus plasma membrane of the apoptotic cell remains intact.

Though the membrane is altered in such a way that the cell and its fragments become avid targets for phagocytes.

The dead cell and its fragments are rapidly cleared before cellular contents have leaked out.

Therefore apoptosis does not elicit an inflammatory response.

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Causes of Apoptosis

Causes of Apoptosis

Apoptosis occurs in many normal physiological situations and serves to eliminate potentially harmful cells and cells that have outlived their usefulness.

It also occurs as a pathologic event when cells are damaged beyond repair, especially when the damage affects the cell’s DNA or proteins.

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Examples of apoptosis in physiologic situations

Examples of apoptosis in physiologic situations

The programmed destruction of cells during embryogenesis.

Formation of interdigital space of fingers and toes.

Involution of hormone-dependent tissues upon hormone deprivation.

Endometrial cell breakdown during the menstrual cycle.

Regression of the lactating breast after weaning.

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Examples of apoptosis in physiologic situations cont…

Examples of apoptosis in physiologic situations cont…

Cell loss in proliferating cell populations, such as intestinal crypt epithelia, in order to maintain a constant number.

Elimination of cells that have served their useful purpose.

Neutrophils after acute inflammatory response.

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Examples of apoptosis in physiologic situations cont…

Examples of apoptosis in physiologic situations cont…

Elimination of potentially harmful self-reactive lymphocytes.

To prevent reactions against the body’s own tissues.

Cell death induced by cytotoxic T lymphocytes.

A defense mechanism against viruses and tumors that serves to kill virus-infected and neoplastic cells.

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Examples of apoptosis in pathologic conditions

Examples of apoptosis in pathologic conditions

DNA damage.

Cell with damage DNA triggers intrinsic mechanisms that induce apoptosis.

Accumulation of misfolded proteins.

Excessive accumulation of these proteins cause endoplasmic reticulum stress, which culminates in apoptotic death of cells.

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Examples of apoptosis in pathologic conditions cont…

Examples of apoptosis in pathologic conditions cont…

Cell injury in certain infections, particularly viral infections.

Apoptotic death that may be induced by the virus.

Pathologic atrophy in parenchymal organs after duct obstruction

e.g. pancreas, parotid gland, and kidney.

Cell death in tumours exposed to chemotherapeutic agents.

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Clearance of Apoptotic Cells

Clearance of Apoptotic Cells

Apoptotic cells entice phagocytes by producing “eat-me” signals.

Phosphatidylserine molecules, appear on the outer surface of the cells, which facilitate their identification.

Cells that are dying by apoptosis also secrete soluble factors that recruit phagocytes.

Some apoptotic bodies express adhesive glycoproteins that are recognized by phagocytes.

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Morphology of Apoptosis

Morphology of Apoptosis

The stages of pyknosis, karyorrhexis and karyolysis can be seen.

The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies.

Apoptosis may be histologically undetectable.

Because these fragments are quickly extruded and phagocytosed without eliciting an inflammatory response.

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Necrosis vs Apoptosis

Necrosis vs Apoptosis

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Key points

Key points

Necrosis elicits an inflammatory reaction.

In coagulative necrosis, tissue architecture is preserved for at least several days.

Brain tissue after to ischemic injury(infarct) elicits liquefactive necrosis.

Caseous necrosis is associated with granuloma formation in TB infection.

Chalky white necrotic areas is seen in fat necrosis.

Fibrinoid necrosis is detected only by histologic examination.

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Key points cont…

Key points cont…

Apoptosis is a form of coordinated and internally programmed cell death.

Caspases enzymes are crucial in apoptosis.

Apoptosis can occur in both physiological by serves to eliminate potentially harmful cells and cells that have outlived their usefulness.

Apoptosis occurs to cells which undergo DNA damage.

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Evaluation

Evaluation

Define necrosis.

Differentiate between dry gangrene from wet gangrene.

How does fat necrosis occur?

List five differences between necrosis and apoptosis.

Explain how apoptotic bodies are cleared.

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References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 20-22.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India . Pg. 47-49.

Kumar V.; Abbas A. K.; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, China. Pg. 18-21.

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