Sequence of Events in Cell

Injury and Cell Death

Prof. Layla S. Abdullah ,MD,FRCPC
Pathology Department
Faculty of Medicine
KAU
Patterns of irreversible Cell Injury:
Apoptosis
– Definition: Programmed cell death
• It is an active (energy- dependant) programmed single cell
death to delete the unwanted or defective cells.
• Genetically programmed and follow programmed
sequence of events.

• Apoptosis is a pathway of cell death in which cells activate

enzymes that degrade the cells’ OWN nuclear DNA and
nuclear and cytoplasmic proteins.
• Fragments of the apoptotic cells then break off, giving the
appearance that is responsible for the name (apoptosis,
“falling off” in greek ).
 Apoptosis
• It has an important role in physiological processes
and pathological conditions
• Apoptosis occurs in many normal 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, especially when the damage affects the
cell’s DNA or proteins; thus, the irreparably
damaged cell is eliminated.
 Apoptosis
– Physiological processes:
• during embryogenesis (organogenesis, developmental involution,
separation of digits in limb development)
• hormone -dependent involution (endometrium during menstruation,
lactating breast after weaning)
• cell deletion in proliferating populations  intestinal crypt epithelium,
bone marrow
• deletion of autoreactive T cells in thymus (failure might result in
autoimmunity)
– Pathological conditions:
• pathologic atrophy-prostate after castration (hormone -dependent
involution)
• Cell death in tumors
• Cell death induced by cytotoxic drugs and ionizing radiation
• Viral infections eg. Councilman’s bodies due to viral hepatitis
 Mechanism of cell death by Apoptosis
• Apoptosis is regulated by biochemical pathways that control the balance of death-
and survival-inducing signals and ultimately the activation of enzymes called
caspases.

• Two distinct pathways converge on caspase activation:

- the mitochondrial pathway
- the death receptor pathway

• The two mechanisms are generally induced under different conditions, involve
different molecules, and serve distinct roles in physiology and disease.
 Apoptosis
Mechanism & Morphology:
– Involves single cells or small clusters.
– The nuclei of apoptotic cells show various stages of chromatin
condensation and aggregation and, ultimately, karyorrhexis.
– Cells shrink rapidly, retain intact plasma membrane
– Formation of cytoplasmic buds
– Fragmentation into apoptotic bodies(composed of membrane-
bound pieces of cytosol and organelles )
– Apoptotic bodies phagocytosed or rapidly degraded
– No inflammatory response
– Entire process from 5 to 30 minutes
Because these fragments are quickly extruded and phagocytosed
without eliciting an inflammatory response, even substantial
apoptosis may be histologically undetectable
Apoptosis
 Clearance of apoptotic cells
• Apoptotic cells and their fragments entice phagocytes by producing a
number of signals where it is recognized by tissue macrophages,
leading to phagocytosis of the apoptotic cells.

• Prompt clearance of the dead cells before the cells undergo

membrane damage and release their contents (which can induce
inflammation).

• So dead cells disappear without leaving a trace, and inflammation is

virtually absent.
 Apoptosis
– Microscopic:
• condensed nuclear
chromatin with peripheral
aggregation, with little
eosinophilic cytoplasm
• Apoptotic cells are typically
surrounded by clear halo
which separates them from
surrounding normal cells
 Apoptosis
Various diseases may be associated with reduced or
increased apoptosis
• Increased apoptosis
– Immune deficiency syndrome (AIDS)
• Reduced apoptosis
• Gene products of bcl-2 inhibits apoptosis
• Gene products of p53 gene enhance apoptosis
– Therefore loss of p53 function or excess Bcl-2 function 
results in cell accumulation (defective cells)  e.g. neoplasia
E.g. : Follicular lymphoma (Excess Bcl-2 )
 Other Pathways of Cell Death
• In addition to necrosis and apoptosis, two other
patterns of cell death have been described that have
unusual features.

• The importance of these pathways in disease

remains to be established.
 Necroptosis.
• This form of cell death is initiated by engagement of TNF receptors as well as other,
poorly defined triggers.
• in necroptosis, kinases called receptor-interacting protein (RIP) kinases are
activated, initiating a series of events that result in the dissolution of the cell, much
like necrosis.
• The name necroptosis implies that there are features of both necrosis and
apoptosis.
• Examples :
-Some infections
- ischemic injury
-inflammatory reactions in which the cytokine TNF is produced.

However, when and why it occurs and how significant it is in human diseases is not well
understood.
 Pyroptosis
• This form of cell death is associated with activation of a cytosolic
danger-sensing protein complex called the inflammasome

• The net result of inflammasome activation is the activation of

caspases
• The production of cytokines that induce inflammation, often
manifested by fever, and others trigger apoptosis. Thus, apoptosis and
inflammation coexist. The name pyroptosis stems from the
association of apoptosis with fever (Greek, pyro = fire).
• E.g. :some infectious microbes cause the death of infected cells.
Its role in other pathologic situations is unknown
 Autophagy
• Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own
components.
• It is a survival mechanism in times of nutrient deprivation, so that the starved cell
can live by eating its own contents and recycling these contents to provide nutrients
and energy.
• may represent an adaptation that helps cells survive lean times. If, however, the
starved cell can no longer cope by devouring its contents, autophagy may
eventually lead to apoptotic cell death.
• Examples :
- Seen in ischemic injury
- some types of myopathies.
- have been associated with inflammatory bowel disease (Need further studies )
Autophagy
 Necrosis Vs Apoptosis
Necrosis Apoptosis:
• Grp of cells or part of tissue • Single cell death in living tissue
• passive process • Active process
• Always pathologic • Physiologic or pathologic
• Mechanism is ATP depletion, mb • Endonucleases
damage • Apoptotic bodies
• Histology: coagulation.
liquefaction • No inflammation
• inflammation
CELL INJURY CELL DEATH &
ADAPTATIONS

INTRACELLULAR
ACCUMULATION
PATHOLOGIC
CALCIFICATION
AGING
Intracellular Accumulations
 Intracellular Accumulations
• Under some circumstances, cells may accumulate
abnormal amounts of various substances, which
may be harmless or may cause varying degrees of
injury. The substance may be located in the
cytoplasm, within organelles (typically lysosomes),
or in the nucleus, and it may be synthesized by the
affected cells or it may be produced elsewhere.
 Intracellular Accumulations
• The main pathways of abnormal intracellular
accumulations are: inadequate removal and
degradation
or
excessive production of an endogenous substance,
or deposition of an abnormal exogenous material
 Intracellular Accumulations
• Fatty Change (Steatosis):
Abnormal accumulation of triglycerides within parenchymal cells
seen in liver (most common) . Also in kidneys, heart, muscles

– Causes
• alcohol abuse, other toxins, anoxia, obesity, protein malnutrition
– Pathogenesis
• Triglycerides accumulation in hepatocytes may result from defects
at any step from fatty acid entry to lipoprotein exit
 Intracellular Accumulations
Fatty Change (Steatosis)
• Pathogenesis:
– Hepatotoxins (alcohol)  alter mitochondrial and SER function
– Carbon tetrachloride CCL4, and protein malnutrition decrease synthesis
of apoproteins
– Anoxia  inhibits fatty acid oxidation
– Starvation, D.M. and obesity  increase fatty acid delivery to liver

• Effect of fatty change on cell function depends on the severity of the

accumulation and the cause:
– May be reversible
– Or/ irreversible
 Intracellular Accumulations
Fatty Change (Steatosis)
• Morphology:
– Fatty accumulation appears as clear vacuoles within
cells
– Liver
• increased weight, yellow color
• fat vacuoles within cytoplasm of hepatocytes
– Heart
• focal fat deposits in myocardium (anemia)
• diffuse fat deposits in myocardium (profound
hypoxia, diphtheric myocarditis)
 Liver,
normal

Liver, fatty
change
 Liver,
Normal

Liver, fatty
change
 Intracellular Accumulations
• Cholesterol and Cholesterol Esters
– Atherosclerosis
• macrophages and smooth muscle cells filled with lipid vacuoles
(cholestrol & cholestrol esters)  appear as foam cells 
atherosclerotic plaques (in aorta and other blood vessels)
– Xanthomas
• macrophage accumulation/hereditary and acquired
hyperlipidemias  clusters of foamy cells in skin  xanthomas
Aorta, atherosclerosis
SKine, xanthomas
 Intracellular Accumulations
• Protein : Nephrotic syndrome
plasma cells (Russell bodies) in
Multiple Myeloma
Hyaline bodies in Alcoholic liver disease

• Glycogen:
Diabetes mellitus : deposition in Renal tubular epithelium ,
in cardiac myocytes, and β cells of the islets of
Langerhans.
Glycogen also accumulates within cells in genetic disorders
called glycogen storage diseases
Intracellular Accumulations: Pigments
• Pigments are colored substances that are either
exogenous, coming from outside the body, such as
carbon, or are endogenous, synthesized within the
body itself, such as lipofuscin, melanin, and certain
derivatives of hemoglobin.
 Intracellular Accumulations
• Carbon (coal dust ) in lung called Anthracosis
When inhaled, it is phagocytosed by alveolar macrophages and
transported through lymphatic channels to the regional
tracheobronchial lymph nodes. Aggregates of the pigment
blacken the draining lymph nodes and pulmonary parenchyma
 Intracellular accumulations

• Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow

granular intracellular material that accumulates in a variety of tissues
(particularly the heart, liver, and brain) with aging or atrophy.
• Lipofuscin represents complexes of lipid and protein that are produced by the
free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular
membranes.
• It is not injurious to the cell but is a marker of past free radical injury. The
brown pigment when present in large amounts, imparts an appearance to the
tissue that is called Brown Atrophy.
 Intracellular Accumulations
• Melanin is an endogenous, brown-black pigment
Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can
accumulate the pigment (e.g., in freckles), as can dermal macrophages.

• Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates
in tissues when there is a local or systemic excess of iron. Excessive deposition of hemosiderin, called
hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis
 PATHOLOGIC
CALCIFICATION
 Pathologic Calcification
• Pathologic calcification :an abnormal deposition of
calcium salts, together with smaller amounts of iron,
magnesium, and other minerals.
• It can occur in two ways:
1. Dystrophic calcification
2. Metastatic calcification
 Pathologic Calcification
• Abnormal deposition of calcium salts (with smaller amounts of iron, Mg, &
others)
• Two types: dystrophic and metastatic calcification

1) Dystrophic Calcification
– Areas of necrosis or injury
– Normal serum calcium
– Intracellular or extracellular
– Examples:
• Areas of necrosis (T.B., fat necrosis)
 Pathologic Calcification
2) Metastatic Calcification
– Occurs in normal tissue
– Occurs with hypercalcemia :
• The major causes of hypercalcemia are:
(1) increased secretion of parathyroid hormone, due to either primary parathyroid tumors or production of
parathyroid hormone–related protein by other malignant tumors.

(2) destruction of bone due to the effects of accelerated turnover (e.g., Paget disease, immobilization, or
tumors (increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal
metastases)

(3) vitamin D–related disorders including vitamin D intoxication and sarcoidosis .

(4) renal failure, in which phosphate retention leads to secondary hyperparathyroidism.

 2) Metastatic Calcification
– Primarily affects blood vessels, kidneys (nephrocalcinosis), lungs, and
gastric mucosa.
– extensive calcifications in the lungs may be evident on radiographs and
may produce respiratory deficits.
 Morphology

• Appears as
chalky white
granules grossly
• Microscopic:
Intracellular or
extracellular
blue
(basophillic)
deposits
CELLULAR AGING
 Cellular Aging
• Individuals age because their cells age .
• Cellular aging is the result of a progressive decline in
the life span and functional capacity of cells.
• Aging from the cosmetic point of view , many
important health consequences (chronic diseases
such as cancer, Alzheimer and Ischemic heart
disease )
• A number of genes and signaling pathways involved
 Cellular Aging/ Mechanisms

• DNA Damage :
- Accumulation of insults overtime will damage the
nuclear and mitochondrial DNA (ROS induced by toxins, radiation exposure)
- Most repaired by DNA repair enzymes
BUT some persist and accumulate in cell.
- repair mechanisms become inefficient over time.
- Patients with syndromes associated with defect in
DNA repair mechanisms may lead to earlier aging.
- Accumulation of mutations in nuclear and mitochondrial DNA ultimately
compromise the functional activities and survival of cells.
 Cellular Aging/ Mechanisms
• Decrease cellular replication :
- Cells from children have the capacity to undergo more rounds of replication than
do cells from older people.
- All normal cells have a limited capacity
of replication after which cell division
become arrested  Cell Replicative Senescence .
 Decrease cellular replication
- The mechanism of replicative senescence involves progressive shorting of
Telomeres.
- Telomeres are repeated amino acids at the end of chromosomes and are important
for ensuring complete cell replication.
- Telomeres length is maintained by an enzyme called Telomerase.
Telomerase is present in germ cell but absent in somatic cells so if somatic cells age,
their telomeres become shorter and can not replicate and generate new cells
- Progressive Replicative senescence will ultimately lead to
cell arrest and Aging.
- In cancer, the telomerase activity is regained and cell replication is indefinite
 Cellular Aging/ Mechanisms
• Defective protein homeostasis
- In aging decrease synthesis and increase turnover
of proteins
- Increase formation of mis-folded proteins
which triggers apoptosis.

All this affect cell function and survival

 Cellular Aging/ Mechanisms
• Aging is exacerbrated by chronic diseases associated
by low grade inflammation
• Stress

• Aging is slowed down by calorie restriction &

Exercise
 THE END
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