Cell death and apoposis

Citra Dewi
Dep PA FK UNSRI/RSMH
 Overview

Injury
Reversible
Cell death
injury

Cellular
swelling Necrosis: always pathologic process

Fatty Apoptosis: normal function, not associated with

change cell injury
 Overview..

Severe damage membranes

Lysosomal enzymes enter the

cytoplasm & digest the cell

Cellular contents leak out

Necrosis
Schematic illustration of the morphologic changes in necrosis
Source: Robbins & Cotrans. Path basis of disease. 9th ed.
a. Normal kidney tubules.b.early reversible injury.c. necrosis of epithelial
cells
 Causes of cell injury

1. Oxygen deprivation
Hypoxia : reducing aerobic oxidative respiration
Causes of hypoxia:
o Ischemia
o Inadequate oxigenation of the bood due to cardiorespiratory
failure
o Decreased of oxygen carrying capacity of blood anemia
o Carbon monoxide poisoning
o Severe blood loss
 Causes..

2. Physical agents
Mechanical trauma
Extreme of temperature (burns and deep
cold)
Sudden changes in atmospheric presure
Radiation
Electric shock
 Causes...

3. Chemical agents and dugs

Simple chemicals: glucose, salt, oxygen (high
concentration)
Poisons: arsenic, cyanide, mercuric salt destroy
cells within minutes
Potensial injurious substance: air pollutans,
insectiside, herbicide, industrial and occuational
hazards (CO&asbestos), drug (alcohol), therapeutic
drugs
 Causes.
4. Infectious agents
Virus
Bacteria
Fungi
parasites
 Causes.
5. Immunologic reactions
Injurious reactions to endogenous self
antigens auto immune disesase
External agent: microbes
 Causes..
6. Genetic derangement
Chromosomal anomaly: down syndrome
Amino acid substitution in RBCdecrease life
span of RBCanemia sickle cell

7. Nutritional imbalance
Cholesterol deposits atherosclerosis
Protein deficiency anorexia nervosa
Obesity
 Mechanism of cells injury
Several principals:
- The cellular response to injurious stimuli depends on the
nature of the injury, its duration & its severity
- The consequences of cells injury depends on the type,
state & adaptability of the injured cells
- Cells injury results from different biochemical mechanism
acting on several essential cellular components.
- Any injurious stimulus may silmutaneously trigger
multiple interconnected mechanism that damage cells
 Necrosis
The morphologic appearance of necrosis is the
result of intracellular protein and enzymatic
digestion of lethally injured cell
Necrotic cell are unable to maintain membrane
integrity & their contents often leak outinduce
anflammation
The enzymes that digest the necrotic cells are
derived from the lysosomal f the dying cells
theselves and from the leucocyte.
 Necrosis..
When large numbers of cells die the tissue or
the organ is said to be necrotic
So myocardial infarct is necrosis portion of the
heart caused by death of many myocardial cells
Necrosis of tissue has several morphologically
distinct patternprovide clues about the
underlaying diseaseused often & their
implication understood bay pathologist &
clinicians
 Morphology
Morphology of necrotic cells:
Increase eosinophilia in HE stainloss of cytoplasmic
RNA (H) , denatured cytoplasmic protein (E)
More glassy homogenous appearance than normal
cellsloss of gylogen particle
Cytoplasmic vacuolitatonenzyme has digested
cytoplasmic organelles
Dead cells may replace by myelin figures large,
whorld phospholipids masses derive from damaged
cell membranephagocytosed or degraded into fatty
acid (generated by sodium soapcalcified)
 Morphology..
Nuclear changes
Ne of three patterndue to nonspesific breakdown of
DNA
Karyolisis: loss of DNA because of enzymatic
degradation by endonucleasesfading of basophilia
of the chromatin
Pyknosis: nuclear shrinkage & increase basophilia.
Chromatin condenses into solid 7 shrunken basophilic
mass.
Karyorrhexis: picnotic nucleus undergoes
fragmentation
Day 2 or 3 the nucleus totally dissapear
 Pattern of necrosis
1. Coagulative necrosis
2. Liquefactive necrosis
3. Ganggrenous necrosis
4. Caseous necrosis
5. Fat necrosis
6. Fibrinoid necrosis
 Coagulative necrosis
Is a form of nerosis which the architecture
of dead tissues preserved for a span of at
least some days
Macroscopy: tissue exhibit a firm texture
Example: ischemia caused by obstruction
in a vessel in all organs except the brain
Localized coagulative necrosis infarct
 Liquefactive necrosis
Characterized by digestion of dead cells,
resulting in transformation of the tissue
into a liquid viscous mass (pus)
Example:
bacterial infection, fungi infection.
Hypoxic death of cell within CNS unknown
reason
 Gangrenous necrosis
Not a spesific pattern, but this term commonly
used in clinical practice
Usually applied to a limb, generally lower
leglost its blood supply & has undergone
necrosis (coagulative nec)
When bacterial infection is superimposed there
is more liquefactive necrosis because of the
action of degradative enzymes in the bacteria &
attracted leucocytes called wet ganggene
 Caseous necrosis
Most often in tubercuous infection
Caseous=cheeselike
Microscopic: the necrotic area appears as
a collection of fragmented or lysed cells &
amorphous granular debris enclosed
within a distinctive inflammatory border
granuloma
 Fat necrosis
Refers to focal areas of fat destruction, typically
resulting from release of activated pancratic
lipase into the substance of the pancreas and
peritoneal cavity.
Example: acute pancreatitislipases split the
TG FA combine with Cafat sapponification
Microscopic: foci of shadowy outlines of necrotic
fat cells, with basophilic calcium deposits,
surrounded by inflammation
 Fibrinoid necrosis
Special pattern of necrosis, usually seen in
immune reaction involving blood vessels.
Example: vasculitis syndrome
Complex Ag-Ab are deposited in the walls
of arteries immune complexes,
togeteher with fibrib that has leaked out of
vesselsresults in a bright pink &
amorphous appearance called fibrinoid
 Ultimately, mst necrotic cells & their contents
dissapear by phagocytosis & enzymatic
digestion by leucocyte

If it is not happenthey tend too attract calcium

salts & other minerals to become
calcifieddystrophic calcification
 Apoptosis
Named after the Greek designation for falling
off
It was a unique mechanism of cell death, distinc
from necrosis
Is a pathway of cell death that is induced bay a
tightly regulated suicide program in which cell
destined to die active enzymes that degrade the
cells own nuclear DNA and nuclear and
cytoplasmic proteins.
 Apoptosis and necrosis may co exist
Induced by some pathologic stimuli progress to
necrosis
Apoptotic cells break up into fragments called
apoptotic bodies which contain cytoplas&
nucleus
The plasma membrane of the apoptotic cells
bodies remain intact, but its structure is
alterredtasty target for hagocytes
 The dead cells & its fragments are rapidly
devoured, before the content leaked out
does not elicit inflammatory reaction
 Causes of apoptosis
Apoptosis in physiologic situation
To eliminate cells that are no longer needed,
& to maintain a steady number of various cell
populations in tissue.
Destruction of cells during embryogenesis
Involution of hormone dependent tissue upon
hormone withdrawal
Endometrial cell breakdown during the menstrual
cycle
Prostatic atrophy after castration
 Causes
Cell loss in prolipherating cell population
Immature lymphocytes in the BM & thymus that fail
to express useful antigen receptors
B lymphocytes in germinal centres
Elimination of potentially harmful self reactive
lymphocytes to prevent reactions againts
ones own tissue
Death of host cells that have served their
useful purpose, such as neutrophils &
lymphocytes
 Causes
Apoptosis in pathologic conditions
DNA damages
Accumulation of misfolded proteins
Cell death in certain infections: reduced
CD4&CD8 cell count in AIDS
Pathologic atrophic in parenchymal organs
after duct obstruction
Degenerative disease of CNS: alzheimers
disease, parkinson disease
 Biochemical features of apoptosis
Activation of caspases
DNA & protein breakdown
Membrane alterations & recognition by
phagocytes
Clinico-pathologic correlations:apoptosis in
health & disease
Growth factor deprivation
Hormone sensitive cells deprived of the
relevant hormone
Apoptos is triggered by the intrinsic
(mitochondrial) pathways
 DNA damage
Involve gene p53
It arrest the cell cycle to allow time for repair
If the damage is too great to be repaired
succesfully, p53 triggers apoptosis
P53 serves as a critical life or death switch
following genotoxic stress
 Disorders associated with
dysregulated apoptosis
Disorders associated with defective
apoptosis & increased cell survval
May form a basis of cancer and autoimmune
disease
Disorders associated with increased
apoptosis & excessive ce death
Neurodegenerativ dis
Ischemic injury death of infected cells
Mechanism of apoptosis
Intrinsic Extrinsic
pathways pathways

Cytochrome Death
C receptors

Caspases Caspases

Cell death
Cell
death
Morphologic changes in apoptosis
Cell shrinkage
Chromatin condensation
Formation of cytoplasmic blebs and
apoptotic bodies
Phagocytosis of apoptotic cells or cell
bodies, uasually by macrophages
Plasma membrane are thought to remain
intact during apoptosis
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N
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[Lymph node)The germinal center is an area of high cell

proliferation and active apoptosis. Numerous
macrophages are present in a germinal center to engulf
and clear dying cell debris. These macrophages are
sometimes called tingible-body macrophages because of
Features of necrosis & apoptosis
 Intracellular Accumulations
Intracellular accumulation of abnormal amounts of
various substances, for example:
- a normal cellular constituent accumulated in
excess, such as water, lipids, proteins and
carbohydrates
- an abnormal substance:
exogenous, such as a mineral or products of infectious
agents
endogenous, such as a product of abnormal synthesis or
metabolism
- a pigment.
 Intracellular Accumulations
- The substance may be either in the
cytoplasm or the nucleus
- In some instances, the cell may be
producing the abnormal substance
- In others it may be merely storing products
of pathologic processes occurring
elsewhere in the body
Mechanisms of cell deposition,
COMMON CAUSES OF INTRACELLULAR
ACCUMULATION

1- A normal endogenous substance is produced at

a normal or increased rate, but the rate of
metabolism is inadequate to remove it. e.g. fatty
change in the liver.
2- A normal or abnormal endogenous substance
accumulates because of genetic or acquired
defects in the metabolism, packaging, transport,
or secretion of these substances. e.g. lysosomal
storage diseases.
COMMON CAUSES OF INTRACELLULAR
ACCUMULATION

3- An abnormal exogenous substance is

deposited and accumulates because the
cell has neither the enzymatic machinery
to degrade the substance nor the ability to
transport it to other sites. e.g.
accumulations of carbon particles.
 LIPIDS
All major classes of lipids can accumulate in
cells:
triglycerides
cholesterol/cholesterol esters
phospholipids
In addition, abnormal complexes of lipids
and carbohydrates accumulate in the
lysosomal storage diseases
 Steatosis (Fatty Change)
The terms steatosis and fatty change is
abnormal accumulations of triglycerides
within parenchymal cells.
Often seen in liver, but it also in heart,
muscle, and kidney.
 Steatosis (Fatty Change)
The causes of steatosis include :
- Toxins
- protein malnutrition
- diabetes mellitus
- obesity
- anoxia and
- alcohol abuse
 Hepatotoxins (e.g., alcohol) alter
mitochondrial and SER function and thus
inhibit fatty acid oxidation
CCl4 and protein malnutrition decrease the
synthesis of apoproteins
Anoxia inhibits fatty acid oxidation
Starvation increases fatty acid mobilization
from peripheral stores
 Steatosis (Fatty Change)
Free fatty acids from adipose tissue or ingested food are
normally transported into hepatocytes.
In the liver, they are esterified to triglycerides, converted
into cholesterol or phospholipids, or oxidized to ketone
bodies.
Release of triglycerides from the hepatocytes requires
apoproteins to form lipoproteins.
Excess accumulation of triglycerides within the liver may
result from defects in any one of the events in the
sequence from fatty acid entry to lipoprotein exit.
 Morphology of Steatosis
Light microscopy: vacuoles in the
cytoplasm displacing the nucleus to the
periphery of the cell
Occasionally, contiguous cells rupture,
and the enclosed fat globules coalesce,
producing so-called fatty cysts
 Cholesterol and Cholesterol
Esters
- Cells use cholesterol for the synthesis of
cell membranes
- Accumulations in the form of intracellular
vacuoles, are seen in several pathologic
processes e.g. Atherosclerosis
 Cholesterol and Cholesterol
Esters
Atherosclerosis. In atherosclerotic plaques,
smooth muscle cells and macrophages within
the intimal layer of arteries are filled with lipid
vacuoles, most of which are made up of
cholesterol and cholesterol esters.
Some of these fat-laden cells rupture, releasing
lipids into the extracellular space.
The extracellular cholesterol esters may
crystallize in the shape of long needles,
producing clefts in tissue sections.
 Cholesterol and Cholesterol
Esters
Xanthomas. Intracellular accumulation of
cholesterol within macrophages is also
characteristic of acquired and hereditary
hyperlipidemic states seen in connective tissue
of the skin and in tendons.
Inflammation and necrosis. Foamy
macrophages are frequently found at sites of cell
injury and inflammation, owing to phagocytosis
of cholesterol from the membranes of injured
cells.
 Cholesterol and Cholesterol
Esters
Cholesterolosis. Accumulations of
cholesterol-laden macrophages in the
lamina propria of the gallbladder.
Niemann-Pick disease, type C. In this
lysosomal storage disease, an enzyme
involved in cholesterol trafficking is
mutated, and hence cholesterol
accumulates in multiple organs.
Russel bodies
 Hyaline change
An alteration within cells or in the extracellular space that
gives a homogeneous, glassy, pink appearance in routine
histologic sections stained with hematoxylin and eosin.
It is widely used as a descriptive histologic term rather than a
specific marker for cell injury. This morphologic change is
produced by a variety of alterations and does not represent a
specific pattern of accumulation.
Intracellular accumulations of protein example:
Russell bodies
Extracellular hyaline:
Collagenous fibrous tissue in old scars may appear hyalinized,
(the biochemical basis of this change is not clear)
In long-standing hypertension and diabetes mellitus, the walls of
arterioles, especially in the kidney, become hyalinized, resulting
from extravasated plasma protein and deposition of basement
membrane material.
 PIGMENTS

Pigments are colored substances, some of

which are normal constituents of cells
(e.g., melanin), whereas others are
abnormal and collect in cells only under
special circumstances.
Pigments can be exogenous, coming from
outside the body, or endogenous,
synthesized within the body itself
 Exogenous Pigments
Carbon
Silica
Iron dust
Lead
Argyria
 Exogenous Pigments

.The most common exogenous pigment is carbon

or coal dust, which is an air pollutant.
. When inhaled, it is picked up by macrophages
within the alveoli and is then transported through
lymphatic channels to the regional lymph nodes.
. Accumulations of this pigment blacken the tissues
of the lungs (anthracosis) and the involved lymph
nodes.
. In coal miners, the aggregates of carbon dust may
induce a fibroblastic reaction or even emphysema
and thus cause a serious lung disease known as
coal worker's pneumoconiosis .
 Exogenous Pigments
Tattooing is a form of localized, exogenous
pigmentation of the skin. The pigments
inoculated are phagocytosed by dermal
macrophages.
 Endogenous Pigments
Lipofuscin is an insoluble pigment, also known
as wear-and-tear or aging pigment.
Lipofuscin is not injurious to the cell or its
functions.
Its importance lies in its being the telltale sign of
free radical injury and lipid peroxidation.
In tissue sections, it appears as a yellow-brown,
finely granular intracytoplasmic, often
perinuclear pigment It is prominent in the liver
and heart of aging patients or patients with
severe malnutrition and cancer cachexia.
 Endogenous Pigments cont.
Melanin, is an endogenous, non-hemoglobin-
derived, brown-black pigment formed when the
enzyme tyrosinase catalyzes the oxidation of
tyrosine to dihydroxyphenylalanine in
melanocytes.
The other black pigment in this category is
homogentisic acid, a black pigment that occurs
in patients with alkaptonuria, a rare metabolic
disease. Here the pigment is deposited in the
skin, connective tissue, and cartilage, and the
pigmentation is known as ochronosis
 Endogenous Pigments cont.
Hemosiderin is a hemoglobin-derived, golden
yellow-to-brown, iron containing pigment in
cells.
Iron is normally stored in the form of ferritin
micelles. When there is a local or systemic
excess of iron, ferritin forms hemosiderin
granules, which are easily seen with the light
microscope.
Excesses of iron cause hemosiderin to
accumulate within cells, either as a localized
process or as a systemic derangement.
 Endogenous Pigments cont.
Local excesses of iron and hemosiderin
result from hemorrhages or vascular
congestion, eg hemosiderosis is the
common bruise.
With lysis of the erythrocytes, the
hemoglobin eventually undergoes
transformation to hemosiderin.
 Endogenous Pigments cont.
Systemic overload of iron, hemosiderin is
deposited in many organs and tissues, a
condition called hemosiderosis.
It is seen with: (1) increased absorption of
dietary iron, (2) impaired use of iron, (3)
hemolytic anemias, and (4) transfusions
because the transfused red cells constitute
an exogenous load of iron
 Endogenous Pigments cont.
Morphology. Iron pigment appears as a coarse,
golden, granular pigment lying within the cell's
cytoplasm usually in the macrophages.In severe
systemic hemosiderosis the pigment may
accumulate in the parenchymal cells throughout
the body (liver, pancreas, heart, and endocrine
organs).
Iron can be visualized in tissues by the Prussian
blue histochemical reaction, in which it appears
blue-black.
 Endogenous Pigments cont
In most cases of systemic hemosiderosis,
the pigment does not damage the
parenchymal cells or impair organ
function.
The more severe cases eg. a disease
called hemochromatosis, it resulting in
liver fibrosis, heart failure, and diabetes
mellitus
Hemosiderin granules
 Pathologic Calcification
Pathologic calcification is the abnormal
tissue deposition of calcium salts.
Two forms:
Dystrophic calcification:
When the deposition occurs locally in dying
tissues; it occurs despite normal serum levels of
calcium and in the absence of derangements in
calcium metabolism.
Metastatic calcification:
The deposition of calcium salts in otherwise normal
tissues, and it almost always results from
hypercalcemia secondary to some disturbance in
calcium metabolism.
 Dystrophic calcification
Seen in areas of necrosis and/or damage
eg.in the atheromas of advanced
atherosclerosis or in aging or damaged
heart valves.
Whatever the site of deposition, the
calcium salts appear macroscopically as
fine, white granules or clumps, often felt as
gritty deposits. Sometimes a tuberculous
lymph node is virtually converted to stone
 Morphology.
Histologically, calcium salts are
basophilic, amorphous granular. They can
be intracellular, extracellular, or both.
In the course of time, heterotopic bone
may be formed in the focus of calcification.
Progressive deposition on outer layers
may create lamellated configurations,
called psammoma bodies (papillary
cancers).
 Metastatic calcification
There are four principal causes of
hypercalcemia:
1) increased secretion of parathyroid hormone
(PTH) with subsequent bone resorption, as in
hyperparathyroidism
2) destruction of bone tissue: Bone tumors (e.g.,
multiple myeloma, leukemia) or metastatic
bone cancers, or immobilization
3) vitamin D-related disorders, including vitamin D
intoxication
4) renal failure, which causes retention of
phosphate, leading to secondary