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cellular adaptation presentation    (2)
Cellular Adaptation, Injury, and
Death
Hamnaz Beegum. P.P
1ST Year MDS
INTRODUCTION
– The cell (from latin word cella meaning “small room”) is
the basic structural and functional unit of an organ or tissue.
– The normal cell is confined to a fairly narrow range of
function and structure by its state of metabolism,
differentiation, and specialization by constraints of
neighboring cells; and by the availability of metabolic
substrates.
– It is nevertheless able to handle physiologic demands,
maintaining a steady state called homeostasis
Cellular Adaptation
as cells encounter stresses they undergo functional or structural
adaptations to maintain viability / homeostasis.
Injury - altered homeostasis
if limits of the adaptive response are exceeded or if adaptation
not possible, a sequence of events called cell injury occurs.
a)Reversible Cell Injury
removal of stress results in complete restoration of structural
& functional integrity.
b) Irreversible Cell Injury / Cell Death
if stimulus persists or is severe enough from the start, the cell
suffers irreversible cell injury and death.
2 main morphologic patterns: necrosis & apoptosis.
cellular adaptation presentation    (2)
CELLULAR ADAPTATION TO STRESS
– Adaptations are reversible changes in the size, number,
phenotype, metabolic activity, or functions of cells in
response to changes in their environment.
– Physiologic adaptations are responses of cells to normal
stimulation by hormones or endogenous chemical
mediators
– Pathologic adaptations are responses to stress that allow
cells to modulate their structure and function and thus
escape injury.
cellular adaptation presentation    (2)
HYPERTROPHY
– Hypertrophy refers to an increase in the size of cells,
that results in an increase in the size of the affected
organ
– The hypertrophied organ has no new cells, just larger
cells.
– Types:
a) physiologic b) pathologic
– Causes:
a) increased functional demand b) hormonal
stimulation
Physiologic hypertrophy
– Enlarged size of uterus in pregnancy
Pathologic hypertrophy
– Hypertrophy of cardiac muscle
e.g. : left ventricular hypertension
– Hypertrophy of smooth muscle
e.g. : Pyloric stenosis
– Hypertrophy of skeletal muscle
e.g. : In athletes & manual labours
Morphologic features
– The affected organ is enlarged and heavy.
– There is enlargement of muscle fibers and
nuclei.
– Increase synthesis of DNA and RNA.
– Increase protein synthesis, increase no. of
organelles like mitochondria endoplasmic
reticulum and myofibrils.
HYPERPLASIA
– Hyperplasia is defined as an increase in the number of cells in
an organ or tissue in response to a stimulus.
– Hyperplasia can only take place if the tissue contains cells
capable of dividing; thus increasing the number of cells.
– Types:
Physiologic hyperplasia
Pathologic hyperplasia
– Physiologic(action of hormones or growth factors )
• Female breast during pregnancy & puberty
• Liver - In individuals who donate one lobe of the liver for
transplantation, the remaining cells proliferate so that the organ
soon grows back to its original size.
– Pathologic(excessive or inappropriate actions of hormones or
growth factors acting on target cells)
• Endometrium – in response to hormones
• Hyperplasia of prostate in old age
• Epidermal hyperplasia (warts) in response to viral infection
Mechanisms of Hyperplasia
Hyperplasia is the result of growth factor-driven
proliferation of mature cells and, in some cases, by
increased output of new cells from tissue stem cells
ATROPHY
– Atrophy is defined as a reduction in the size of an organ or
tissue due to a decrease in cell size and number
PHYSIOLOGIC
• Embryonic structures – notochord, thyroglossal duct
• Post partum uterus
PATHOLOGIC
• Disuse atrophy
• Denervation atrophy
• Ischemic atrophy
• Loss of nutrition – Marasmus, cachexia
• Loss of endocrine stimulation
• Pressure atrophy
– Mechanisms of Atrophy
Atrophy results from,
 Decreased protein synthesis
 Increased protein degradation in cells
Morphological features
– Organ is small, often shrunken.
– Shrinkage of cell size is due to reduction in cell organelles,
chiefly mitochondria, myofilaments and endoplasmic
reticulum.
– Increase in the number of autophagic vacuoles.
METAPLASIA
– Metaplasia is a reversible change in which one differentiated
cell type (epithelial or mesenchymal) is replaced by another
cell type.
– the influences that predispose to metaplasia, if persistent, can
initiate malignant transformation in metaplastic epithelium
Types
– Epithelial metaplasia.
– Mesenchymal metaplasia.
Epithelial metaplasia
 More common type
 Results in stronger but less well specialized
epithelium.
 Depending upon the type of epithelium
transformed,
Squamous metaplasia
Columnar metaplasia
Squamous metaplasia
o In bronchus (normally lined by
pseudostratified columnar epithelium) in
chronic smokers.
o A deficiency of vitamin A (retinoic acid)
induces squamous metaplasia in the
respiratory epithelium
Columnar metaplasia
o Barrett esophagus, in which the esophageal
squamous epithelium is replaced by intestinal-like
columnar cells.
Columnar metaplasia oesophagus
(Barrett’s oesophagus).
Part of the oesophagus which is normally
lined by squamousepithelium undergoes
metaplastic change to columnar epithelium
of intestinal type
Mesenchymal metaplasia
 formation of cartilage, bone, or adipose tissue
(mesenchymal tissues) in tissues that normally do not
contain these elements.
 bone formation in muscle, designated myositis ossificans,
occasionally occurs after intramuscular hemorrhage.
 This type of metaplasia is less clearly seen as an adaptive
response, and may be a result of cell or tissue injury
Mechanisms of Metaplasia
• Reprogramming of stem cells that are known to
exist in normal tissues or of undifferentiated
mesenchymal cells present in connective tissue.
DYSPLASIA
– Dysplasia means ‘disordered cellular development’, often accompanied with
metaplasia and hyperplasia; it is therefore also referred to as atypical hyperplasia.
– Epithelial dysplasia is characterized by cellular proliferation and cytologic changes.
These changes include,
1. Increased number of layers of epithelial cells
2. Disorderly arrangement of cells from basal layer to the surface layer
3. Loss of basal polarity i.e. nuclei lying away from basement membrane
4. Cellular and nuclear pleomorphism
5. Increased nucleocytoplasmic ratio
6. Nuclear hyperchromatism
7. Increased mitotic activity.
– Dysplastic changes often occur due to, chronic irritation
or pstimulus, the changes may disappear.
– Dysplasia progresses into carcinoma in situ(cancer
confined to rolonged inflammation. On removal of the
inciting layers superficial to basement membrane)or
invasive cancer
Feature Metaplasia Dysplasia
i) Definition Change of one type of epithelial or
mesenchymal
cell to another type of adult epithelial or
mesenchymal cell
Disordered cellular development, may be
accompanied with hyperplasia or metaplasia
ii) Types Epithelial (squamous, columnar) and
mesenchymal (osseous, cartilaginous
Epithelial only
iii) Tissues affected Most commonly affects bronchial mucosa,
uterine endocervix; others mesenchymal
tissues (cartilage, arteries)
Uterine cervix, bronchial mucosa
iv) Cellular changes Mature cellular development Disordered cellular development
(pleomorphism, nuclear hyperchromasia,
mitosis, loss of polarity)
v) Natural history Reversible on withdrawal of stimulus May regress on removal of inciting stimulus,
or may progress to higher grades of
dysplasia or carcinoma in situ
CELL INJURY
– Cell injury results when,
• Cells are stressed so severely that they are no
longer able to adapt
• When cells are exposed to inherently damaging
agents
2 Types
o Reversible Injury
o Irreversible Injury
– Reversible Injury- injury that persists within certain limits, cells
return to a stable baseline
– Irreversible Injury- With continuing damage the injury becomes
irreversible, at which time the cell cannot recover and it dies.
a. Necrosis- Irreversible cell death caused due to blood flow
problems, diseases or injury.
b. Apoptosis-cell death that is induced by a tightly regulated
suicide program in which cells destined to die activate
intrinsic enzymes that degrade the cells’ own nuclear DNA
and nuclear and cytoplasmic proteins
CAUSES OF CELL INJURY
1. Hypoxia (deficiency of oxygen)
Causes:
a.Ischemia
b.Inadequate oxygenation of the blood
c.Reduction in the oxygen-carrying capacity of the blood
2. Chemical Agents
a.glucose, salt or oxygen
b.poisons
c.environmental toxins
d.therapeutic drugs
3. Physical agents
- trauma, extremes of temperature, radiation, electric
shock, & sudden changes in atmospheric pressure
4. Infectious agents
5. Immunologic reactions
Example: anaphylactic reaction to a foreign protein or a
drug reaction to self antigens
6. Genetic defects
Examples are genetic malformations associated with
Down Syndrome, sickle cell anaemia & inborn errors
of metabolism
7. Nutritional Imbalances
MECHANISMS OF CELL INJURY
– General principles of cell injury:
1. The cellular response to injurious stimuli depends on the nature
of the injury, its duration, and its severity.
2. The consequences of cell injury depend on the type, state, and
adaptability of the injured cell
3. Different biochemical mechanisms acting on several essential
cellular components
I. Depletion of ATP
II. Mitochondrial Damage
III. Influx of Calcium and Loss of Calcium Homeostasis
IV.Accumulation of Oxygen-Derived free radical (Oxidative
stress)
V. Defects in Membrane Permeability
Depletion of ATP
Mitochondrial Damage
– Three major consequences of mitochondrial damage.
 Mitochondrial damage often results in the formation of a high-
conductance channel in the mitochondrial membrane, called the
mitochondrial permeability transition pore. The opening of this
conductance channel leads to the loss of mitochondrial membrane
potential, resulting in failure of oxidative phosphorylation and
progressive depletion of ATP
 Abnormal oxidative phosphorylation also leads to the formation of
reactive oxygen species
 Increased permeability of the outer mitochondrial membrane may result
in leakage of proteins(cytochrome c and proteins ) that are capable of
activating apoptotic pathways into the cytosol and death by apoptosis
cellular adaptation presentation    (2)
Influx of Calcium and Loss of Calcium Homeostasis
Ca2+ levels direct
activation of caspases and by
increasing mitochondrial
permeability apoptosis
Ischemia and
certain toxins
Accumulation of Oxygen-Derived Free Radicals
(Oxidative Stress)
– Free radicals have an unpaired electron in their outer orbit
– Reactive oxygen species (ROS) are a type of oxygen derived free radical
– Increased production or decreased scavenging of ROS may lead to an excess of
these free radicals, a condition called oxidative stress.
– Generation of Free Radicals
– The reduction oxidation reactions that occur during normal metabolic process
In normal respiration, molecular O2 is reduced by the transfer of four
electrons to H2 to generate two water molecules. During this process partially reduced
intermediates are produced
superoxide anion (O2 • −, one electron), hydrogen peroxide (H2O2, two electrons),
and hydroxyl ions (˙OH, three electrons
 Absorption of radiant energy (e.g., ultraviolet light, x-rays). For
example, ionizing radiation can hydrolyze water into ˙OH and
hydrogen (H) free radicals.
Rapid bursts of ROS are produced in activated leukocytes during
inflammation.
 Enzymatic metabolism of exogenous chemicals or drugs can
generate free radicals.
Transition metals such as iron and copper donate or accept free
electrons during intracellular reactions and catalyze free radical
formation, as in the Fenton reaction
Nitric oxide (NO), an important chemical mediator generated by
endothelial cells, macrophages, neurons, and other cell types , can
act as a free radical and can also be converted to highly reactive
peroxynitrite anion (ONOO-) as well as NO2 and NO3
-.
cellular adaptation presentation    (2)
Defects in Membrane Permeability
REVERSIBLE INJURY
 In early stages or mild forms of injury, the
functional and morphologic changes are reversible
if the damaging stimulus is removed.
Morphology of reversible cell injury
Best examples are cellular swelling and fatty
change
• Cellular swelling(hydropic change or vacuolar degeneration)
oIt is the first manifestation of almost all forms of injury to cells
oCellular swelling appears whenever cells are incapable of
maintaining ionic and fluid homeostasis and is the result of
failure of energy-dependent ion pumps in the plasma membrane
o Gross - It causes some pallor, increased turgor, and increase in
weight of the organ.
o Light microscopy –
 The cells are swollen and the microvasculature are
compressed.
 small clear vacuoles may be seen within the cytoplasm; these
represent distended and pinched-off segments of the ER
 Cells may also show increased eosinophilic staining.
o ultrastructural changes
o Plasma membrane alterations, such as
blebbing, blunting, and loss of
microvilli
o Mitochondrial changes, including
swelling and the appearance of
small amorphous densities
o Dilation of the ER, with
detachment of polysomes;
intracytoplasmic myelin figures may
be present.
o Nuclear alterations, with disaggregation
of granular and fibrillar elements
Fatty changes (steatosis)
 Fatty change occurs in hypoxic injury and various
forms of toxic or metabolic injury.
 There is an abnormal accumulations of
triglycerides within parenchymal cells
 It is manifested by the appearance of lipid
vacuoles in the cytoplasm.
 It is seen mainly in cells involved in and
dependent on fat metabolism, such as
hepatocytes and myocardial cells.
NECROSIS
– The morphologic appearance of necrosis as well as
necroptosis is the result of denaturation of intracellular
proteins and enzymatic digestion of the lethally injured
cell.
– The enzymes responsible for digestion of the cell
are derived either from the:
1) Lysosomes of the dying cells themselves
2) lysosomes of leukocytes that are recruited as
part of the inflammatory reaction to the dead cells
Morphologic alterations in Necrosis
– Increased eosinophilia in hematoxylin and eosin (H&E) stains
– The cytoplasm becomes vacuolated and appears moth-eaten.
– Myelin figures (whorled phospholipid masses)
– Nuclear changes assume one of three patterns all due to
breakdown of DNA & chromatin:
1) Karyolysis : Dissolution of cell nucleus.
2) Pyknosis characterized by nuclear shrinkage and
increased basophila
3) Karyorrhexis – fragmentation and dissolution
– Breakdown of plasma and organellar membranes
– Leakage and enzymatic digestion of cellular contents
Patterns of Tissue Necrosis
– The morphology of necrosis can be explained in
following tissue patterns
• Coagulative necrosis
• Liquefactive necrosis
• Gangrenous necrosis
• Caseous necrosis
• Fat necrosis
• Fibrinoid necrosis
Coagulative Necrosis
➢A form of tissue necrosis in which the
component cells are dead but the basic tissue
architecture is preserved for at least several
days
➢ It is characteristics of infarcts ( areas of
ischemic necrosis) in all solid organs except
the brain.
A wedge-shaped kidney Infarct
(yellow) with preservation of the
outlines
– The injury denatures not only structural
proteins but also enzymes and so blocks the
proteolysis of the dead cells.
– Cause is mainly Ischemia caused by
obstruction in a vessel
– A localized area of coagulative necrosis is
called an infarct.
Liquefactive necrosis
– In contrast to coagulative necrosis, is
characterized by digestion of the dead
cells, resulting in transformation of the
tissue into a liquid viscous mass.
– The necrotic material is frequently
creamy yellow because of the presence
of dead leukocytes and is called pus.
– Best example is necrosis in brain
Gangrenous necrosis (wet gangrene)
– It is a type of coagulative necrosis with superimposed
bacterial infection.
– It is seen in multiple tissue planes
– Best example is a limb, generally the lower leg, that
has lost its blood supply
Caseous necrosis
– Caseous necrosis is encountered most often in
foci of tuberculous infection
– The term “caseous” (cheese like) is derived
from the friable white appearance of the area
of necrosis.
– On microscopic examination, the necrotic area
appears as a structureless collection of
fragmented or lysed cells and amorphous
granular debris enclosed within a distinctive
inflammatory border; this appearance is
characteristic of a focus of inflammation
known as a granuloma
Fat Necrosis
– Refers to focal areas of fat destruction,
typically resulting from release of activated
pancreatic lipases into the substance of the
pancreas and the peritoneal cavity
– Occurs in acute pancreatitis
– On histologic examination the necrosis takes
the form of foci of shadowy outlines of
necrotic fat cells, with basophilic calcium
deposits, surrounded by an inflammatory
reaction.
Fibrinoid necrosis
– Fibrinoid necrosis is a special form of necrosis
usually seen in immune reactions involving blood
vessels.
– This pattern of necrosis typically occurs when
complexes of antigens and antibodies are deposited
in the walls of arteries.
– Deposits of these “immune complexes,” together
with fibrin that has leaked out of vessels, result in a
bright pink and amorphous appearance in H&E
stains, called “fibrinoid” (fibrin-like) by
pathologists.
APOPTOSIS
– Apoptosis is a pathway of cell death that is induced by a
tightly regulated suicide program in which cells destined
to die activate intrinsic enzymes that degrade the cells’
own nuclear DNA and nuclear and cytoplasmic proteins.
– Apoptotic cells break up into fragments, called apoptotic
bodies(portions of the cytoplasm and nucleus)
– Because cellular contents do not leak out, unlike in
necrosis, there is no inflammatory reaction.
Causes of Apoptosis
– Apoptosis in Physiologic Situations
 The destruction of cells during embryogenesis
 Physiologic involution of cells in hormone-dependent tissues
e.g. endometrial shedding, regression of lactating breast after
withdrawal of breast-feeding
 Cell loss in proliferating cell populations
e.g. immature lymphocytes in the bone marrow and thymus and B
lymphocytes in germinal centers that fail to express useful antigen
receptors
 Death of host cells that have served their useful purpose, such as
neutrophils in an acute inflammatory response, and lymphocytes at the
end of an immune response
– Apoptosis in Pathologic Conditions
 DNA damage; Radiation, cytotoxic anticancer drugs, and hypoxia
can damage DNA, either directly or via production of free radicals
 Accumulation of misfolded proteins ; Excessive accumulation of
misfolded proteins in the ER leads to a condition called ER stress,
which culminates in apoptotic cell death.
 Cell death in certain infections, particularly viral infections, in
which loss of infected cells is largely due to apoptosis that may be
induced by the virus (as in adenovirus and HIV infections) or by the
host immune response (as in viral hepatitis).
MORPHOLOGIC CHANGES IN APOPTOSIS
– Cell shrinkage. The cell is smaller in size; the
cytoplasm is dense and the organelles, though
relatively normal, are more tightly packed .
– Chromatin condensation. This is the most
characteristic feature of apoptosis. The chromatin
aggregates peripherally, under the nuclear
membrane, into dense masses of various shapes and
sizes .The nucleus itself may break up, producing
two or more fragments
– Formation of cytoplasmic blebs and apoptotic
bodies. The apoptotic cell first shows extensive
surface blebbing, then undergoes fragmentation into
membrane-bound apoptotic bodies composed of
cytoplasm and tightly packed organelles, with or
without nuclear fragments
– Phagocytosis of apoptotic cells or cell bodies,
usually by macrophages. The apoptotic bodies
are rapidly ingested by phagocytes and
degraded by the phagocyte’s lysosomal
enzymes
MECHANISMS OF APOPTOSIS
– Two Major Pathways in the Initiation of Apopotosis
1) Mitochondrial ( intrinsic) pathway
Triggered by loss of survival signals, DNA damage and
accumulation of misfolded proteins (ER stress)
2) Death receptor (extrinsic) pathway
Responsible for the elimination of self-reactive lymphocytes
and damage by cytotoxic T lymphocytes
Mitochondrial ( intrinsic) pathway
– It is the major mechanism of apoptosis in all mammalian cells
– It results from increased permeability of the mitochondrial
outer membrane with consequent release of death-inducing
(pro-apoptotic) molecules from the mitochondrial
intermembrane space into the cytoplasm .
– The release of mitochondrial pro-apoptotic proteins is tightly
controlled by the BCL2 family
a.Antiapoptotic:BCL2, BCL-XL, and MCL1
b.Proapoptotic. BAX and BAK
c.Sensors. Members of this group, including BAD, BIM, BID,
Puma, and Noxa , act as sensors of cellular stress and damage
cellular adaptation presentation    (2)
Smac/Diablo
Death receptor (extrinsic) pathway
– This pathway is initiated by engagement of plasma membrane
death receptors on a variety of cells
– Death receptors are members of the TNF receptor family that
contain a cytoplasmic domain involved in protein-protein
interactions that is called the death domain
– The best known death receptors are the type 1 TNF receptor
(TNFR1) and a related protein called Fas
– The ligand for Fas is called Fas ligand (FasL). FasL is
expressed on T cells that recognize self antigens
– When FasL binds to Fas, three or more
molecules of Fas are brought together, and
their cytoplasmic death domains form a
binding site for an adaptor protein that also
contains a death domain and is called FADD
(Fas-associated death domain).
– FADD that is attached to the death
receptors in turn binds an inactive form of
caspase-8 (and, in humans, caspase-10),
again via a death domain
– FLIP, which binds to pro-caspase-8 but
cannot cleave and activate the caspase
because it lacks a protease domain
Execution Phase of Apoptosis
– The two initiating pathways converge to a cascade of
caspase activation, which mediates the final phase of
apoptosis
– Executioner caspases (caspase-3 and -6) cleave an inhibitor
of a cytoplasmic DNase and thus make the DNase
enzymatically active, this enzyme induces cleavage of DNA
– Caspases also degrade structural components of the nuclear
matrix and thus promote fragmentation of nuclei
Removal of Dead Cells
– The formation of apoptotic bodies breaks cells up into “bite-sized”
fragments that are edible for phagocytes
– Phosphatidylserine is present on the inner leaflet of the plasma
membrane, but in apoptotic cells this phospholipid “flips” out and is
expressed on the outer layer of the membrane, where it is recognized by
several macrophage receptors.
– Cells that are dying by apoptosis secrete soluble factors that recruit
phagocytes.
INTRACELLULAR ACCUMULATIONS
– One of the manifestations of metabolic derangements
in cells is the intracellular accumulation of abnormal
amounts of various substances that may be harmless
or associated with 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 may be produced elsewhere.
Four main pathways of abnormal intracellular
accumulations
– Inadequate removal of a normal substance
secondary to defects in mechanisms of packaging
and transport, as in fatty change (steatosis) in the
liver
– Accumulation of an abnormal endogenous
substance as a result of genetic or acquired defects
in its folding, packaging, transport, or secretion,
as with certain mutated forms of α1-antitrypsin
– Failure to degrade a metabolite due to inherited
enzyme deficiencies. The resulting disorders
are called storage diseases .
– Deposition and accumulation of an abnormal
exogenous substance when the cell has neither
the enzymatic machinery to degrade the
substance nor the ability to transport it to other
sites. Accumulation of carbon or silica
particles is an example of this type of
alteration.
cellular adaptation presentation    (2)
Lipids
Steatosis (Fatty Change)
– The terms steatosis and fatty change describe
abnormal accumulations of triglycerides within
parenchymal cells
– Most often seen in the liver but may also occur in
the heart, Skeletal muscle, kidney and other
organs
– May be caused by toxins, protein malnutrition,
diabetes mellitus, obesity and anoxia
– Alcohol abuse and diabetes associated with
obesity are the most common causes of fatty
liver
Cholesterol and Cholesterol Esters
– Atherosclerosis: In atherosclerotic plaques, smooth
muscle cells and macrophages within the intimal layer
of the aorta and large arteries are filled with lipid
vacuoles, most of which are made up of cholesterol and
cholesterol esters.
– Xanthomas: Intracellular accumulation of cholesterol
within macrophages is also characteristic of acquired
and hereditary hyperlipidemic states
– Clusters of foamy cells are found in the subepithelial
connective tissue of the skin and in tendons, producing
tumorous masses known as xanthomas.
– Cholesterolosis: This refers to the focal
accumulations of cholesterol-laden
macrophages in the lamina propria of the
gallbladder. The mechanism of
accumulation is unknown.
– NiemannPick disease, type C. This
lysosomal storage disease is caused by
mutations affecting an enzyme involved in
cholesterol trafficking, resulting in
cholesterol accumulation in multiple
organs
Proteins
– Intracellular accumulations of proteins usually appear as
rounded, eosinophilic droplets, vacuoles, or aggregates in the
cytoplasm.
– By electron microscopy they can be amorphous, fibrillar, or
crystalline in appearance
 Reabsorption droplets in proximal renal tubules are seen in
renal diseases associated with protein loss in the urine
(proteinuria).
 protein appears as pink hyaline droplets within the cytoplasm of
the tubular cell
 The process is reversible; if the proteinuria diminishes, the
protein droplets are metabolized and disappear.
– Defective intracellular transport and secretion of
critical proteins: In α1-antitrypsin deficiency, mutations
in the protein significantly slow folding, resulting in the
buildup of partially folded intermediates, which aggregate
in the ER of the liver and are not secreted
– Aggregation of abnormal proteins: Abnormal or
misfolded proteins may deposit in tissues and interfere
with normal functions. The deposits can be intracellular,
extracellular, or both, and the aggregates may either
directly or indirectly cause the pathologic changes.
Certain forms of amyloidosis
Hyaline Change
– The term hyaline usually refers to 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.
– This morphologic change is produced by a variety of
alterations and does not represent a specific pattern of
accumulation.
Glycogen
– Glycogen is a readily available energy
source stored in the cytoplasm of healthy
cells. Excessive intracellular deposits of
glycogen are seen in patients with an
abnormality in either glucose or glycogen
metabolism.
– Glycogen masses appear as clear vacuoles
within the cytoplasm.
Pigments
Exogenous Pigments
– Exogenous pigments are the pigments introduced into the
body from outside such as by inhalation, ingestion or
inoculation.
– The most common exogenous pigment is carbon (coal
dust), a ubiquitous air pollutant in urban areas.
ANTHRACOSIS
– When inhaled Carbon 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
and the involved lymph nodes.
COAL WORKER’S PNEUMOCONIOSIS
– In coal miners the aggregates of carbon dust may induce a
fibroblastic reaction or even emphysema and thus cause a
serious lung disease
TATTOOING
– is a form of localized, exogenous pigmentation of the skin. The
pigments inoculated are phagocytosed by dermal macrophages,
in which they reside for the remainder of the life of the
embellished
– The pigments do not usually evoke any Inflammatory response.
Endogenous Pigments
Lipofuscin (lipochrome or wear-and-tear pigment)
– An insoluble brownish-yellow granular intracellular
material that accumulates in the heart, liver, & brain
as a function of age or atrophy represents complexes
of lipid & protein that derive from the free radical-
catalyzed peroxidation of polyunsaturated lipids
–It is not injurious to the cell but is important as 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
Melanin
– is an endogenous, brown-black, pigment formed
when the enzyme tyrosinase catalyses the
oxidation of tyrosine to dihydroxyphenyl alanine
in melanocytes
Homogentisic acid
– Black pigment that occurs in patients with
alkaptonuria
– Here the pigment is deposited in the skin,
connective tissue, and cartilage, and the
pigmentation is known as ochronosis
Hemosiderin
– Hemoglobin-derived, golden yellow to brown, granular or
crystalline pigment is one of the major storage forms of iron
– When there is systemic overload of iron hemosiderin may be
deposited in many organs and tissues, a condition called
hemosiderosis.
– The main causes of hemosiderosis are
(1) increased absorption of dietary iron due to an inborn
error of metabolism called hemochromatosis
(2) hemolytic anemias, in which premature lysis of red cells
leads to release of abnormal quantities of iron,
(3) repeated blood transfusions, because transfused red
cells constitute an exogenous load of iron
PATHOLOGIC CALCIFICATION
– Pathologic calcification is the abnormal tissue deposition of calcium salts,
together with smaller amounts of iron, magnesium, and other mineral salts
– Types
 Dystrophic
• deposition occurs locally in dying tissues
• it occurs despite normal serum levels of calcium
• In absence of derangements in calcium metabolism
 Metastatic
• deposition of calcium salts in otherwise normal tissues
• results from hypercalcemia
• secondary to some disturbance in calcium metabolism.
Dystrophic calcification
– Dystrophic calcification is encountered in areas of necrosis
– Examples
• in the atheromas of advanced atherosclerosis
• develops in aging or damaged heart valves
– Morphology
• Gross
- fine, white granules or clumps, often felt as gritty deposits
• Microscopy –
– intracellular or extracellular, basophilic, amorphous granular, sometimes clumped
appearance
– The progressive acquisition of outer layers may create lamellated configurations,
called psammoma bodies – In papillary lesions of thyroid, meningiomas etc
– In asbestosis of the lung, iron and calcium deposition creates dumbbell shaped forms
Metastatic Calcification
Metastatic calcification may occur in normal tissues whenever there is
hypercalcemia
Four major causes of hypercalcemia
1) Increased secretion of parathyroid hormone, due to either 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 like vitamin D intoxication and sarcoidosis
( in which macrophages activate a vitamin D precursor )
4) Renal failure, in which phosphate retention leads to secondary
hyperparathyroidism
cellular adaptation presentation    (2)
CELLULAR AGING
– Cellular aging is the result of a progressive decline in cellular function and
viability caused by genetic abnormalities and the accumulation of cellular
and molecular damage due to the effects of exposure to exogenous
influences
DNA Damage
–A variety of exogenous (physical, chemical, and biologic)
agents and endogenous factors such as ROS threaten the
integrity of nuclear and mitochondrial DNA
–Although most DNA damage is repaired by DNA repair
enzymes, some persists and accumulates as cells age.
– Patients with Werner syndrome show premature
aging, and the defective gene product is a DNA
helicase, a protein involved in DNA replication and
repair and other functions requiring DNA unwinding.
– A defect in this enzyme causes rapid accumulation of
chromosomal damage that may mimic the injury that
normally accumulates during cellular aging.
– Cellular Senescence: All normal cells have a limited capacity for
replication, and after a fixed number of divisions cells become
arrested in a terminally nondividing state, known as replicative
senescence
Mechanisms cellular senescence:
 Telomere attrition: One mechanism of replicative senescence
involves progressive shortening of telomeres, which ultimately
results in cell cycle arrest.
 Telomeres are short repeated sequences of DNA (TTAGGG) present
at the linear ends of chromosomes that are important for ensuring
the complete replication of chromosomal ends and for protecting
chromosomal termini from fusion and degradation.
– Telomere length is normally maintained by nucleotide addition
mediated by an enzyme called telomerase.
– Telomerase is a specialized RNA-protein complex that uses its own
RNA as a template for adding nucleotides to the ends of
chromosomes.
– Telomerase activity is highest in germ cells and present at lower
levels in stem cells, but it is usually undetectable in most somatic
tissues Therefore, as somatic cells divide, their telomeres become
shorter, and they exit the cell cycle, resulting in an inability to
generate new cells to replace damaged ones.
cellular adaptation presentation    (2)
Defective Protein Homeostasis:
– Protein homeostasis involves two mechanisms:
those that maintain proteins in there correctly folded
conformations
that degrade misfolded proteins by the autophagy-lysosome
system and ubiquitin-proteasome system.
• Both normal folding and degradation of misfolded proteins are
impaired with aging
• Mutant mice deficient in chaperones of the heat shock protein
family age rapidly, and conversely, those that overexpress such
chaperones are long-lived
Nutrient sensing system
– Caloric restriction increases longevity.
– Two major neurohormonal circuits that regulate metabolism,
 Insulin and insulin like growth factor 1 (IGF1) signaling
pathway.
• IGF-1 is produced in many cell types in response to growth
hormone secretion by the pituitary. IGF-1, as indicated by its
name, mimics intracellular signaling by insulin and thereby
informs the cells of the availability of glucose, promoting an
anabolic state as well as cell growth and replication.
 Sirtuins: Sirtuins are a family of NAD-dependent protein
deacetylases.
• Functions to adapt various environmental stresses, including
food deprivation and DNA damage.
• Sirtuins are thought to promote the expression of several genes
whose products increase longevity.
•These include proteins that inhibit metabolic activity, reduce
apoptosis, stimulate protein folding, and inhibit the harmful
effects of oxygen free radicals.
 caloric restriction increases longevity both by reducing the
signaling intensity of the IGF-1 pathway and by increasing sirtuins.
CONCLUSION
– Cells are the basic structural units of tissues ,which form organs and systems in
the human body. In health, the cells remain in accord with each other.
– In general, cells of the body have inbuilt mechanism to deal with changes in
environment to an extent.
– The cellular response to stress may vary and depends upon many variables.
– Study of abnormalities in structure and function of cells in disease has remained
the focus of attention in understanding of diseases.
– Most forms of diseases begin with cell injury followed by consequent loss of
cellular function.
– In order to learn the fundamentals of disease processes at cellular level, it is
essential to have an understanding of the causes and mechanisms of cell injury
and cellular adaptations.
REFERENCES
– Textbook of pathology- Robbin’s 8th edn &9TH edition
– Cell biology and signaling ; Ali El Baya
cellular adaptation presentation    (2)

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cellular adaptation presentation (2)

  • 2. Cellular Adaptation, Injury, and Death Hamnaz Beegum. P.P 1ST Year MDS
  • 3. INTRODUCTION – The cell (from latin word cella meaning “small room”) is the basic structural and functional unit of an organ or tissue. – The normal cell is confined to a fairly narrow range of function and structure by its state of metabolism, differentiation, and specialization by constraints of neighboring cells; and by the availability of metabolic substrates. – It is nevertheless able to handle physiologic demands, maintaining a steady state called homeostasis
  • 4. Cellular Adaptation as cells encounter stresses they undergo functional or structural adaptations to maintain viability / homeostasis. Injury - altered homeostasis if limits of the adaptive response are exceeded or if adaptation not possible, a sequence of events called cell injury occurs. a)Reversible Cell Injury removal of stress results in complete restoration of structural & functional integrity. b) Irreversible Cell Injury / Cell Death if stimulus persists or is severe enough from the start, the cell suffers irreversible cell injury and death. 2 main morphologic patterns: necrosis & apoptosis.
  • 6. CELLULAR ADAPTATION TO STRESS – Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. – Physiologic adaptations are responses of cells to normal stimulation by hormones or endogenous chemical mediators – Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury.
  • 8. HYPERTROPHY – Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ – The hypertrophied organ has no new cells, just larger cells. – Types: a) physiologic b) pathologic – Causes: a) increased functional demand b) hormonal stimulation
  • 9. Physiologic hypertrophy – Enlarged size of uterus in pregnancy Pathologic hypertrophy – Hypertrophy of cardiac muscle e.g. : left ventricular hypertension – Hypertrophy of smooth muscle e.g. : Pyloric stenosis – Hypertrophy of skeletal muscle e.g. : In athletes & manual labours
  • 10. Morphologic features – The affected organ is enlarged and heavy. – There is enlargement of muscle fibers and nuclei. – Increase synthesis of DNA and RNA. – Increase protein synthesis, increase no. of organelles like mitochondria endoplasmic reticulum and myofibrils.
  • 11. HYPERPLASIA – Hyperplasia is defined as an increase in the number of cells in an organ or tissue in response to a stimulus. – Hyperplasia can only take place if the tissue contains cells capable of dividing; thus increasing the number of cells. – Types: Physiologic hyperplasia Pathologic hyperplasia
  • 12. – Physiologic(action of hormones or growth factors ) • Female breast during pregnancy & puberty • Liver - In individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size. – Pathologic(excessive or inappropriate actions of hormones or growth factors acting on target cells) • Endometrium – in response to hormones • Hyperplasia of prostate in old age • Epidermal hyperplasia (warts) in response to viral infection
  • 13. Mechanisms of Hyperplasia Hyperplasia is the result of growth factor-driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells
  • 14. ATROPHY – Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number
  • 15. PHYSIOLOGIC • Embryonic structures – notochord, thyroglossal duct • Post partum uterus PATHOLOGIC • Disuse atrophy • Denervation atrophy • Ischemic atrophy • Loss of nutrition – Marasmus, cachexia • Loss of endocrine stimulation • Pressure atrophy
  • 16. – Mechanisms of Atrophy Atrophy results from,  Decreased protein synthesis  Increased protein degradation in cells
  • 17. Morphological features – Organ is small, often shrunken. – Shrinkage of cell size is due to reduction in cell organelles, chiefly mitochondria, myofilaments and endoplasmic reticulum. – Increase in the number of autophagic vacuoles.
  • 18. METAPLASIA – Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. – the influences that predispose to metaplasia, if persistent, can initiate malignant transformation in metaplastic epithelium Types – Epithelial metaplasia. – Mesenchymal metaplasia.
  • 19. Epithelial metaplasia  More common type  Results in stronger but less well specialized epithelium.  Depending upon the type of epithelium transformed, Squamous metaplasia Columnar metaplasia
  • 20. Squamous metaplasia o In bronchus (normally lined by pseudostratified columnar epithelium) in chronic smokers. o A deficiency of vitamin A (retinoic acid) induces squamous metaplasia in the respiratory epithelium
  • 21. Columnar metaplasia o Barrett esophagus, in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells. Columnar metaplasia oesophagus (Barrett’s oesophagus). Part of the oesophagus which is normally lined by squamousepithelium undergoes metaplastic change to columnar epithelium of intestinal type
  • 22. Mesenchymal metaplasia  formation of cartilage, bone, or adipose tissue (mesenchymal tissues) in tissues that normally do not contain these elements.  bone formation in muscle, designated myositis ossificans, occasionally occurs after intramuscular hemorrhage.  This type of metaplasia is less clearly seen as an adaptive response, and may be a result of cell or tissue injury
  • 23. Mechanisms of Metaplasia • Reprogramming of stem cells that are known to exist in normal tissues or of undifferentiated mesenchymal cells present in connective tissue.
  • 24. DYSPLASIA – Dysplasia means ‘disordered cellular development’, often accompanied with metaplasia and hyperplasia; it is therefore also referred to as atypical hyperplasia. – Epithelial dysplasia is characterized by cellular proliferation and cytologic changes. These changes include, 1. Increased number of layers of epithelial cells 2. Disorderly arrangement of cells from basal layer to the surface layer 3. Loss of basal polarity i.e. nuclei lying away from basement membrane 4. Cellular and nuclear pleomorphism 5. Increased nucleocytoplasmic ratio 6. Nuclear hyperchromatism 7. Increased mitotic activity.
  • 25. – Dysplastic changes often occur due to, chronic irritation or pstimulus, the changes may disappear. – Dysplasia progresses into carcinoma in situ(cancer confined to rolonged inflammation. On removal of the inciting layers superficial to basement membrane)or invasive cancer
  • 26. Feature Metaplasia Dysplasia i) Definition Change of one type of epithelial or mesenchymal cell to another type of adult epithelial or mesenchymal cell Disordered cellular development, may be accompanied with hyperplasia or metaplasia ii) Types Epithelial (squamous, columnar) and mesenchymal (osseous, cartilaginous Epithelial only iii) Tissues affected Most commonly affects bronchial mucosa, uterine endocervix; others mesenchymal tissues (cartilage, arteries) Uterine cervix, bronchial mucosa iv) Cellular changes Mature cellular development Disordered cellular development (pleomorphism, nuclear hyperchromasia, mitosis, loss of polarity) v) Natural history Reversible on withdrawal of stimulus May regress on removal of inciting stimulus, or may progress to higher grades of dysplasia or carcinoma in situ
  • 27. CELL INJURY – Cell injury results when, • Cells are stressed so severely that they are no longer able to adapt • When cells are exposed to inherently damaging agents 2 Types o Reversible Injury o Irreversible Injury
  • 28. – Reversible Injury- injury that persists within certain limits, cells return to a stable baseline – Irreversible Injury- With continuing damage the injury becomes irreversible, at which time the cell cannot recover and it dies. a. Necrosis- Irreversible cell death caused due to blood flow problems, diseases or injury. b. Apoptosis-cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins
  • 29. CAUSES OF CELL INJURY 1. Hypoxia (deficiency of oxygen) Causes: a.Ischemia b.Inadequate oxygenation of the blood c.Reduction in the oxygen-carrying capacity of the blood 2. Chemical Agents a.glucose, salt or oxygen b.poisons c.environmental toxins d.therapeutic drugs
  • 30. 3. Physical agents - trauma, extremes of temperature, radiation, electric shock, & sudden changes in atmospheric pressure 4. Infectious agents 5. Immunologic reactions Example: anaphylactic reaction to a foreign protein or a drug reaction to self antigens 6. Genetic defects Examples are genetic malformations associated with Down Syndrome, sickle cell anaemia & inborn errors of metabolism 7. Nutritional Imbalances
  • 31. MECHANISMS OF CELL INJURY – General principles of cell injury: 1. The cellular response to injurious stimuli depends on the nature of the injury, its duration, and its severity. 2. The consequences of cell injury depend on the type, state, and adaptability of the injured cell 3. Different biochemical mechanisms acting on several essential cellular components
  • 32. I. Depletion of ATP II. Mitochondrial Damage III. Influx of Calcium and Loss of Calcium Homeostasis IV.Accumulation of Oxygen-Derived free radical (Oxidative stress) V. Defects in Membrane Permeability
  • 34. Mitochondrial Damage – Three major consequences of mitochondrial damage.  Mitochondrial damage often results in the formation of a high- conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore. The opening of this conductance channel leads to the loss of mitochondrial membrane potential, resulting in failure of oxidative phosphorylation and progressive depletion of ATP  Abnormal oxidative phosphorylation also leads to the formation of reactive oxygen species  Increased permeability of the outer mitochondrial membrane may result in leakage of proteins(cytochrome c and proteins ) that are capable of activating apoptotic pathways into the cytosol and death by apoptosis
  • 36. Influx of Calcium and Loss of Calcium Homeostasis Ca2+ levels direct activation of caspases and by increasing mitochondrial permeability apoptosis Ischemia and certain toxins
  • 37. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) – Free radicals have an unpaired electron in their outer orbit – Reactive oxygen species (ROS) are a type of oxygen derived free radical – Increased production or decreased scavenging of ROS may lead to an excess of these free radicals, a condition called oxidative stress. – Generation of Free Radicals – The reduction oxidation reactions that occur during normal metabolic process In normal respiration, molecular O2 is reduced by the transfer of four electrons to H2 to generate two water molecules. During this process partially reduced intermediates are produced superoxide anion (O2 • −, one electron), hydrogen peroxide (H2O2, two electrons), and hydroxyl ions (˙OH, three electrons
  • 38.  Absorption of radiant energy (e.g., ultraviolet light, x-rays). For example, ionizing radiation can hydrolyze water into ˙OH and hydrogen (H) free radicals. Rapid bursts of ROS are produced in activated leukocytes during inflammation.  Enzymatic metabolism of exogenous chemicals or drugs can generate free radicals. Transition metals such as iron and copper donate or accept free electrons during intracellular reactions and catalyze free radical formation, as in the Fenton reaction Nitric oxide (NO), an important chemical mediator generated by endothelial cells, macrophages, neurons, and other cell types , can act as a free radical and can also be converted to highly reactive peroxynitrite anion (ONOO-) as well as NO2 and NO3 -.
  • 40. Defects in Membrane Permeability
  • 41. REVERSIBLE INJURY  In early stages or mild forms of injury, the functional and morphologic changes are reversible if the damaging stimulus is removed. Morphology of reversible cell injury Best examples are cellular swelling and fatty change
  • 42. • Cellular swelling(hydropic change or vacuolar degeneration) oIt is the first manifestation of almost all forms of injury to cells oCellular swelling appears whenever cells are incapable of maintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane
  • 43. o Gross - It causes some pallor, increased turgor, and increase in weight of the organ. o Light microscopy –  The cells are swollen and the microvasculature are compressed.  small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the ER  Cells may also show increased eosinophilic staining.
  • 44. o ultrastructural changes o Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli o Mitochondrial changes, including swelling and the appearance of small amorphous densities o Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figures may be present. o Nuclear alterations, with disaggregation of granular and fibrillar elements
  • 45. Fatty changes (steatosis)  Fatty change occurs in hypoxic injury and various forms of toxic or metabolic injury.  There is an abnormal accumulations of triglycerides within parenchymal cells  It is manifested by the appearance of lipid vacuoles in the cytoplasm.  It is seen mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells.
  • 46. NECROSIS – The morphologic appearance of necrosis as well as necroptosis is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell. – The enzymes responsible for digestion of the cell are derived either from the: 1) Lysosomes of the dying cells themselves 2) lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells
  • 47. Morphologic alterations in Necrosis – Increased eosinophilia in hematoxylin and eosin (H&E) stains – The cytoplasm becomes vacuolated and appears moth-eaten. – Myelin figures (whorled phospholipid masses) – Nuclear changes assume one of three patterns all due to breakdown of DNA & chromatin: 1) Karyolysis : Dissolution of cell nucleus. 2) Pyknosis characterized by nuclear shrinkage and increased basophila 3) Karyorrhexis – fragmentation and dissolution – Breakdown of plasma and organellar membranes – Leakage and enzymatic digestion of cellular contents
  • 48. Patterns of Tissue Necrosis – The morphology of necrosis can be explained in following tissue patterns • Coagulative necrosis • Liquefactive necrosis • Gangrenous necrosis • Caseous necrosis • Fat necrosis • Fibrinoid necrosis
  • 49. Coagulative Necrosis ➢A form of tissue necrosis in which the component cells are dead but the basic tissue architecture is preserved for at least several days ➢ It is characteristics of infarcts ( areas of ischemic necrosis) in all solid organs except the brain. A wedge-shaped kidney Infarct (yellow) with preservation of the outlines
  • 50. – The injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells. – Cause is mainly Ischemia caused by obstruction in a vessel – A localized area of coagulative necrosis is called an infarct.
  • 51. Liquefactive necrosis – In contrast to coagulative necrosis, is characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass. – The necrotic material is frequently creamy yellow because of the presence of dead leukocytes and is called pus. – Best example is necrosis in brain
  • 52. Gangrenous necrosis (wet gangrene) – It is a type of coagulative necrosis with superimposed bacterial infection. – It is seen in multiple tissue planes – Best example is a limb, generally the lower leg, that has lost its blood supply
  • 53. Caseous necrosis – Caseous necrosis is encountered most often in foci of tuberculous infection – The term “caseous” (cheese like) is derived from the friable white appearance of the area of necrosis. – On microscopic examination, the necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma
  • 54. Fat Necrosis – Refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity – Occurs in acute pancreatitis – On histologic examination the necrosis takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium deposits, surrounded by an inflammatory reaction.
  • 55. Fibrinoid necrosis – Fibrinoid necrosis is a special form of necrosis usually seen in immune reactions involving blood vessels. – This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. – Deposits of these “immune complexes,” together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists.
  • 56. APOPTOSIS – Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins. – Apoptotic cells break up into fragments, called apoptotic bodies(portions of the cytoplasm and nucleus) – Because cellular contents do not leak out, unlike in necrosis, there is no inflammatory reaction.
  • 57. Causes of Apoptosis – Apoptosis in Physiologic Situations  The destruction of cells during embryogenesis  Physiologic involution of cells in hormone-dependent tissues e.g. endometrial shedding, regression of lactating breast after withdrawal of breast-feeding  Cell loss in proliferating cell populations e.g. immature lymphocytes in the bone marrow and thymus and B lymphocytes in germinal centers that fail to express useful antigen receptors  Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response
  • 58. – Apoptosis in Pathologic Conditions  DNA damage; Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly or via production of free radicals  Accumulation of misfolded proteins ; Excessive accumulation of misfolded proteins in the ER leads to a condition called ER stress, which culminates in apoptotic cell death.  Cell death in certain infections, particularly viral infections, in which loss of infected cells is largely due to apoptosis that may be induced by the virus (as in adenovirus and HIV infections) or by the host immune response (as in viral hepatitis).
  • 59. MORPHOLOGIC CHANGES IN APOPTOSIS – Cell shrinkage. The cell is smaller in size; the cytoplasm is dense and the organelles, though relatively normal, are more tightly packed . – Chromatin condensation. This is the most characteristic feature of apoptosis. The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes .The nucleus itself may break up, producing two or more fragments
  • 60. – Formation of cytoplasmic blebs and apoptotic bodies. The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments – Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. The apoptotic bodies are rapidly ingested by phagocytes and degraded by the phagocyte’s lysosomal enzymes
  • 61. MECHANISMS OF APOPTOSIS – Two Major Pathways in the Initiation of Apopotosis 1) Mitochondrial ( intrinsic) pathway Triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress) 2) Death receptor (extrinsic) pathway Responsible for the elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes
  • 62. Mitochondrial ( intrinsic) pathway – It is the major mechanism of apoptosis in all mammalian cells – It results from increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules from the mitochondrial intermembrane space into the cytoplasm . – The release of mitochondrial pro-apoptotic proteins is tightly controlled by the BCL2 family a.Antiapoptotic:BCL2, BCL-XL, and MCL1 b.Proapoptotic. BAX and BAK c.Sensors. Members of this group, including BAD, BIM, BID, Puma, and Noxa , act as sensors of cellular stress and damage
  • 65. Death receptor (extrinsic) pathway – This pathway is initiated by engagement of plasma membrane death receptors on a variety of cells – Death receptors are members of the TNF receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain – The best known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas – The ligand for Fas is called Fas ligand (FasL). FasL is expressed on T cells that recognize self antigens
  • 66. – When FasL binds to Fas, three or more molecules of Fas are brought together, and their cytoplasmic death domains form a binding site for an adaptor protein that also contains a death domain and is called FADD (Fas-associated death domain). – FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain – FLIP, which binds to pro-caspase-8 but cannot cleave and activate the caspase because it lacks a protease domain
  • 67. Execution Phase of Apoptosis – The two initiating pathways converge to a cascade of caspase activation, which mediates the final phase of apoptosis – Executioner caspases (caspase-3 and -6) cleave an inhibitor of a cytoplasmic DNase and thus make the DNase enzymatically active, this enzyme induces cleavage of DNA – Caspases also degrade structural components of the nuclear matrix and thus promote fragmentation of nuclei
  • 68. Removal of Dead Cells – The formation of apoptotic bodies breaks cells up into “bite-sized” fragments that are edible for phagocytes – Phosphatidylserine is present on the inner leaflet of the plasma membrane, but in apoptotic cells this phospholipid “flips” out and is expressed on the outer layer of the membrane, where it is recognized by several macrophage receptors. – Cells that are dying by apoptosis secrete soluble factors that recruit phagocytes.
  • 69. INTRACELLULAR ACCUMULATIONS – One of the manifestations of metabolic derangements in cells is the intracellular accumulation of abnormal amounts of various substances that may be harmless or associated with 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 may be produced elsewhere.
  • 70. Four main pathways of abnormal intracellular accumulations – Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and transport, as in fatty change (steatosis) in the liver – Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion, as with certain mutated forms of α1-antitrypsin
  • 71. – Failure to degrade a metabolite due to inherited enzyme deficiencies. The resulting disorders are called storage diseases . – Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration.
  • 73. Lipids Steatosis (Fatty Change) – The terms steatosis and fatty change describe abnormal accumulations of triglycerides within parenchymal cells – Most often seen in the liver but may also occur in the heart, Skeletal muscle, kidney and other organs – May be caused by toxins, protein malnutrition, diabetes mellitus, obesity and anoxia – Alcohol abuse and diabetes associated with obesity are the most common causes of fatty liver
  • 74. Cholesterol and Cholesterol Esters – Atherosclerosis: In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters. – Xanthomas: Intracellular accumulation of cholesterol within macrophages is also characteristic of acquired and hereditary hyperlipidemic states – Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons, producing tumorous masses known as xanthomas.
  • 75. – Cholesterolosis: This refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder. The mechanism of accumulation is unknown. – NiemannPick disease, type C. This lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs
  • 76. Proteins – Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm. – By electron microscopy they can be amorphous, fibrillar, or crystalline in appearance  Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria).  protein appears as pink hyaline droplets within the cytoplasm of the tubular cell  The process is reversible; if the proteinuria diminishes, the protein droplets are metabolized and disappear.
  • 77. – Defective intracellular transport and secretion of critical proteins: In α1-antitrypsin deficiency, mutations in the protein significantly slow folding, resulting in the buildup of partially folded intermediates, which aggregate in the ER of the liver and are not secreted – Aggregation of abnormal proteins: Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular, extracellular, or both, and the aggregates may either directly or indirectly cause the pathologic changes. Certain forms of amyloidosis
  • 78. Hyaline Change – The term hyaline usually refers to 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. – This morphologic change is produced by a variety of alterations and does not represent a specific pattern of accumulation.
  • 79. Glycogen – Glycogen is a readily available energy source stored in the cytoplasm of healthy cells. Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism. – Glycogen masses appear as clear vacuoles within the cytoplasm.
  • 80. Pigments Exogenous Pigments – Exogenous pigments are the pigments introduced into the body from outside such as by inhalation, ingestion or inoculation. – The most common exogenous pigment is carbon (coal dust), a ubiquitous air pollutant in urban areas.
  • 81. ANTHRACOSIS – When inhaled Carbon 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 and the involved lymph nodes. COAL WORKER’S PNEUMOCONIOSIS – In coal miners the aggregates of carbon dust may induce a fibroblastic reaction or even emphysema and thus cause a serious lung disease TATTOOING – is a form of localized, exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages, in which they reside for the remainder of the life of the embellished – The pigments do not usually evoke any Inflammatory response.
  • 82. Endogenous Pigments Lipofuscin (lipochrome or wear-and-tear pigment) – An insoluble brownish-yellow granular intracellular material that accumulates in the heart, liver, & brain as a function of age or atrophy represents complexes of lipid & protein that derive from the free radical- catalyzed peroxidation of polyunsaturated lipids –It is not injurious to the cell but is important as 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
  • 83. Melanin – is an endogenous, brown-black, pigment formed when the enzyme tyrosinase catalyses the oxidation of tyrosine to dihydroxyphenyl alanine in melanocytes Homogentisic acid – Black pigment that occurs in patients with alkaptonuria – Here the pigment is deposited in the skin, connective tissue, and cartilage, and the pigmentation is known as ochronosis
  • 84. Hemosiderin – Hemoglobin-derived, golden yellow to brown, granular or crystalline pigment is one of the major storage forms of iron – When there is systemic overload of iron hemosiderin may be deposited in many organs and tissues, a condition called hemosiderosis. – The main causes of hemosiderosis are (1) increased absorption of dietary iron due to an inborn error of metabolism called hemochromatosis (2) hemolytic anemias, in which premature lysis of red cells leads to release of abnormal quantities of iron, (3) repeated blood transfusions, because transfused red cells constitute an exogenous load of iron
  • 85. PATHOLOGIC CALCIFICATION – Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts – Types  Dystrophic • deposition occurs locally in dying tissues • it occurs despite normal serum levels of calcium • In absence of derangements in calcium metabolism  Metastatic • deposition of calcium salts in otherwise normal tissues • results from hypercalcemia • secondary to some disturbance in calcium metabolism.
  • 86. Dystrophic calcification – Dystrophic calcification is encountered in areas of necrosis – Examples • in the atheromas of advanced atherosclerosis • develops in aging or damaged heart valves – Morphology • Gross - fine, white granules or clumps, often felt as gritty deposits • Microscopy – – intracellular or extracellular, basophilic, amorphous granular, sometimes clumped appearance – The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies – In papillary lesions of thyroid, meningiomas etc – In asbestosis of the lung, iron and calcium deposition creates dumbbell shaped forms
  • 87. Metastatic Calcification Metastatic calcification may occur in normal tissues whenever there is hypercalcemia Four major causes of hypercalcemia 1) Increased secretion of parathyroid hormone, due to either 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 like vitamin D intoxication and sarcoidosis ( in which macrophages activate a vitamin D precursor ) 4) Renal failure, in which phosphate retention leads to secondary hyperparathyroidism
  • 89. CELLULAR AGING – Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences
  • 90. DNA Damage –A variety of exogenous (physical, chemical, and biologic) agents and endogenous factors such as ROS threaten the integrity of nuclear and mitochondrial DNA –Although most DNA damage is repaired by DNA repair enzymes, some persists and accumulates as cells age.
  • 91. – Patients with Werner syndrome show premature aging, and the defective gene product is a DNA helicase, a protein involved in DNA replication and repair and other functions requiring DNA unwinding. – A defect in this enzyme causes rapid accumulation of chromosomal damage that may mimic the injury that normally accumulates during cellular aging.
  • 92. – Cellular Senescence: All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally nondividing state, known as replicative senescence Mechanisms cellular senescence:  Telomere attrition: One mechanism of replicative senescence involves progressive shortening of telomeres, which ultimately results in cell cycle arrest.  Telomeres are short repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosomal ends and for protecting chromosomal termini from fusion and degradation.
  • 93. – Telomere length is normally maintained by nucleotide addition mediated by an enzyme called telomerase. – Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes. – Telomerase activity is highest in germ cells and present at lower levels in stem cells, but it is usually undetectable in most somatic tissues Therefore, as somatic cells divide, their telomeres become shorter, and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones.
  • 95. Defective Protein Homeostasis: – Protein homeostasis involves two mechanisms: those that maintain proteins in there correctly folded conformations that degrade misfolded proteins by the autophagy-lysosome system and ubiquitin-proteasome system. • Both normal folding and degradation of misfolded proteins are impaired with aging • Mutant mice deficient in chaperones of the heat shock protein family age rapidly, and conversely, those that overexpress such chaperones are long-lived
  • 96. Nutrient sensing system – Caloric restriction increases longevity. – Two major neurohormonal circuits that regulate metabolism,  Insulin and insulin like growth factor 1 (IGF1) signaling pathway. • IGF-1 is produced in many cell types in response to growth hormone secretion by the pituitary. IGF-1, as indicated by its name, mimics intracellular signaling by insulin and thereby informs the cells of the availability of glucose, promoting an anabolic state as well as cell growth and replication.
  • 97.  Sirtuins: Sirtuins are a family of NAD-dependent protein deacetylases. • Functions to adapt various environmental stresses, including food deprivation and DNA damage. • Sirtuins are thought to promote the expression of several genes whose products increase longevity. •These include proteins that inhibit metabolic activity, reduce apoptosis, stimulate protein folding, and inhibit the harmful effects of oxygen free radicals.  caloric restriction increases longevity both by reducing the signaling intensity of the IGF-1 pathway and by increasing sirtuins.
  • 98. CONCLUSION – Cells are the basic structural units of tissues ,which form organs and systems in the human body. In health, the cells remain in accord with each other. – In general, cells of the body have inbuilt mechanism to deal with changes in environment to an extent. – The cellular response to stress may vary and depends upon many variables. – Study of abnormalities in structure and function of cells in disease has remained the focus of attention in understanding of diseases. – Most forms of diseases begin with cell injury followed by consequent loss of cellular function. – In order to learn the fundamentals of disease processes at cellular level, it is essential to have an understanding of the causes and mechanisms of cell injury and cellular adaptations.
  • 99. REFERENCES – Textbook of pathology- Robbin’s 8th edn &9TH edition – Cell biology and signaling ; Ali El Baya

Notas del editor

  1. Small doses of a chemical toxin or brief periods of ischemia may induce reversible injury, whereas large doses of the same toxin or more prolonged ischemia
  2. Superoxidase dismutases (SODs
  3. outer mitochondrial membranes as well as the cytosol and ER membranes mitochondrial outer membrane impermeable they prevent leakage of cytochrome c and other death-inducing proteins
  4. Second mitochondria derived activation protein IAPs is to block the activation of caspases,