Cell Injury,

Adaptation and
Death
DR.dr.Karyono Mintaroem,SpPA
Dr.R.Sarwo Bekti

Lecture Overview

Hyperplasia
Hypertrophy
Atrophy
Metaplasia

Cell Responses
1. Cellular Adaptations

Overview - Pathology
Study (logos) of disease (pathos)

bridge between the basic sciences and

clinical medicine
scientific foundation for medicine
Divided into
General pathology

Reactions of cells and tissues to

abnormal stimuli and inherited defects
Systemic pathology

Alterations in specialized organs and

tissues responsible for disorders
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Overview - Pathology
Four aspects of a disease
1. Cause (etiology)
2. Mechanisms of its development
(pathogenesis)
3. Biochemical and structural
alterations (molecular and
morphologic changes)
4. Functional consequences (clinical
manifestations)
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Cell Response

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Etiology/etiologi/penyebab
Two major classes of etiologic factors
a. intrinsic / genetic
b. acquired / didapat / ekstrinsik :
infectious, nutritional, chemical, physical
Old concept : 1 agent 1 disease
New concept : 1 agent n diseases
n agents 1 disease
Primary cause backbone dx, disease
understood, tx.
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Pathogenesis
The squence of events in the response of
cells or tissues to the etiologic agent, from
the initial stimulus to the ultimate
expression of the disease
Etiologic agent initial stimulus response
of cells / tissues clinical significance

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Morphologic Changes
The structural alterations in cells or tissues
that are either characteristic of the disease
or diagnostic of the etiologic process
The limitations of morphology for diagnosing
diseases have become increasingly evident
the field of diagnostic pathology has
expanded to encompass molecular biologic
& immunologic approaches for analyzing
disease states.
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Kmr/2007
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Kmr/2007

FCD
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FCD

Kmr/2007
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Inflammatory Ca.: peau dorange, penebalan,

kasar
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Kmr/2007

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Medullary Ca : nuklei pleomorfik

nukleoli prominen
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Kmr/2007
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Principles that are relevant to most forms of

cell injury
The cellular response to injurious stimuli depends on
the type of injury, its duration and its severity.
* chemical toxin : doses and duration
* ischemia : severity and duration
The consequences of cell injury depend on the type,
state, and adaptability of the injured cell.
striated muscle cell in the leg >< muscle cell of the
heart
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Adaptations General
Cellular Adaptations =
Physiologic and morphologic
alterations in cells to more
severe physiologic stresses and
some pathologic stimuli
Severe physiologic stresses / pathologic
stimuli physiologic & morphologic
cellular adaptation new steady states &
modulating its function

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Adaptations General
Can be
1. Hyperplasia = increase in the number of
cells
2. Hypertrophy = increase in the sizes of
individual cells
3. Atrophy = decrease in the size and
function of cells
4. Metaplasia = cells change from one
type to another

Sub - cellular alterations = if cells

exposed to sub lethal or chronic

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Adaptations Hyperplasia
Increase in the number of cells in an
organ or tissue & mass of the organ
or tissue
Stimulus =Hyperplasia and hypertrophy
= occur together (triggered by the same
stimulus)
Types = physiologic or pathologic
caused by = growth factors, growth
factor receptors and intracellular
signaling pathways

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Adaptations Hyperplasia
Physiologic
Hormonal
pregnant uterus
female breast at puberty

Compensatory
after damage
partial resection

Pathologic
Cancerous proliferation
Hormonal
Endometrium hyperplasia
Benign prostatic hyperplasia

Growth factors
wound healing
viral infections

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Adaptataion - Hyperplasia

Physiologic
Hyperplasia

Pathologic
Hyperplasia

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Adaptations Hyperplasia

Normal

Pathologic Hyperplasia

Endometrial Carcinoma

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Adaptations Hypertrophy
An increase in the size of cells, resulting in an
increase in the size of the organ

No new cells, just larger cells due not to cellular swelling but
to the synthesis of more structural components.
Nondividing cells undergo hypertrophy
can be physiologic or pathologic
Example = uterus during pregnancy, muscle tigthness of
sportsmen
Mechanisms of Hypertrophy
Result of increased production of cellular proteins either by
hormonal induced ofr increasing workload
Re-expression of fetal or neonatal proteins
form replacing -myosin heavy chain (decreased ATPase,
slower, more energetically economical contraction)
Atrial natriuretic factor (ANF) secretion by atrium &
ventricle
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Adaptations
Hypertrophy

The genes that are induced during cardiac muscle

hypertrophy include those encoding :
Transcription factors ( c-fos, c-jun),
Growth Factors (TGF-, IGF-1, Fibroblast GF)
Vasoactive agents : -adrenergic agonist,
endothelin-1, angiotensin II
Hyperplasia & hypertrophy often occur
concomitantly
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Adaptations Hypertrophy (Mechanism)

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Mechanisms of Hypertrophy
Signal Transduction Pathways

Adaptations Hypertrophy
Physiologic
Hormonal
pregnant uterus

Workload

Pathologic
Growth factors
Cardiac hypertrophy
Acromegaly

after damage
Trained muscle

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Physiologic hypertrophy (uterus during pregnancy)

gravid

Gross

normal

normal

gravid

Microscopy

Adaptations Hypertrophy
Normal

Pathologic Hypertrophy

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Adaptations Atrophy
Shrinkage in the size of the cell by loss of cell
substance
Adaptive response and may lead to cell death
Atrophic cells are not dead cells but if the stimulus
continues, die, often by apoptosis.
Mechanisms = proteolytic systems by Lysosomes or
Ubiquitin - proteasome pathway
Decreased workload (atrophy of disuse)
Early development
Loss of innervation (denervation atrophy)
Notochord
Diminished blood supply
Thyroglossal duct
Inadequate nutrition
Loss of endocrine stimulation
Uterus
Aging (senile atrophy)
Pressure

Physiologic

Pathologic

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Adaptations Atrophy

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Adaptations Metaplasia
Reversible change in which one adult cell
type is replaced by another adult cell type
Metaplastic cells survive but protective
mechanism is lost

If persistent stimulus Malignant transformation

Types = Epithelial or Mesenchymal
a) Epithelial
1.columnar to squamous ( Squamous metaplasia) =
Respiratory tract in cigarette smoking and vitamin A
deficiency &stones in the excretory ducts
2. Squamous to columnar type (Columnar or Intestinal
metaplasia) = Barretts esophagus

b) Mesenchymal = Myositis ossifican

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Adaptations Metaplasia

Barretts

Squamous metaplasia

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Adaptations Metaplasia - Mechanism

Reprogramming
Stem cells in
normal tissues

Undifferentiated
mesenchymal cells

Not because of change in the phenotype

of a differentiated cell
precursor cells differentiate along a new
pathway

Cell Responses
2. Cell Injury

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Cell injury results from functional and

biochemical abnormalities in one or more of
several essential cellular components.

1. Aerobic respiration involving mitochondrial

oxydative phosphorylation & production of ATP
2. The integrity of cell membranes, on which the ionic
& osmotic homeostasis of cell & its organelles
depends
3. Protein synthesis
4. The cytoskeleton
5. The integrity of the genetic apparatus of the cell
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General
Most characteristic of irreversibility.
inability to reverse mitochondrial
dysfunction
profound disturbances in membrane
function

Markers of tissue-specific cellular

injury and death
By detecting elevated blood serum
samples.

Cardiac muscle specific creatine kinase and

&Troponins
Liver (specifically bile duct epithelium)
temperature-resistant alkaline phosphatase
Hepatocytes transaminases
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Cell Injury

Cell Injury

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Two patterns of reversible cell injury can be

recognized under the light microscope :
Cellular swelling
Fatty change

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Cellular swelling
Loss of function of plasma membrane
energy-dependent ion pumps incapable
of maintaining ionic & fluid homeostasis.
When it affects many cells in organ :
pallor, turgor , weight .
Microscopic : small clear vacuoles within
the cytoplasm
Synonim : hydropic change / vacuolar
degeneration
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Fatty change / Steatosis

Abnormal accumulations of triglycerides within
parenchymal cells.
Principally encountered in cells involved in & dependent
on metabolism : hepatocyte, myocardial cells.
Causes : toxins, protein malnutrition, diabetes mellitus,
obesity, anoxia, alcohol abuse.
Microscopic : small or large vacuoles in the cytoplasm.
To identify the fat : stained with Sudan IV or Oil Red-O

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Reversible cell injury- Ultra structural (EM)

normal

R. Injury

Cell swelling
Plasma membrane blebbing,
Microvilli blunting & distortion
Loosening intercellular attachments
Myelin figures
Fatty degeneration or change
begins with the development of minute, membrane-bound
inclusions (Liposomes) closely applied to the ER
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Adaptations Reversible Injury

Fatty Liver ( Normal in inset)

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Irreversible cell injury Irreversible injury = no clear answer

In Myocardium
Structural -amorphous densities in mitochondria
Functional- loss of membrane permeability &
inability to reverse mitochondrial dysfunction
development of profound disturbances in
membrane function.
Injury to the lysosomal membranes
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Irreversible cell injury- Ultra structural (EM)

normal

R. Injury

I. Injury

Studied in Myocardium
Loss of membrane integrity
Dense mitochondrial densities

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Cell
Mechanism
of injuryCell InjuryMechanisms

1. ATP depletion & decrease ATP synthesis

2. Mitochonddrial damage
3. Influx of Intracellular Calcium & loss of Calcium
Homeostasis
4. Accumulation of Oxygen-derived Free Radicals
(Oxydative Stress)
5. Defects in Membrane Permeability
6. Direct/spontaneous disruption in DNA
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Cell injury- Mechanisms

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Cell Responses
3. Cell Death

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Lecture Plan
Cell death
Apoptosis
Necrosis

Example of Cell injury &

death
Ischemia & Hypoxia
Chemicals & Drugs
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Cell Injury and death

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NECROSIS

Definition:
spectrum of morphologic changes that follow cell
death in living tissue, largely resulting from the
progressive degradative action of enzymes on the
lethally injured cell
Morphology
LM (light Microscopy)

Increased eosinophilia
Myelin figures
Calcification of dead cells

Cytoplasm

Membrane discontinuities
large amorphous mitochondria densities
Aggregates of fluffy material (denatured protein)

Nucleus
Pyknosis (nuclear shrinkage and increased basophilia also seen
in apoptotic cell death)
Karyorrhexis (fragmentation)
Karyolysis (breakdown of DNA by DNase activity)
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Necrosis
Types

1. Coagulative = preservation of

2.

the basic outline of necrotic

cell
Mechanism protein
denaturation
characteristic of hypoxic cell
death in all tissues (except
Brain)
Best example MI
Liquefactive= Cell outlines are
obscured & Replaced by
yellow pus
Mechanism bacterial/fungal
enzymatic digestion &
inflammatory response
Whatever is the stimulus in
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brain it is always

Necrosis
Types

3. Caseous =

distinctive form of Coagulative

necrosis but tissue
architecture is completely
lost
MC in TB (also in fungal)
Meaning - cheesy white gross
appearance of necrosis
Microscopy - granulomatous
reaction
(what is granulomatous
reaction?)

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Necrosis
Types

4. Fat Necrosis =

not a specific pattern

Grossly - chalky white areas
of calcium & fatty acids(fat
saponification)
Seen in acute pancreatitis &
trauma of breast
Ghost cells are seen in
microscopy

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APOPTOSIS
Is pathway of cell death that is induced by tightly regulated
intracellular pogram
Cell destined to die activate enzymes that degrade the cells
own nuclear DNA and nuclear and cytoplasmic proteins.
The cells plasma membrane remain intact, but its structure
is altered the apoptotic cells become an avid target for
phagocytosis.
Apoptosis is fundamentally different from necrosis.
Apoptosis and necrosis sometimes coexist, and they may
share some common features and mechanisms.
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Apoptosis in physiologic situations

The programmed destruction of cell during embryogenesis.
Hormone-dependent involution in adult
endometrial cell breakdown (M cycle,
ovarian follicular atresia
regression lactating breast after weaning

Cell deletion in proliferating cell populations

Death of host cells that have served their purpose
neutrophils in acute inflammatory response
lymphocytes at the end of an immune response

Cell death induced by cytotoxic T cells, a defence

mechanism against viruses and tumors (eliminate virusinfected and neoplastic cells)
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Apoptosis Morphology

LM- (H&E)

Single cells or small clusters of cells

Round or oval mass of intensely Eosinophilic cytoplasm with dense
nuclear chromatin fragments

EM
Cell shrinkage, Chromatin condensation-most characteristic feature
,Phagocytosis, cytoplasmic blebs and apoptotic bodies\

Severity of stimulus determines the form of

death
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Apoptosis Mechanisms
Initiation phase- caspases activation
1. Extrinsic/ receptor-initiated
pathway
2. Intrinsic/ mitochondrial pathway
Execution phase- enzymes cause cell
death

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Apoptosis

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Apoptosis Deregulation
Apoptosis
Neuro degenerative disorders- Spino muscular
dystrophies (SMA)
Ischemic injury- MI
Apoptosis of viral infected cells by CTLs

Apoptosis
Mutations/absence of p53
Hormone dependent Tumors- Breast, Ovary,
Prostate
Auto-immune diseases ( Auto-reactive
Lymphocytes)
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Difference Apoptosis &

Necrosis
Descriptor
Apoptosis
Nekrosis
Ukuran sel
Inti
Membran plasma
Isi sel

Mengecil /shrinkage
Fragmentasi

Membesar / swelling
Pyknosis karyolysis

Utuh/intact, perubahan Pecah / disrupted

struktur : lemak
Utuh; lepas sbgai
apoptotic bodies

Reaksi radang sekitar

Tidak ada

Fungsi fisio / patologik

Sering fisiologik :
eliminasi sel yg tidak
perlu
Patologik : kerusakan
DNA

Pencernakan
enzimatik,
Sel bocor
Sering
Patologik, bervariasi :
fase akhir dr injury sel
yg irreversible

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Summary

Hyperplasia
Hypertrophy
Atrophy
Metaplasia

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