1. 1
HDB 21004 Basic & Systemic Pathology
Topic Outline
• Terms & Definitions in Pathology
• Health, diseases & syndrome
• Aspect of disease process (Etiology, pathogenesis,
molecular & morphologic changes, Clinical manifestations)
• Predisposing factors
• Investigating Disease
• Cellular Responses to Stress
• Cellular adaptations
• Cell injury and death
• Cellular Aging
• Decreased cellular replication
• Accumulation of metabolic and genetic damage
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HDB 21004 Basic & Systemic Pathology
Learning Outcomes
Course Learning Outcomes;
1. Differentiate correctly between normal and diseased cells, tissue or organs
(gross & microscopically). (C4)
Topic Learning Outcomes;
Define health according to WHO
Define disease and state at least 2 of its synonyms.
Explain the etiology of diseases due to genetic and agents by producing example of scenario.
Describe 4 examples of pathogenesis in less than 50 words.
Outline the steps involved in investigating disease.
Explain all stages of the cellular response to stress and injurious stimuli
Discriminate cell adaptation, reversible and irreversible cell injury based on aetiology, pathogenesis
and histological appearance.
Explain the mechanism of cell adaptation in pathological and physiological situation.
Describe all patterns of tissue necrosis.
Explain the mechanism of cell injury
Describe the physiological & pathological cause of apoptosis.
List in temporal order the genetic and biochemical steps in apoptosis.
Differentiated necrosis & apoptosis
Describe the mechanism and implications of cellular aging
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HDB 21004 Basic & Systemic Pathology
Terms & Definitions in Pathology
Pathology
• Pathos = suffering (english = disease), logos= study
• Def: the study of structural, biochemical, and functional changes in
cells, tissue and organs that underlie disease.
• Attempts to;
• Explain the whys and wherefore of the signs and symptoms
• Provide rational basis for clinical care and therapy.
Pathology is Diverse
Blood Bank
Cardiovascular
Chemistry
Coagulation
Cytology Dermapathology
Gastrointestinal
Gynecologic
Hematopathology
Forensics
Molecular
Neuropathology
Ophthalmic
Pediatric
Pulmonary
Renal
Bone
ENT
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HDB 21004 Basic & Systemic Pathology
Pathologist
• One who study disease
• Anatomic pathologist
• Study the structural abnormalities of cells and tissues that can be detected by gross and
microscopic examination of the tissues removed from the patient.
• Clinical pathologist
• Is concerned with biochemical and microbiologic procedures performed in blood, tissue fluids
or other substances secreted or excreted by the body such as sputum, urine and cerebrospinal
fluid
Terms & Definitions in Pathology
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HDB 21004 Basic & Systemic Pathology
Basic Terminology
Terms & Definitions in Pathology
(WHO)
Health
• A state of complete physical, mental and social well-being
• Not merely the absence of disease or infirmity
Disease
• Any deviation from or interruption of normal structure or function of any body
parts, organs, or systems
• Manifested by a characteristic set of symptoms and signs and whose etiology and
prognosis may be known or unknown
• Synonyms = illness, disorder, medical condition
Syndrome
• a set of medical signs and symptoms that are correlated with each other
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HDB 21004 Basic & Systemic Pathology
Terms & Definitions in Pathology
1. Etiology
• Study of the cause, initiator of illness
• Major classes;
• Genetic (congenital, acquired, idiopathic)
• Agents (infectious, nutritional, chemical, physical, immunologic, physiological)
Aspect of the Disease Process
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HDB 21004 Basic & Systemic Pathology
Congenital
Hereditary
• d/t defect in the genes of one or other
parent which is transmitted to the
offspring (diabetes mellitus,
hypertension)
Molecular
•Disease caused by abnormality in chemical
structure or concentration of single
molecule (protein or enzyme), inherited
(sickle anemia)
Acquired
Metabolic
•d/t disturbances or abnormality in the
intricate processes of metabolism (diabetes
mellitus, hyperthyroidism)
Degenerative
•Result from the degenerative changes that
occur in tissue and organs (osteoporosis)
Neoplastic
•d/t abnormal or uncontrolled growth of
cells (cancer)
Terms & Definitions in Pathology
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HDB 21004 Basic & Systemic Pathology
2. Pathogenesis
• The mechanism through which the etiology
operates to produce the pathological & clinical
manifestations
• Describe the development of the disease
(pathological changes)
• Explain how the etiological agents act to produce
the clinical and pathological changes characteristic
of the disease
• Depending on the time range:
• Acute – severe and sudden in onset
• Chronic - long-developing syndrome, develop
slowly
• Incubation period – time period between the
occurrence of infection and the onset of
disease symptoms
• Latent period – period of time between the
occurrence of infection and the onset of
infectiousness (when the infected individual
becomes infectious)
Terms & Definitions in Pathology
Aspect of the Disease
Process
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• deterioration of a tissue or
an organ in which its vitality
is diminished or its structure
impaired
• deterioration in which
specialized cells are replaced
by less specialized cells (as in
fibrosis or in malignancies)
or in which cells are
functionally impaired (as by
deposition of abnormal
matter in the tissue)
Degeneration
• The mechanism by which
cancer-causing agents result in
the development of tumors.
Carcinogenesis
• a protective tissue response to
injury or destruction of tissues,
which serves to destroy, dilute,
or wall off both the injurious
agent and the injured tissues.
• The classical signs of acute
inflammation are pain (dolor),
heat (calor), redness (rubor),
swelling (tumor), and loss of
function (functio laesa).
Inflammation
• any response of the immune
system to an antigenic
stimulus, including antibody
production, cell-mediated
immunity, and immunological
tolerance.
Immune reactions
Terms & Definitions in Pathology
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Terms & Definitions in Pathology
3. Molecular & Morphologic Changes
• Structural alterations in cells or tissues that are (1) characteristic of a disease
or (2) diagnostic of an etiologic process.
• Become the evidence in diagnosing disease
• Macroscopic (gross) or microscopic
Aspect of the Disease
Process
4. Clinical Manifestation
• The functional abnormalities that lead to;
• Sign & symptoms (clinical manifestations) of disease
• The progress of the disease (clinical outcome)
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HDB 21004 Basic & Systemic Pathology
Predisposing Factor
Terms & Definitions in Pathology
A condition or situation that may make a
person more at risk or susceptible to
disease.
Eg: Age, gender, lifestyle, ethnicity,
heredity
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HDB 21004 Basic & Systemic Pathology
Investigating Diseases
Clinical History
Can often reveal diagnosis
“Listen to your
patient; they
are telling you
the diagnosis”
Physical Examination
Process of evaluating
objective anatomic
findings through the
use of observation,
palpation, percussion,
and auscultation
Differential Diagnostic
The determination of
which one of several
diseases may be
producing the
symptoms.
Diagnostic Services
Utilizing any device or process
(medical test) that design to
aid in the diagnosis and
detection of a suspected
disease or condition
Terms & Definitions in Pathology
Smith, 2003
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HDB 21004 Basic & Systemic Pathology
Investigating Diseases
Clinical History
Sign
Symptom
Syndrome
Physical Examination
Inspection
Palpation
Percussion
Auscultation
Differential Diagnostic
The determination of
which one of several
diseases may be
producing the
symptoms.
Diagnostic Services
Invasive
Minimally invasive
Non-invasive
Terms & Definitions in Pathology
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HDB 21004 Basic & Systemic Pathology
• Non-invasive
no break in the skin is created and there is no contact with the mucosa, or skin
break, or internal body cavity beyond a natural or artificial body orifice.
Eg: electrodiagnostics, electroencephalogram (EEG), electromyogram (EMG),
diagnostic imaging, CT scan, fluoroscopy, ultrasound, magnetic resonance imaging,
x-ray, mammography, electrocardiogram (ECG)
• Invasive
Cystoscopy, biopsy, endoscopy, colonoscopy, laparoscopy, arthroscopy, surgical
excision, & depending upon the collection method, laboratory tests including
cultures, cytology
Terms & Definitions in Pathology
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Diseases Outcomes
Terms & Definitions in Pathology
Prognosis
• Remission – A disappearance of a disease as a result of treatment.
Complete remission means that all disease is gone. Partial
remission means that the disease is significantly improved by
treatment, but residual traces of the disease are still present.
• Relapse – A return of the signs and symptoms of an illness.
• Complication - a secondary disease or condition that develops in
the course of a primary disease or condition and arises either as a
result of it or from independent causes
• Mortality - the state of being mortal, or susceptible to death
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Cellular Responses to Stress
Cellular adaptations
Cell injury and death
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Recall
Homeostasis
• The state of steady internal conditions maintained by living things
Metabolic activity
• All chemical reactions that involved in maintaining the living state of the
cells and the organism. Divided into two categories:
• Catabolism - the breakdown of molecules to obtain energy
• Anabolism - the synthesis of all compounds needed by the cells
• Energy formation is one of the vital components of metabolism.
Cell proliferation
• The process that results in an increase of the number of cells, and is
defined by the balance between cell divisions and cell loss through cell
death or differentiation
Normal structure of cell
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Cellular Responses to Stress
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Dysplasia
Neoplasia
Stages of the cellular response to stress and injury stimuli
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HDB 21004 Basic & Systemic Pathology
The relationship between normal, adapted, reversibly injured and dead myocardial cells. The cellular adaptation is myocardial hypertrophy, caused
by increased blood flow requiring greater mechanical effort by myocardial cells. This adaptation leads to thickening of the left ventricular wall to over
2 cm (normal: 1 – 1.5 cm). In reversibly injured myocardium, there are generally only functional effect, without any readily apparent gross or even
microscopic changes. In the specimen showing necrosis (a form of cell death), the light area in the posterolateral left ventricle represents an acute
myocardial infarction caused by reduced blood flow (ischemia). All three transverse sections of the heart have been stained with triphenyltetrazolium
chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme loss following cell death.
Cellular Responses to Stress
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HDB 21004 Basic & Systemic Pathology
Different type of stress
Cellular Responses to Stress
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HDB 21004 Basic & Systemic Pathology
Cellular Responses to Stress
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Dysplasia
Neoplasia
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Dysplasia
Neoplasia
Stages of the cellular response to stress and injury stimuli
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Adaptations of Cellular Growth &
Differentiation
Reversible changes in size, number, phenotypic, metabolic activity, or
functions of cells in response to changes in their environment.
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Cellular Adaptations
• Increase in the size of cells, due to an increase in the size an
organ.
• Hypertrophied organ has no new cells, just larger cells.
• Response to increased work load (cardiac, skeletal muscle -
pathologic) or hormonal stimulation (uterine muscle –
physiologic)
• Permanently differentiated cells, cannot resume cell cycle to
increase their number
Hypertrophy
• Decrease in the size of an organ or tissue and results from a
decrease in mass of preexisting cells
•Decrease in cell size and number
• Response to decreased work load, hormonal or neuronal
stimulation, blood supply, nutrition, or aging
• Adult (atrophy) or during development (hypoplasia/aplasia)
Atrophy
•Increase in the size of organ or tissue caused by an
increase in number of cells
•Response to hormonal stimulation or compensatory to
damage
•Cells that normally turn over resume cells cycle to increase
in number
Hyperplasia
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• Replacement of one cell type (different tissue) by
another within an organ
• Response to different concentration or
assortment of growth factors or ECM
components, which is a response to irritation or
injury
Metaplasia
• Replacement of one cell type (different tissue) by
another within an organ
• Change in cellular organization, size, and organ
architecture (usually describe changes in
epithelium)
• Response to irritation and damage (pap smear)
Dysplasia
• Replacement of one cell type (different tissue) by
another within an organ
• Irreversible cell proliferation even if any evoking
stimulus has stopped
• Proliferated cells are abnormal-shaped
Neoplasia
Cellular Adaptations
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Mechanism of Adaptations:
Hypertrophy
Hypertrophy can be physiologic or pathologic caused either by increased
functional demand or by specific hormonal stimulation.
The striated muscle cells in (1) skeletal muscle and (2) heart can undergo
only hypertrophy in response to increased demand because in the adult they
have limited capacity to divide
Physiological:
Weightlifter can develop
a rippled physique
hypertrophy of individual
skeletal muscle cells
induced by an increased
workload.
Muscle hypertrophy in
athletes increased
muscle activity
Pathological:
Left ventricular hypertrophy in response
to an increase in afterload (resistance) or
preload (hypertension or aortic valve
disease)
Smooth muscle hypertrophy in the urinary
bladder in response to urethral
obstruction
Surgical removal of one kidney with
compensatory hypertrophy of the other
kidney.
Cellular Adaptations
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HDB 21004 Basic & Systemic Pathology
Cellular Responses to Stress
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Dysplasia
Neoplasia
Stages of the cellular response to stress and injury stimuli
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ATP
• Oxidative phosphorylation in mitochondria (redox reaction)
• Glucose + 6O2 + 36 ADP 6 CO2 + 6H2O + 36 ATP
• Glycolytic pathway
• Glucose + 2 ADP 2 Lactate + 2 ATP
• Glycogen + 3 ADP 2 Lactate + 3 ATP
ROS
• Oxygen-derived free radicals, normally produce in small amounts
Autocatalytic
• If one of the reaction products is also a catalyst for the same or a coupled reaction
Hypoxia vs ischemia
• Oxygen deficiency vs loss of blood supply
Recall
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Cell Injury and Death
Sequential development of biochemical and morphologic changes in cell injury. Cells may become
rapidly non-functional after the onset of injury, although they are still viable, with potentially
reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell
death. Note that irreversible biochemical alterations may cause cell death, and typically this
precedes ultrastructural, light microscope and grossly visible morphologic changes.
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Damaging
stimulus is
removed
Reduced oxidative
phosphorylation,
reduced ATP
Damaging
stimulus is
continued
Lysosomal enzymes
enter the cytoplasm,
digest cell and cellular
contents leaking out
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Reversible
Injury
2 main features under the light microscope: cellular swelling & fatty
change.
Swelling of cells is reversible.
Microscopic examination: small clear vacuoles within cytoplasm
(represent distended and pinched-off segments of the ER) known
as hydropic change or vacuolar degeneration.
Cells show increased eosinophilic.
Ultrastructural changes: (1) plasma membrane alterations – blebbing,
blunting, loss of microvilli. (2) mitochondria changes – swelling and
the appearance of small amorphous densities. (3) Dilation of the ER –
detachment of ribosomes, fine intracytoplasmic myelin figure. (4)
nuclear alteration – disaggregation of granular and fibrillary elements
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Irreversible
Injury /
Necrosis
Morphologic appearance: denaturation of intracellular proteins
and enzymatic digestion of the lethally injured cell
Swelling of cells is irreversible and ruptured of ER,
mitochondria and lysosomes.
Cells show marked eosinophilic.
Ultrastructural changes: (1) plasma membrane alterations –
severe degradation. (2) mitochondria changes – marked
dilation with the appearance of large amorphous densities. (3)
large phospholipid masses (myelin figure). (4) nuclear
alteration – Pyknosis (nuclear shrinkage, increased basophilia)
karyorrhexis (fragmentation of pyknotic nucleus)
karyolysis (enzymatic degradation, reflects loss of DNA)
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Reversible Irreversible
Swelling, increase fat storage Cellular Response Loss of cellular permeability. Chemical
absorption and toxin formation
Intact with few blebbing, with
loss of microvillus
Plasma Membrane Cell membrane starts to degrade,
including organelle membranes.
Membrane intact Lysosome Membrane damaged with vacuoles
Swelling and accumulation of
phospholipid rich densities
Mitochondrial
Changes
Sever mitochondrial membrane
swollen, leakage of cytochrome C into
cell cytoplasm, calcification
Aggregation of fibular elements
in the nucleus/ clumping of
chromatin
Nucleus /Chromatin
Response
Pyknosis karyorrhexis karyolysis
/Dissolution of chromatin
Eosinophilic with fine myelin
figure
Cytoplasm Shows course myelin figure
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Patterns of Tissue Necrosis
Coagulative
Most common type, cause from sudden loss of blood supply to organ, it
occurs in solid organs. Necrosis with the preservation of cellular & tissue
architecture. The nucleus, cytoplasm & cellular outlines remain intact
slower process.
Liquefactive
Characterized by digestion of the dead cells / autolysis transform tissue
into a liquid viscous mass. Typically seen in brain following ischemia.
Necrotic materials is frequently creamy yellow (pus).
Gangrenous
Not a distinctive pattern of cell death, but commonly used n clinical
practice. Usually applied to a limb, due to lost its blood supply and necrosis
(typically coagulative necrosis). Type: dry gangrene (blackening of tissue);
wet gangrene (coagulative necrosis progressing to liquefactive necrosis +
severe bacterial infection); gas gangrene (bacteria infect & destroyed tissue
producing gas).
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Patterns of Tissue Necrosis
Caseous (chees-like)
Most often in mycobacterial infections, caseous tissue no longer resembles
cells but becomes chucks of unrecognizable debris, cheeslike friable white
appearance of the necrotic area. Enclosed within a distinctive inflammatory
border granuloma
Fat
Refers to focal areas of fat destruction, (1) enzymatic fat necrosis - resulted
from release of activated pancreatic lipases into the substance of pancreas and
the peritoneal cavity; (2) traumatic fat necrosis – due to trauma to fat (physical
blow or surgery). Lipases release free fatty acids which combie with calcium to
produce detergents(soapy deposits in the tissue)
Fibrinoid (microscopic)
Commonly seen in immune reactions involving blood vessels, when complexes
of antigen and antibodies are deposited in the wall of arteries. Deposits of
“immune complexes” + fibrin (leaked out of vessels) bright pink and
homogenous pink material (fibrinoid/fibrin-like)
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
General Principle of Cell Injury
• Cellular response to injury depends on nature (toxic,
hypoxia, ischemia, radiation), duration and severity of
injury
• Consequences depend on the type, status, adaptability
and genetic makeup of the injured cell
• Brain vs liver
• Liver has greater glycolytic capacity are able to survive loss of oxygen and
decreased oxidative phosphorylation better than brain with limited capacity
for glycolysis
• Cardiac muscle vs skeletal muscle
• When the striated muscle cell in the leg is deprived of its blood supply, it can
be placed at rest and preserved; not so the striated muscle of the heart
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 might result in cell death, or in slow
irreversible injury leading in time to cell death
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
General Principle of Cell Injury
• Multiple biochemical alterations may be triggered by any
one injurious insult
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
• Reduced supply of oxygen & nutrients*
• Mitochondrial damage
• Actions of some toxin (cyanide)
Major causes of depletion
• Plasma membrane ATP-dependent sodium pump activity is
reduced cell swelling, dilation of ER
• Increase in anaerobic glycolysis Lactic acid accumulates,
intracellular pH , cellular enzyme activity
• Failure of ATP-dependent Ca2+ pumps Ca2+ influx
• Structural disruption of protein synthetic apparatus protein
synthesis
Reduce of 5-10% ATP from normal levels
Mechanism of Injury: Depletion of ATP
*Tissue with greater glycolytic capacity (e.g liver) can tolerate better than tissue with lower
glycolytic capacity (e.g brain)
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Consequences of ATP Depletion
Reduce of 5-10% ATP from
normal levels
• In cells deprived of O2
or glucose, proteins
may become
misfolded trigger
the unfolded protein
response cell death
• Irreversible damage
to mitochondrial and
lysosomal membranes
cell necrosis
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Mechanism of Injury: Mitochondrial Damage
• Reduced supply of oxygen
• Increases of cytosolic Ca2+
• Reactive Oxygen Species (ROS)
Major causes of depletion
• Formation of high-conductance channel
(mitochondrial permeability transition pore) loss
of membrane potential
• Release of pro-apoptotic proteins (e.g cytochrome C)
trigger apoptosis
Major consequences
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Mechanism of Injury: Calcium Influx
• Normally calcium exists in a very low
concentration within cells.
• Cellular injury can result in elevated
cellular calcium by 2 ways;
• Release from intracellular stores
• Transfer across the plasma membrane
• Mechanism of injury by elevated calcium
• Elevated cytosolic calcium activates
enzymes such as
• Phospholipase
• Protease
• Endonuclease
• ATPases
• Elevated cellular calcium can trigger
apoptosis
• Increased mitochondrial permeability
• Caspase activation
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Mechanism of Injury: Oxidative Stress
• Free radicals = chemical species with a single unpaired electron in the
outer orbit; very unstable
• Reactive oxygen species (ROS) = oxygen-derived free radicals; normally
produced in small amounts in mitochondrial redox reaction
• Increased free radicals production:
• absorption of radiant energy (radiation therapy on a patient with tumor)
• enzymatic metabolism of exogenous chemicals (CCl4 CCL3)
• Inflammation (ROS generated from inflammatory cells is to kill the
microorganism)
• Free radicals/ROS can react with proteins, carbohydrates, lipids, nucleic
acids
• Free radicals/ROS = Autocatalytic – regeneration of free radicals allowing
propagation of this effects
• Molecules with which they react are themselves converted into free radicals, thus
propagating the chain of damage.
Cell Injury and Death
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Kumar et al: Robbins & Cotran Pathologic Basis of Disease, 8th Edition
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Superoxide:
• Mechanism of
production: incomplete
reduction of O2 during
oxidative
phosphorylation; by
NADPH oxidase in
leukocyte.
• Mechanism of
activation: conversion
to H2O2 spontaneously
or via superoxide
dismutase (SOD)
• Pathologic effects:
stimulates production
of degradative
enzymes; may directly
damage lipids, protein,
DNA; acts close to site
of production
Hydrogen Peroxide:
• Mechanism of
production: generated
from O2
- by SOD and
oxidase in peroxisomes
• Mechanism of
activation: conversion
to H2O and O2 by
catalase (peroxisomes),
glutathione peroxidase
(cytosol, mitochondria)
• Pathologic effects: can
be converted to OH
(Fenton reaction) and
OCL- (by
myeloperoxidase in
leukocytes) which
destroy microbes and
cells; can act distantly
from production
Hydroxyl Radical:
• Mechanism of
production: generated
from H2O by hydrolysis
(radiation); from H2O2
by Fenton rxn; from O2
-
• Mechanism of
activation: conversion
to H2O by glutathione
peroxidase (GPx)
• Pathologic effects:
most reactive oxygen-
derived free radicals,
principals ROS
responsible for
damaging lipids,
protein and DNA.
(From Pathologic Basis of Disease, 9th Edition, Table 2-3)
Cell Injury and Death
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Cell
Injury
Cell Injury and Death
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Pathologic Effect
of Free Radicals
Cell Injury and Death
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Mechanism to
Remove Free
Radicals
Minimize level of iron & copper
By binding to storage &
transport proteins
(e.g transferrin)
Reduce ROS
Cell Injury and Death
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Why does any of this matter?
• Superoxide dismutase: mutated in ALS (amyotrophic lateral
sclerosis)
• Serum glutathione in alcoholics liver damage,
hemolytic anemia
• Patients ask about antioxidant: role in cancer prevention;
dangerous during cancer treatment?
Cell Injury and Death
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Mechanism of Injury: Defect in Membrane
Permeability
Causes: Decreased phospholipid synthesis due to
impaired mitochondrial function
Increased phospholipid breakdown due to
activation of phospholipases by increased Ca2+
Lipid peroxidation of cell membrane by ROS
Cytoskeletal abnormalities due to proteases
Lipid breakdown products (unesterified free fatty
acids) have a detergent effect
Cell Injury and Death
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MITOCHONDRIAL
MEMBRANE DAMAGE:
Allow the opening of the
mitochondrial permeability
transition pore
decreased ATP and
release apoptotic
protein
PLASMA MEMBRANE
DAMAGE:
Loss of osmotic balance
Influx of fluids and
outflow of cellular
contents
LYSOSOMAL
MEMBRANE DAMAGE:
Leakage of enzymes into
the cytoplasm and
activation of acid
hydrolase
Enzymatic digestion
of cells
Consequences of Membrane Damage
Cell Injury and Death
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• Cells have its own mechanism to repair damage DNA.
• In severe damage (e.g., exposure to DNA damaging drugs, radiation,
oxidative stress), the repair could not be initiated.
• Leading to the cell suicide program
Damage to DNA
• In improperly folded protein, repair could not be initiated.
• Leading to the cell suicide program
Damage to Protein
Mechanism of Injury: Damage to DNA &
Protein
Apoptosis
Cell Injury and Death
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Cell Injury and Death
1842
(Karl Vogt)
• First to
describe the
principle of
apoptosis
1885
(Walther
Flemming)
• Delivered
more precise
description of
the
programmed
cell death
process
1965
(John Foxton
Ross Kerr)
• Able to
distinguish
apoptosis from
traumatic cell
death
1972
(JFR Kerr, A
Wyllei, AR
Currie)
• First introduced
term apoptosis
in a publication
2002
(S Brenner,
Horvitz and JE
Sukston)
• Was awarded
with Nobel
Prize in
Medicine for
their work in
identifying
genes that
control
apoptosis
Discovery of
Apoptosis
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
Definition
• Is an energy dependent programmed cell death for removal of
unwanted individual cells
• Is induced by a tightly regulated suicide program, controlled by
specific genes
• In which cells destined to die activate enzymes that degrade the
cell’s own nuclear and cytoplasmic protein
Apoptotic bodies
• Apoptotic cells that break up into fragments
• Contain portions of the cytoplasm and nucleus
Apoptosis
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Cell Injury and Death
Physiologic
Situations
Embryogenesis & fetal
development
Eliminate cells that not needed, to
maintain a steady number of various
cell populations
Hormone dependent
involution
Endometrial cell breakdown during
menstrual cycle, ovarian follicular
atresia in menopause
Cell loss in proliferating
populations
Immature lymphocyte in the bone
marrow and thymus that fail to
express full antigen receptors
Elimination of self-
reactive lymphocytes
Either before or after they have
completed their maturation to
prevent reaction against one’s own
tissue
Death of cells that have
served their function
Neutrophils in an acute inflammatory
response, lymphocyte at the end of an
immune response
Cause of Apoptosis
In the human body, about 100,000 cells are produced every
second by mitosis and a similar number die by apoptosis
(Vaux & Korsmeyer, 1999)
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Cell Injury and Death
Pathologic
Situations
DNA damage Due to radiation, chemotherapy,
hypoxia
Accumulation of
misfolded proteins
May arise due to mutations or
extrinsic factors (free radicals),
may lead to ER stress, able to
trigger degenerative disease of
CNS and etc.
Cell death in infection Viral infection: HIV / adenovirus
induced apoptosis to infected
cells
Hepatitis infection: host immune
response induced apoptosis
Organ atrophy After duct obstruction such as in
the pancreas, or kidney
Cause of Apoptosis
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HDB 21004 Basic & Systemic Pathology
Necrosis Apoptosis
Affect large areas of contiguous
cells
Cellular Response Affects scattered individual cells
Cell membrane ruptures as
terminal event and cell contents
are released (chemotactic).
Chemotactic factors lead to
neutrophil infiltration to
degrade dead cells.
Plasma Membrane Blebs form and apoptotic bodies
containing nuclear fragments are shed
Phagocytosis of intact apoptotic
bodies, no chemotactic factors are
generated
When DNA is cleaved,
fragments are random in size
(smear pattern in gels)
Chromatin Response Chromatin condensation and DNA
fragmentation occur together; DNA
cleaved into multiples of 200 base
pair units (ladder pattern in gels)
Cells and its organelles swell Cytoplasm Cells contract
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Distinct morphological features of
apoptosis and necroptosis. (a)
Apoptosis is characterized by cell
shrinkage, membrane blebbing
condensation, margination of nuclear
chromatin, and packaging of apoptotic
bodies and its engulfment by neighbor
cells. (b) Necroptosis is characterized
by the increase in cell volume, swelling
of organelles, perforation of plasma
membrane, cellular collapse, and
release of cellular contents.
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
Agarose gel electrophoresis of DNA extracted
from culture cells. Ethidium bromide stain;
photographed under ultraviolet illumination
Lane A: viable cells in culture
Lane B: culture of cells exposed to heat
showing extensive apoptosis; note
ladder pattern of DNA fragments,
which represent multiples of oligo-
nucleosomes.
Lane C: Culture showing cell necrosis; note
diffuse smearing of DNA
(From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical
perspective. In Tomei LD, Cope FO: Apoptosis: The molecular Basis of Cell Death.
Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1991, p 13.)
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
NECROSIS Apoptosis
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
NECROSIS Apoptosis
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
NECROSIS Apoptosis
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HDB 21004 Basic & Systemic Pathology
• Death Receptor (Extrinsic) Pathway
• Mitochondrial (Intrinsic) Pathway
• Execution Phase
• Removal of Dead Cells
Steps:
Mechanism of Apoptosis
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
A: cell viability is maintained by the induction of anti-apoptotic proteins (Bcl-2) by
survival signals. These proteins maintain the integrity of mitochondrial membranes
and prevent leakage of mitochondrial proteins
B: loss of survival signals or DNA damage activate sensors that antagonize the anti-
apoptotic proteins and activate the pro-apoptotic proteins Bax/Bak, which form
channels in the mitochondrial membrane. The subsequent leakage of cytochrome
c leads to caspase activation and apoptosis.
• Triggered by loss of survival
signals, DNA damage,
accumulation of misfolded
proteins (ER stress)
• Inhibited by survival signals
(growth factors)
• The choice between cell
survival and death is
determined by the
permeability of mitochondria
Intrinsic Pathway
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
• a.k.a the death receptor
pathway
• Initiated by engagement of
plasma membrane death
receptors (death domain)
• Death receptor are
members of the tumor
necrosis factor receptor
family and a related
protein called Fas (CD95)
Extrinsic Pathway
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HDB 21004 Basic & Systemic Pathology
Execution Phase
• The intrinsic and extrinsic pathway converge to a caspase
(cysteine-aspartic-acid-proteases) activation cascade mediates the
final phase of apoptosis.
• Family of at least 12 proteases, a few are involved in inflammation and
many are involved in apoptosis
• Initiator caspases (8,9,10) activate the executioner caspases
(3,6) to signal DNA cleavage
• Caspases disassemble a cell by;
• Cleave structural proteins leading to nuclear breakdown
• Converts cytoplasmic DNase to active form
• DNase induces the characteristic cleavage of DNA into nucleosome-sized
pieces
• Caspases also degrade structural components of the nuclear
matrix fragmentation of nuclei
Cell Injury and Death
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HDB 21004 Basic & Systemic Pathology
Cell Injury and Death
Removal
of Dead
Cell
• Formation of cytoplasmic buds on the cell membrane
containing nuclear fragments, mitochondria and protein
fragments
• Breaking off of cytoplasmic buds apoptotic bodies
• Dying cells secreted factors that recruit phagocytes
• Phagocytosis of apoptotic bodies by neighboring cells or
macrophages
• Dead cells disappear without a trace and do not
produce inflammation
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Cellular aging is a 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.
Cellular Aging
Cells have
limited
capacity for
replication
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HDB 21004 Basic & Systemic Pathology
Cellular Aging
1. Decreased cellular replication
Population doubling of primary human fibroblast derived from a
newborn, a 100-year-old person, and a 20-year-old patients
with Werner syndrome (rare disease with premature aging). The
ability of cells to grow to a confluent monolayer decreases with
increasing population-doubling level.
(From Dice JF; Cellular and molecular mechanism of aging.
Physiol Rev 73:150, 1993)
Cell from children
undergo more round
of replication than do
cells from older
people
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The role of
telomere
(short repeated
sequences of DNA
present at the linear
ends of chromosomes)
and telomerase
(nucleotide addition
mediated enzyme,
specialized RNA-
protein complex).
Cellular Aging
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2. Accumulation of Metabolic & Genetic Damage
Cellular Aging
Examples Overload of reactive oxygen species in body
Over expression of SOD and CAT extends life span in
Drosophila
Werner’s syndrome – defective DNA helicase (a
protein involved in DNA replication & repair)
Ataxia telangiectasia – ineffective repair of dsDNA
breaks
Damaged organelles accumulate as cells age
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HDB 21004 Basic & Systemic Pathology
Structural & Biochemical Changes with Aging
Cellular Aging
Oxidative phosphorylation is reduced
Synthesis of nucleic acid, structural proteins, enzymes, cell receptors
and transcription factors are reduced
Capacity for nutrient uptake and repair of DNA damage are decreased
Accumulation of abnormally folded proteins
Cytological changes
Editor's Notes
Acute conditions are severe and sudden in onset. This could describe anything from a broken bone to an asthma attack. A chronic condition, by contrast is a long-developing syndrome, such as osteoporosis or asthma. Note that osteoporosis, a chronic condition, may cause a broken bone, an acute condition. An acute asthma attack occurs in the midst of the chronic disease of asthma. Acute conditions, such as a first asthma attack, may lead to a chronic syndrome if untreated.
The latent period is defined as the period of time between the occurrence of infection and the onset of infectiousness (when the infected individual becomes infectious).
The incubation period represents the time period between the occurrence of infection (or transmission) and the onset of disease symptoms. The incubation period may be the same as the latent period (defined above) if the onset of symptoms is the same as the onset of infectiousness.
Streptococcus bacteria that has caused the inflammation of the tonsils
process of evaluating objective anatomic findings through the use of observation, palpation, percussion, and auscultation