General Pathology

Cell Injury
 Introduction

• Pathology: the study ( logos) of suffering ( pathos)

• Four aspects of a disease process that form the core of
pathology
1- Its cause ( etiology)
2- Mechanism of its development ( pathogenesis)
3- Structural alteration induced in cells & organs
( morphological changes)
4- Functional consequences of the morphologic
changes ( clinical significance)
Definition
Cell injury: The effect of a variety of stresses due to
etiological agents a cell encounters resulting in changes in
its internal and external environment.

Cellular response to stress vary and depend upon

1- Host factors: type of cell and tissue involved
2- Factors pertaining injurious agent: extent and type
cell injury
Causes of cell injury
1- Genetic causes
2- Acquired causes
1- Oxygen deprivation
🔹ischemia ( loss of blood supply from impeded arterial
flow or reduce venous drainage)
• local e.g. embolus
• systemic e.g. Cardiac failure
🔹 Hypoxia ( deficiency of oxygen causing cell injury by
reducing aerobic oxidative respiration
• oxygen problems e. g. altitude
• hemoglobin problems e. g Anaemia
🔹oxidative phosphorylation
🔹e.g. cyanide poisoning
 2- Physical Agents
❖ Trauma
❖ Heat
❖ Cold
❖ Radiation
❖ Electric Shock
 3- Chemical agents and drugs

1. Endogenous products: urea

2. Exogenous agents
a- Therapeutic drugs: hormones
b- Non therapeutic agents : lead or alcohol
 4- Free Radical Initiation

❖ Absorption of energy (UV light and x-rays)

oxidative metabolic reactions
❖ Enzymatic conversion of exogenous
❖ chemical drugs ( CCI4> CCI3)
❖ oxygen-derived radicals
❖ superoxide
 5- Infection Agents

❖ Viruses
❖ Rickettsia
❖ Bacteria
❖ Fungi
❖ parasites
 6- Abnormal immunological reaction

The immune process is normally protective but

in certain circumstances that reaction may become
deranged
❖ Hypersensitivity to various substances can lead to
anaphylaxis or to more localized lesions such as
asthma

❖ In other circumstances the immune process may act

against the body cells- autoimmity
 7- Nutritional imbalance

❖ Protein-calorie deficiencies are the most examples of

nutritional de
❖ Vitamins deficiency
❖ Excessive in nutrition are important causes of
morbidity and mortality
❖ Excessive calories and diet rich in animal fat are one
strongly implicated in the development of
atherosclerosis
❖ Obesity alone lead to an increased vulnerability to
certain disorders such as atherosclerosis, coronary
heart disease, diabetes mellitus
 8- Aging

❖ Programmed aging whereby after a defined number of

divisions
❖ Terminal differentiation
❖ Development of an increasing population of cells
irreversibly committed to senescence and death
❖ Increase susceptibility to somatic mutation and a
build-up of errors leading to an eventual error
catastrophe
❖ Faulty DNA repair mechanism
9- Psychogenic disease:- no specific biochemical or
morphologic changes in acquired mental disease
problems of drug addiction, alcoholism and smoking results
in various organic diseases such as liver damage , chronic
bronchitis, lung cancer, peptic ulcer, HT, IHD, etc.
10 Genetic derangements:- result in a defect as sever as the
congenital malformations associated with down syndrome,
caused by chromosomal abnormalities
inborn error of metabolism arising from enzymatic
abnormalities.
11- latrogenic causes
12- idiopathic disease ( unknown cause): exact cause is
undetermined.
The most common form of HT 90% is idiopathic (or essential)
HT.
 Classification of morphologic forms of cell injury

1- reversible cell injury • Retrogressive changes

• Cell-death necrosis
2- irreversible cell injury • Apoptosis
3- programmed cell death • Intracellular accumulation of lipid
protein
4- deranged cell metabolism • Carbohydrate
5- after-effected of necrosis • Gangrene , pathologic calcification
 Stages of the cellular response to stress and
injurious stimuli
Normal and abnormal stimulation

Cellular
swelling
Fatty changes

Hyperplasia
Hypertrophy
Atrophy
Metaplasia
Dysplasia
 Cells React To Adverse
Influences
◼ Cellular adaptation
1- hyperplasia
2- hypertrophy
3- Atrophy
4- metaplasia
5- dysplasia
◼ Reversible injury
1- intracellular edema
2- fatty change
3- Hyaline change
4- amyloidosis
5- mucoid degeneration 6- pathologic pigment
◼ Irreversible injury and dying:- Necrosis, Gangren, pathologic
calcification
 Necrosis
Definition
Localized area of death of tissue followed by
degradation of tissue by hydrolytic enzymes liberated
from dead cells.
•it is invariably accompanied by inflammatory reaction
• various agents such as hypoxia, chemical and
physical agents, microbial agents immunological
injury, etc.
• Two essential changes characteristics irreversible cell injury in
necrosis of all types
1- Cell digestion by lytic enzymes
2- Denaturation of proteins

Types of necrosis
1- Coagulative Necrosis
2- Liquefaction Necrosis
3- Caseous Necrosis
4- Fat Necrosis
5- Fibrinoid Necrosis
Coagulative necrosis
It is a form of tissue necrosis in which the component cells
are dead but the basic tissue architecture is preserved for at
least several days
• The affected tissue take on a firm texture
• presumably the injury denaturation not only structural
proteins but also enzymes and so blocks the proteolysis of the
Dead cells
- as a result, eosinophilic, anucleate cells may persist for days
or weeks.
- ultimately, the necrotic cells are removed by phagocytosis of
the cellular debris.
 Coagulative necrosis
Most common type of necrosis
• Mostly from sudden flow ( ischemia)
• less often from bacterial and chemical agents
•It's characteristics of infarcts
( area of ischemic necrosis in all solid organ except the brain
•The organs commonly affected are the heart, kidney and
spleen
 Morphology
Gross
- foci of coagulative necrosis in the early stage are pale, firm and
slightly swollen
- with progression, they become more yellowish softer and shrunken
Microscopically
- the hallmark of coagulative necrosis- the conversion of normal
cells into their tombstone
The outline of the cells are retained so that the cell type but their
cytoplasmic and nuclear details are lost
- The necrosed cells are swollen and appear more eosinophilic than the
normal, along with nuclear changes described above
- but cell digestion and Liquefaction fail to occur
-eventually, the necrosis focus is infiltratef by inflammation cells
- finally the dead cells are phagocytosed leaving granular debris and
fragments of cells
Liquefaction necrosis

• Due to ischemic injury and bacteria or fungal infection

•degradation of tissue by the action of powerful hydrolytic
enzyme
•the common examples are infarct brain and abscess cavity
•whatever the pathogenesis, Liquefaction completely digests the
dead cell, resulting in transformation of the tissue into liquid
viscous mass
• if the process was initiated by acute inflammation, the
material is frequently creamy yellow and is called pus
 Morphology

Gross
-The affected area is soft with liquefied centre
containing necrosis debris
- later, a cyst wall is formed

Microscopically
-The cystic space containing necrotic cell debris and
macrophages filled with phagocytosed material
- The cyst wall is formed by proliferating capillaries,
inflammatory cells and gliosis (proliferating glial cells) in the
case of brain
-Proliferating fibroblasts in the case of abscess cavity
Caseous necrosis

❖ Found in the center of foci of tuberculous infection

❖ It combines features of both coagulative and liquefactive
necrosis
❖ Term " caseous " ( cheese like) is derived from the friable
❖ Yellow-white
❖ Appearance of the area of necrosis
 Morphology
Grossly
- Foci of caseous necrosis
-As the name implies, resemble dry cheese and are soft, granular and
yellowish.
- This appearance is partly attributed to the histo toxic effects of
lipopolysaccharides present in the capsule of the tubercle bacilli,
mycobacterium tuberculosis
Microscopically
-The necrosed foci are structureless, eosinophilic, and contain granular
debris
-The surrounding tissue shows characteristic granulomatous inflammatory
reaction
• Consisting of epithelioid cells with interspersed
giant cells of Langerhans or foreign body type
• And peripheral mantle of lymphocytes
 Morphology
Grossly
-Fat necrosis appears as yellowish-white and firm
deposits
-Formation of calciu soaps imparts the
necrosed foci firmer and chalky white
appearance

Microscopically
-The necrosed fat cells have cloudy
appearance
-Surrounded by an inflammatory reaction.
Formation of calcium soaps
is identified in the tissue section
as amorphous, granular and
basophilic material
Fibrinoid necrosis

• Characterised by deposition of fibrin-like material whish

has the staining properties of fibrin .
• it is encountered in various examples of immunologic tissue
injury
- immune complex vasculitis
-autoimmune diseases
-arthus reaction
Arterioles in hypertension , peptic ulcer
 Morphology
Microscopically
- identified by brightly eosinophilic, hyalinonic-like deposition in the vessel
wall
- necrotic focus is surrounded by nuclear debris of neutrophils
( leucocytoclasis)
- local hemorrhage may occur due to rupture of the blood vessels
 Gangrene

❖ A form of necrosis of tissue with superadded putrefaction.

❖ All types of Gangrene , necrosis undergoes Liquefaction by
the action of putrefactive bacteria .
❖ It may be caused either ischemia or inflammatory
❖ Coagulatve necrosis due to ischemia
- Gangrene of the bowel
- Gangrene of the limb
❖ Gangrenous or necrotizing inflammation:
primarily inflammation provoked by virulent
bacteria resulting in massive tissue necrosis
- gangrenous appendicitis
- gangrenous stomatitis ( noma , cancrum oris)
 Types of Gangrene

2 Main forms of Gangren

◼ Dry Gangrene

◼ Wet Gangrene
- Gas Gangrene
kind of wet Gangrene
 Dry Gangren
• Begins in the distal part of a limb due to ischemia
• The Gangrene spreads slowly upward until it reaches a
point where the blood supply is adequate to keep the
tissue viable.
• A line of separation is formed at this point between
gangrenous part and the viable part.
- Toes and feet of an old patients due to arteriosclerosis
- Thromboangitis obliterans ( buerger's disease)
- Raynaud's disease
- Traue
- Ergot poisoning
 Morphology
•Glossy
- the affected part is dry shrunken
and dark black resembling the foot
of a mummy
- it is black due to liberation of
hemoglobin from hemolysed
red blood cells which is acted
upon by hydrogen disulfied
( H2S) produced by bacterial
resulting in formation of black
iron sulfide
-the line of separation usually
with eventual falling off of the
gangrenous tissue if it is not removed surgically

•Histologically:- ecrosis with smudging of the tissue

- the line of separation consists of inflammatory granulation tissue
 Wet Gangren
naturally moist tissue and organs such as the mouth,
bowel, lung, cervix, vulva
•develops rapidly due to blockage of venous, and
less commonly, arterial blood flow from thrombosis or
embolism.
• the affected part is stuffed with blood which favours
the rapid growth of putrefactive bacteria,
• The toxic products formed by bacterial are absorbed
causing profound systemic manifestation of septicemia,
and finally death.
 Wet Gangren
• Diabetes foot
high sugar content
in the necrosis tissue
which favours
growth of bacteria
•Bed sores
- bed-ridden patient
due to pressure
on sites like the
sacrum, buttock
and heels
 Morphology features
•Grossly
- the affected part is soft, swollen, putrid, rotten, and dark
- the classic example is Gangren of bowel, commonly due to strangulated
hernia, volvulus or intussusception
- the part is stained dark due to the same mechanism as in dry Gangren

• Histologically
- coagulatve necrosis with stuffing of affected part with blood
- there is ulceration of the mucosa and intense inflammatory
infiltration
- lumen of thebowelcontains mucus and blood
- the line of demarcation between gangrenous segment and
viable bowel is generally not clear-cut
Gas Gangren
 Morphologic features
•Grossly
-the affected area is swollen, oedematous, painful and crepitant
due to accumulation of gas bubbles within the tissue
- subsequently, the affected tissue becomes dark black and foul
smelling

• Microscopically
- the muscles fibres undergo coagulatve necrosis with
Liquefaction
-large number of gram-positive bacilli can be identified
- at the periphery a zone of leucocystic infiltration, oedema and
congestion are found
- Capillary and venous thrombi are common
 Pathologic calcification
Definition
Abnormal deposits of calcium salts occur in any tissues except
bone and teeth.
two distinct types of pathologic calcification
•Dystrophic calcification
characteristics by deposition of calcium salts in dead or
degenerated tissue with normal calcium metabolism and normal
serum calcium levels
• metastatic calcification
apparently normal tissue and is associated with deranged calcium
metabolism and hypercalcemia
 Morphological features
• etiology and pathogenesis of the two are different.
• but morphologically the deposits in both resemble normal minerals of
the bone.
•H and E stained section
-- calcium salts appear as deeply basophilic, irregular and granular clumps.
-- the deposits may be intracellular, extracellular, or at both.
-occasionally, heteropic bone formation (ossification) may occur
-- calcium deposits can be confirmed by special stains
• silver impregnation method of Von-kossa producing blackcolour
• Alizarin red S that produces red staining
-- pathologic calcification is often accompanied by diffuse or granular
deposits of iron
• positive prussian blue reaction in perl's stain
 Dystrophic calcification
• Encountered in areas of
necrosis of any type
• althoug Dystrophic
calcification may be an
incidental finding indicating
insignificant past cell injury,
it my also be a cause of
organ dysfunction
• May occur due to
2 types of causes
--Dead tissue
-- Degenerated tissue
 Necrosis and apoptosis
• Key points
•Necrosis:- occurs when the injury is too sever or prolonged
to allow adaptation and is usually consequence of disrupted
blood supply
•Local and systemic indicators of cell death
include pain, elevated serum enzyme levels,
inflammation ( fever, elevated WBC count, malasia)
and loss function
• Differenttissues exhibit necrosis of different types: Heart (
coagulatve) , brain ( Liquefaction) , lung
( caseous) andpancreas (fat)
• Gangren
refers to a large area of necrosis that may be described as dry,
wet or gas Gangren
gas Gangren and wet Gangren may be rapidly fatal

• Apoptosis
is cell death resulting from activation of intracellular signaling
cascades that cause cell suicide.
Apoptosis is tidy and not usually associated with systemic
manifestations of inflammation
Comparison of cellular changes in necrosis and apoptosis

◼Pathological cell death

is more often due to necrosis ➡️
🔹process release intracellular enzyme
( useful diagnostically)
🔹 mediators that stimulate inflammation ➡️
followed by healingby repair, scarring,
contracture and distortion of tissue architecture
Apoptosis
◼ cell death can also occur through apoptosis
🔹it may be physiological deletion of selected cell
( e.g morphogenesis, cyclic hyperplasia of
reproductive process) or
🔹 it mayoccur in response to a pathological stimuli

◼ number of cells in tissue is tightly regulated

by controlling rate of cell division and rate of cell deat
🔹 if cells are no longer needed they activate a cellular
death pathway resulting in cell suicide

note: there are no gross structural changes involved

with apoptosis
Apoptosis (2)
◼ in contrast to necrosis, which is messy and results in
information and collateral tissue damage →
🔹 apoptosis is tidy and does not elicit information
◼ Apoptosis is not rare event → large number of cells are
continually undergoing programmed cell death
as tissues remodel
for example:-
🔹during fetal development more than half of nerve cells that
form undergo apoptosis
🔹it stimulated that more than 95% of lymphocytes that are
generated in bone marrow are induced to undergo apoptosis
after reaching thymus
Apoptosis (3)
The initiation of apoptosis requires two process
priming- a reversible stage in which specialist
machinery for apoptosis (e.g transglutamase,
calcium/magnesium endonucleases) are activated
Triggering-- the irreversible point which leads to a
sustained rise in cytosolic calcium and induction of new
mRNA species for c-foc, c-myc and heat-shock
proteins
Apoptosis then proceeds
1- cytosol and nucleus lost half their volume
2- fragmentation of nucleus and cytosol
(----> activation of transglutamase that form an
insoluble layer beneath the intact cell membrane
3- condensation of chromatin ( pyknosis)
4- macrophages bind to cell fragments prior to
phagocytosis
( non-specific mechanism)