CELL INJURY

Stages in the cellular response to stress and

injurious stimuli

Principles

Human disease occurs because of injury

to cells / tissue
Most human disease results from injury to
epithelium
Injury to one tissue usually affects the
adjacent or underlying tissue as well
Cell injury produces morphologic changes

Pathologists classify
and diagnose disease
based upon the
morphologic change
induced by cell &
tissue injury
Visual changes
in the cell or
tissue
morphology is
seen under
microscopy when
cells are stained

CELL INJURY
DAMAGE OR ALTERATION OF ONE OR MORE CELLULAR
COMPONENTS
1.

Many types of injury are tissuespecific

because
of
anatomic
relationships and tissue tropism of
chemical and infectious agents.

2.

Cell injury perturbs cell physiology;

the cell does not function at full
capacity

Consequences of
Injury
1.

2.

3.

No long term effects- - the cell damage is

repaired, the effects of the injury are
reversible.
The cell
stimulus.

adapts

to

the

damaging

The cell dies, undergoing necrosis. The

damage is irreversible.

Cell Injury Produces

1.

Signs - abnormal physical findings Objective

2.

Symptoms - complaints experienced by

the patient - Subjective

Adaptation to injury
1. Hypertrophy - an increase in the size of the
cell secondary to an increase in cell function.
Increase in the number of mitochondria and
ER, etc.
2. Hyperplasia - an increase in the number of
cells of a tissue in response to a stimulus or
injury.
3. Metaplasia - replacement of one type of
tissue with another in response to an injury.
4. Atrophy - decrease in the size and functional

HYPERTROPHY

No change in cell number

Reversible increase in cell size
Hypertrophy is the rule in non-dividing
cells since they can not divide
Myocardium, skeletal muscle, neurons
Increase amount of DNA, RNA, protein
Increased synthesis, reduced loss

Hypertrophy versus
Necrosis

MORE CELLS
(PROLIFERATI
STEM CELL
ON)
COMPARTMENT

PHYSIOLOGICAL
BREAST: (PUBERTY,
PREGNANCY,
LACTATION)
UTERUS: PREGNANCY

CONDITIONALLYDIVIDING
NON-DIVIDING CELLS:
NO

HYPERPLASIA

COMPENSATORY
KIDNEY

(NEPHRECTOMY)
LIVER (PARTIAL
HEPATECTOMY)

PATHOLOGICAL
PSORIASIS
GOITER

HYPERPLASIA
CONDITIONALLY DIVIDING: MORE OF
THE SAME
RENEWING TISSUES:

Physiologic hypertrophy of the uterus during pregnancy.

A, Gross appearance of a normal uterus (right) and a gravid
uterus (removed for postpartum bleeding) (left). B, Small
spindle-shaped uterine smooth muscle cells from a normal
uterus (left) compared with large plump cells in gravid uterus
(right).

Changes in the expression of selected genes

and proteins during myocardial hypertrophy.

Metaplasia

Diagram of columnar to squamous metaplasia.

Metaplasia

Cell Atrophy, Causes

1.
2.
3.
4.

Loss of blood supply or innervations

Loss of endocrine factors (ex. TSH)
Decrease in the workload
Aging, chronic illness

Atrophy
Cell

Organ

Reduction in cell
size

Reduction
in size: cell
size and or
number*

Reduced organelles
Reduced synthesis
of macromolecules
Increased protein
degradation

Hypoplasia

*Reduced Proliferation *
Increased loss

A, Atrophy of the brain in an 82-year-old male with atherosclerotic

disease. Note that loss of brain substance narrows the gyri and
widens the sulci.
B, Normal brain of a 36-year-old male.

Outcomes from cell injury depend

upon:
1.
2.
3.
4.

Type of injury
Severity of the injury
Duration of the injury
Type of cell being injured- Some cell
types sustain injury better than
others; some tissues (e.g. liver) have
a capacity to regenerate

Reversible Cell Injury

1.

Cell swelling usually accompanies all

types of injury. Results from an
increase
in
water
permeability.
Reverses once membrane function is
restored

2.

Increase in extracellular metabolite -Because

of
a
biochemical
derangement.
i.e.:
Increase
in
extracellular glycogen in diabetes

Reversible Cell Injury

3.

Fatty change in liver. Vacuoles of fat

accumulate within the liver cell following
many types of injury: alcohol intoxication,
chronic illness, diabetes mellitus, etc.

This may be due to:

.
An increase in entry of free fatty acids
.
An increase in synthesis of free fatty
acids
.
A decrease in fatty acid oxidation

Vulnerable Sites of the

Cell
1.
2.
3.
4.

Cell membranes
Mitochondria
Endoplasmic reticulum
Nucleus

Cell Membranes- easily injured :

1.

Membrane is in contact with the

external environment:
- sustains trauma
- extracellular oxidants, proteases,
etc.

2.

Requires a constant supply of ATP for

normal function (ion pumps)

3.

Lipid molecules in the membrane are

easily oxidized and support oxidative
chain reaction called lipid peroxidation

Cell Membrane
Injury

Epithelial cell proximal kidney tubule

A. Normal
B. Reversible ischemic changes
C. Irreversible ischemic changes

Mitochondrial dysfunction in cell injury.

Cell
Death

Apoptosi
s

Necrosis

Agarose gel electrophoresis

of DNA extracted from
culture cells
A. Control
B. Exposed to heat
C. Massive necrosis

Morphology of
Necrosis

Pyknosis

Shrunken nucleus with dark staining

Seen in a necrotic (dead) cell

Karyorrhexis

Fragmentation of pyknotic nucleus

Karyolysis

Extensive hydrolysis of pyknotic nucleus

with loss of staining

Represents breakdown of the denatured

chromatin

Karyolysis

Coagulative Necrosis

Dead cells remain as ghost-like remnants of

their former self

Classically seen in an MI

Liquefactive Necrosis

The dead cell undergoes extensive

autolysis, caused by the release of
lysosomal hydrolases (proteinases,
DNases, RNases, lipases, etc.)

Seen classically in the spleen and

brain following infarction

Liquefactive
Necrosis

(A) Coagulative vs. (B) Liquefactive

Necrosis

Caseous Necrosis
(caseum - cheesy)

Resembles cottage cheese

Soft, friable, whitish-grey
Present within infected
tissues
Seen in Tuberculosis
(Mycobacterium tuberculosis)

Caseous Necrosis

Caseous
Necrosis

Fat
Necrosis
Leakage of lipases from dead cells attack
triglycerides in surrounding fat tissue and
generate free fatty acids and calcium soaps
These soaps have a chalky-white appearance
Seen in the pancreas following acute
inflammation

Causes of Cell
and Tissue Injury

Causes of Cell and Tissue Injury

1.
2.
3.
4.
5.
6.

Physical agents
Chemicals and drugs
Infectious pathogens
Immunologic reactions
Genetic mutations
Nutritional imbalances

Causes of Cell and Tissue Injury

7.

Hypoxia and Ischemiacell injury resulting from

inadequate levels of oxygen.
Causes:
A. Inadequate blood supply
B. Lung disease
C. Heart failure
D. Shock

Hypoxia and Ischemia

All cells in the body require a
continuous supply of oxygen in
order to produce ATP via oxidative
phosphorylation in mitochondria.
ATP is absolutely critical for life.

Susceptibility of specific
cells to ischemic injury

Neurons: 3 to 5 min.

Cardiac myocytes, hepatocytes,

renal epithelium: 30 min. to 2 hr.

Cells of soft tissue, skin, skeletal

muscle: many hours

Functional and morphologic consequences of decreased

intracellular ATP during cell injury.

Hypoxic Injury
Reversible Changes
1.
2.

3.

4.

Decrease in extracellular ATP levels

Decrease in the Na pump: cell
swelling
Increase in glycolysis, with a decrease
in intracellular pH
Decrease in protein synthesis

Hypoxic Injury
Irreversible Changes
1.

2.
3.

Activation of lysosomal enzymes:

lysosomal enzymes are active at low
pH, ca. pH 4-5
Degradation of DNA and protein
Influx of Ca++, which activates many
lipases and proteases

Problem
Ischemia Reperfusion
Oxygen free radicals produce severe
injury to cellular membranes,
proteins, RNA and DNA.

Hypoxic cells are exposed to

damage from oxygen radicals
1.

2.

Hypoxic patients are given high

levels of oxygen. This oxygen is
toxic to the cells lining the
alveolar spaces in the lung
because the high [02] produces
oxygen radicals
Hypoxic tissues are often
infiltrated with PMNs, which have
enzymes & myleoperoxidases
producing activated oxygen

Hypoxic cells are exposed

to damage from oxygen
radicals
3.

Hypoxic tissues are often reperfused

once the blood supply is restored.
Xanthine oxidase, produced from
proteolysis during hypoxia,
generates free radicals when the 02
is brought back to normal levels.

GOOD / BAD REACTION

SOD

02- + 02- + 2H+

H202 + 02

BAD REACTIONS
1. H202

H. + 0H.

(very reactive)

2. FE++ + H202
FE
- FENTON REACTION
0H
3.
HABER-WEISS REACTION

H202 + 02

+++

+ 0H. +

0H + 0H + 02
.

GOOD REACTIONS
02 + 2H20
1 2 H 2 02
GLUTATHIONE PEROXIDASE
.
2 0H. + 2 GSH
2 H20 + GSSG
2 H 0 + 2 GSH 2 H 0 + GSSG
2 2
2
.

Burns
Outcomes, depend upon:
1.
Total surface area burned
2.
Depth of burn injury- partial vs
full thickness
3.
Whether lungs were injured
4.
Whether treatment was prompt

Burns complications
1.
2.
3.
4.

Neurogenic shock, fluid loss

Infection-Pseudomonas, Staph
Hypermetabolic state
Anemia

Exertional Heat Stroke

1.
2.
3.

Hot, dry skin

Usually lactic acidosis
May lead to ATN, DIC, multi organ failure

Classic Heat Stroke

1.
2.

3.

Hot, dry skin

No lactic acidosis, but respiratory
alkalosis
May lead to hypotension, coma, ATN,
DIC very uncommon

Hypothermic Injury
1.
2.

3.

May lead to coma, death.

Metabolism in brain is inadequate.
Freezing of cells. This causes local
concentrations of salt to markedly
increase.
Poor perfusion of tissuesvasoconstriction, increased
viscosity of blood.

The toes were involved in a frostbite injury. This is an example

of "dry" gangrene in which there is mainly coagulative
necrosis from the anoxic injury.

Electrical Injury

Death from lightening occurs from heat

production, disruption of neural, cardiac
nerve transmission, cell damage from
electroporation of salts across cell
membranes

Death can occur from household levels of

AC current, esp. if the skin is wet, or from
respiratory arrest from tetany of chest
muscles

Summary

All human disease occur because of

cell/tissue injury
Membranes-outer and mitochondrial are
key targets
Many early steps are reversible
Cell death follows going beyond a point of
no return -drop in pH, rise in Ca2+