COURSE CODE: 301

Dr. UZMA NAZ

OVERVIEW
• INTRODUCTION TO PATHOLOGY
• DIVISIONS OF PATHOLOGY
• COMMON TERMS USED IN PATHOLOGY
• SUFFIXES, ROOTS, PREFIXES
• CELLULAR RESPONSE TO NOXIOUS STIMULI
• CELLULAR ADAPTATIONS
• CELL INJURY
• CAUSES OF CELL INJURY
TODAY’S TOPIC
MECHANISMS OF CELL
INJURY AND
REVERSIBLE CELL
INJURY
 INDEX
• Main principles involved in cell injury

• Mechanisms of cell injury

 Hypoxia mediated cell injury
 Free radical mediated cell injury
 Chemical mediated cell injury

• Clinical correlates
1. The cellular response to injurious stimuli
depends on the nature of the injury, its
duration, and its severity.
• 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
either in instantaneous cell death or in slow,
irreversible injury leading in time to cell death.
2. The consequences of cell injury depend on
the type, state, and adaptability of the
injured cell.
• The cell’s nutritional and hormonal status and
its metabolic needs are important in its
response to injury.
• How vulnerable is a cell, for example, to loss of
blood supply and hypoxia?
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.
3. Cell injury results from different biochemical
mechanisms acting on several essential
cellular components
• The cellular components that are most
frequently damaged by injurious stimuli
include mitochondria, cell membranes, the
machinery of protein synthesis and
packaging, and DNA.
MECHANISMS OF CELL
INJURY
3 main mechanisms:

1. Free radical mediated cell injury

2. Hypoxia mediated cell injury

3. Chemical mediated cell injury

FREE RADICAL MEDIATED
CELL INJURY
FREE RADICAL:
Highly reactive chemical specie with single
electron in the outer most orbit. They mediate
autocatalytic reactions.
E.G OH-, H2O2, HOCL, etc
 FORMATION OF FREE RADICAL
1. Absorption of radiant energy in form of X-
Ray, UV radiations

2. Oxidation –reduction reaction

3. Enzymatic reactions
 PARTS OF CELL WHICH ARE TARGETTED BY
FREE RADICALS
1. CELL MEMBRANE  LIPID PEROXIDATION

2. MITOCHONDRIA  NON PEROXIDATIVE DAMAGE

TO MITOCHONDRIA

3. ENDOPLASMIC RETICULUM

4. NUCLEUS PYKNOSIS, KARYORRHEXIS,

KARYOLYSIS
PATHOLOGIC EFFECTS OF FREE RADICALS

• LIPID PEROXIDATION IN MEMBRANES

• OXIDATIVE MODIFICATION OF PROTEINS

• LESIONS IN DNA
 EXAMPLES OF FREE RADICAL MEDIATED
CELL INJURY
1. PULMONARY FIBROSIS

2. RETROLENTAL FIBROPLASIA
 HYPOXIA
MEDIATED
CELL INJURY
 Morphology of Cell Injury
Reversible Injury

• Generalized Cellular swelling

• Blebbing of the plasma membrane
• Dilation of Endoplasmic reticulum
• Mitochondrial Changes
• Nuclear Alteration
• Reversible hypoxic/ ischemic injury
• Loss of ATP generation by mitochondria initially results in
reversible events:

•  Na+/K+ ATPase membrane pump leads to a loss of ionic

and osmotic gradient ( ↑Ca+2+ Na+, ↓K+ and osmotic gain
of water) resulting cell swelling & ER dilatation)

• ↑ anaerobic glycolysis results in glycogen depletion and

lactate accumulation (↓pH).

•  Reduced protein synthesis due to ribosome detachment

from the RER
ISCHEMIC INJURY
ALTERATION IN THE PLASMA MEMBRANE

• Cellular swelling
• Formation of cytoplasmic blebs.
• loss of osmotic balance and influx of
fluids and ions
• Loss of cellular contents
• Leakage of metabolites necessary to
produce ATP.
 MITOCHONDRIAL CHANGES
• Early, appears condensed as a result of loss of
matrix protein following loss of ATP

• Followed by swelling due to ionic shifts due to

opening of pores so Ca moves into the
cytoplasm.

• It activates enzymes like phospholipases,

endonucleases, ATPases.

• Release of proteins that trigger apoptopic death

ENDOPLASMIC RETICULUM CHANGES
• Dilatation

• Detachment of
ribosomes and
disaggregation of
polysomes with
decreased protein
synthesis
 CHANGES IN THE LYSOSOMES
• Lysosomal membrane damages  leakage of
enzymes

• Activation of acid hydrolases  enzymatic digestion

of proteins, RNA, DNA and glycogen.

• Cells die by necrosis.

CHEMICAL MEDIATED CELL INJURY
• Chemical injury remains a frequent problem in
clinical medicine and is a major limitation to
drug therapy.

• Because many drugs are metabolized in the liver,

this organ is a frequent target of drug toxicity.
• In fact, toxic liver injury is perhaps the most
frequent reason for terminating the therapeutic
use or development of a drug
CHEMICAL MEDIATED CELL INJURY
DIRECT INJURY
For example: mercuric chloride poisoning,
mercury binds to the sulfhydryl groups of cell
membrane proteins, causing increased
membrane permeability and inhibition of ion
transport.
CONVERSION OF BIOLOGICALLY INACTIVE
METABOLITES INTO REACTIVE TOXIC
METABOLITES IN TARGETTED CELLS:
These toxic metabolites causes membrane
damage and cell injury by formation of free
radicals.

• Acetaminophen, an analgesic drug, is also

converted to a toxic product during
detoxification in the liver, leading to cell injury
CLINICAL CORRELATES
 ISCHEMIC AND HYPOXIC INJURY

• Ischemia is the most common type of cell

injury in clinical medicine and it results from
hypoxia induced by reduced blood flow, most
commonly due to a mechanical arterial
obstruction.
• In contrast to hypoxia, during which energy
production by anaerobic glycolysis can
continue, ischemia compromises the delivery
of substrates for glycolysis.
• Thus, in ischemic tissues, not only is aerobic
metabolism compromised but anaerobic
energy generation also stops after glycolytic
substrates are exhausted, or glycolysis is
inhibited by the accumulation of metabolites
that would otherwise be washed out by
flowing blood.
• For this reason, ischemia tends to cause more
rapid and severe cell and tissue injury than
does hypoxia in the absence of ischemia.
NEXT LECTURE