THE CELL AND REACTION

TO INJURY
Dilip K. Das, MBBS, MD, PhD, DSc, FRCPath
Department of Pathology,
Faculty of Medicine
Kuwait University
 Cell Structure and Function

• The cell membrane: Cell movement, cell

recognition, cell growth, cell adhesion,
and transfer function.
• The cell nucleus: Chromatin (DNA) is the
essential genetic material (replication of
DNA and control of gene action),
nucleolus (RNA formation).
• The cytoplasm: mitochondria (energy
production), lysosomes (lysosomal
enzymes), RER with ribosomes (protein
synthesis), SER (drug metabolism,
carbohydrate and cholesterol
metabolism), Golgi complex
(modification and packaging of material
synthesized by RER), cytoskeletal
system containing microtubules, actin
filaments, intermediate filaments
(rigidity, locomotion, and excretion).
 Cellular Responses to Injury

• Cellular adaptations.
• Cell injury.
• Cell death.
• Intracellular accumulations.
• Pathologic calcifications.
• Cell aging.
 States of Progressive Encroachment on the
Cell’s Normal Function and Structure
• Normal homeostasis: Cell is able to handle normal
physiologic demands.
• Cellular adaptations (adaptive reaction): As a response
to more excessive physiologic stress or some pathologic
stimuli, new but altered steady states are achieved, preserving
the viability of the cell and modulating its function.
• Cell injury: Occurs, if the limits of adaptive response to a
stimulus are exceeded or in certain instances when adaptation
is not possible. The cell injury may be reversible or irreversible.
• Reversible cell injury: Cell injury is reversible up to a
certain point.
• Irreversible cell injury: If the stimulus persists or is severe
enough from the beginning, the cell reaches the point of no
return and suffers irreversible cell injury and cell death.
• Cell death: Cell death is the ultimate result of cell injury. It
has two principal patterns: (1) necrosis; (2) apoptosis.
 Cause of Cell Injury
Internal Events:
1. Genetic derangements: E.g. Enzyme defects (inborn
errors of metabolism), sickle cell anemia.
2. Nutritional imbalances: Deprivation of essential chemicals
like hormones and vitamins, and nutritional excesses, e.g.
excesses of lipids.
3. Oxygen deprivation: Ischemia (loss of blood supply),
hypoxia (Inadequate oxygenation)
4. Hypersensitivity Reactions: Anaphylactic reaction to a
foreign protein or drug.
External Reactions:
6. Physical agents: heat, cold, trauma, and radiation.
7. Chemical agents: poisons, drugs, and free oxygen
radicals .
8. Microbial: Invasion by infectious organisms and effect of
toxins.
Critical role of oxygen in cell injury
 Ischemic and Hypoxic Cell Injury
• Most common type of cell injury in clinical practice, being
major cause of mortality (heart disease) and of morbidity (e. g.
cerebral and renal ischemic disease). Ischemia tends to injure
tissues faster than hypoxia because in contrast to hypoxia,
during which glycolytic energy production can continue,
ischemia compromises the delivery of substrates for
glycolysis.
• Types of cell injury: Reversible and irreversible ischemic
injuries.
 Reversible Ischemic Injury
• Pathologic changes characteristic of ischemic cells that can recover
when they are given an opportunity to do so.
• The first point of attack of hypoxia is the cell’s aerobic respiration, that
is, oxidative phosphorylation by mitochondria. ATP production
reduced→ sodium pump impaired→ retention of sodium and escape
of potassium→ accumulation of fluid in the sacs of RER→ acute
swelling of cell due to water logging.
• Anerobic glycolysis is switched on→ production of pyruvate→ lactic
acid. reduction of intracellular pH.
• Ribosomes detached from ER→ protein synthesis reduced.
• Besides swelling of ER, other swelling of ultrastructural changes are
mitochondrial swelling, plasma membrane alterations, clumping of
nuclear chromatin.
• Cessation of function of active cells, e. g. heart muscle ceases to
contract within 60 seconds of coronary occlusion.
• If oxygen is restored all these disturbances are reversible.
• If ischemia persists, irreversible injury ensues.
 Free Radical Induced Cell Injury
• Free radicals are chemical species that have a single unpaired
electron in an outer orbit.
• Free radicals may be initiated within cells by: (1) absorption of
radiant energy (e.g., ultraviolet light, x-rays. Ionizing radiation
can hydrolyze water into OH and H); (2) enzymatic metabolism
of exogenous chemical or drugs (e.g., CCl4 can generate CCl3);
(3) the reduction-oxidation reaction that occurs during normal
metabolic processes.
• Three reactions by these reactive species are relevant to cell
injury: Lipid peroxidation of membranes, oxidative modification
of proteins, and lesions in DNA.
• Enzymatic and non-enzymatic systems that contribute to inactivation of free radicals: (1)
antioxidants (vitamins A, C and E), binding proteins for iron and copper (transferrin,
ceruloplasmin), and enzymes that act as free radical-scavenging system ( catalase,
glutathione peroxidase).
 Damage Caused by Chemicals, Drugs, and
Toxins:
Mechanism:
• Some chemicals act directly: Cyanide poisons mitochondrial
cytochrome oxidase and blocks oxidative phosphorylation.
• Some chemicals act after being converted to reactive free
radicals: The toxic effects of CCl4 is due to its conversion
active to CCl3.
• Inhibition of transcription of DNA to mRNA (actinomysin D).
• Inhibition of movement of ribosomes along mRNA→ inhibition
of protein synthesis (Diphtheria toxin).
General Biochemical Mechanisms of Cell
Injury
1. ATP depletion.
2. Role of oxygen and oxygen-derived free radicals.
3. Defect in membrane permeability.
4. Intracellular calcium and loss of calcium
homeostasis.
5. Irreversible mitochondrial damage.
 Morphological Changes in Cells with
Reversible Cell Injury

• Changes associated with accumulation of water in

the cell: Cloudy Swelling, Vacuolar Degeneration, Hydropic
Degeneration.
• Changes associated with accumulation of fat: Fatty
degeneration or fatty infiltration.
• Hyaline degeneration or hyaline-droplet change.
 Changes Associated with Accumulation of
Water in the Cell: Cloudy Swelling, Vacuolar
Degeneration, Hydropic Degeneration
• Cause: adverse conditions like
ischemia, hypoxia, and the effects
of a poison.
• Gross: Occurs frequently in
parenchymatous cells, e. g. liver
and kidney. Affected organ is soft;
has a grey, parboiled appearance,
and its cut surfaces bulge outwards.
• Micro: The cells are swollen due to
an accumulation of fluid (water-
logging). The cytoplasm is granular
in cloudy swelling, vacuolar in
vacuolar degeneration, and pale and
homogeneous in hydropic
degeneration.
• Significance: Condition is reversible
but in most severe form may
terminate in death
 Changes Associated with the Accumulation of
Fat (Fatty Change)
• Definition: An accumulation of excess stainable neutral fat in
parenchymal cells.
• Cause: Ischemia, hypoxia, and the effects of a poison.
• Examples of affected sites: Liver (fatty liver) in
alcoholism, cirrhosis, and congestive cardiac failure. Kidney
and heart are also affected by fatty change.
• Gross pathology: Fatty liver is enlarged, pale to yellow (in
severe cases). Its cut surface bulges, and greasy to touch.
Kidney is pale and its cortex is swollen. Yellow flecks in
endocardial surface of heart (thrush-breast, or tabby-cat heart).
• Microscopic findings: The cells are swollen and contain
small droplets composed of neutral fat (glyceryl triesters).
Earlier the term fatty degeneration was used for early changes
and fatty infiltration (one large fat globule pushing the nucleus
to one side) for advanced cases. Now the term fatty change is
used to include both conditions.
Fatty change in liver
Fate of a Cell with Degenerative Changes
• The cells subjected to adverse conditions show a complex
reaction: changes may be regarded as adaptive, degenerative,
or even lethal.
• A damaged cell is not an inactive cell and its reaction to injury
may end in recovery: Parts injured beyond recovery are lysed
or extruded, and the remaining structures reform the lost
components.
• The cells may return to normal but some alterations may
persist (e.g. metaplasia). There may be altered function,
appearance, or both.
• Various degenerative changes indicating hyperfunction,
hypofunction, altered function, and focal degeneration can all
occur within a single cell either simultaneously or sequentially.
• Light microscope can give a vague impression of intracellular
events and detect the changes when they are severe enough to
affect the cell as a whole.
• Electron microscopy can reveal which parts of the cell are
affected and indicate the sequence of events and metabolic
changes which are occurring.
Ultrastructural Changes in Cell with Reversible
Injury
Nuclear Changes:
Condensation of chromatin adjacent
to the nuclear membrane and
around the nucleolus, loss of
granular component of nucleoli and
fragmentation into smaller and more
numerous nucleoli. Impaired
synthesis of ribosomal material and
mRNA, and reduced protein
synthesis.
Cytoplasmic Changes:
Swelling of the mitochondria,
fragmentation of cell membranes
(endoplasmic reticulum, etc.), and
increased permeability of cell
membrane. Various degenerative
changes indicating hyperfunction,
and hypofunction can all occur
within a single cell either
simultaneously or sequentially.
 Ultrastructural Changes in the Cell and Mechanism of
Reversible Injury
1. Evidence of increased function (hyperfunction): Increase in smooth
endoplasmic reticulum, free ribosomes, rough endoplasmic reticulum, Golgi
complex, lysosomes, and mitochondria (e. g. oncocytes). Cell’s metabolism
increased due to stimulation of protein synthesis, ATP production, glycogen
synthesis, and catabolic activity. May indicate an adaptive mechanism, an
attempt to increase the cell’s ability to detoxify the substance.
• Evidence of decreased function (hypofunction): In hydropic degeneration the
damaged liver cells have dilatation of sacs of RER and loss of attached
ribosomes leading to impaired protein synthesis. In cloudy swelling,
mitochondria are swollen due to accumulation of fluid in the matrix and
membranes. Cristae are also swollen, shortened, and reduced in number.
Impaired function results in reduced oxidative phosphorylation, and
decreased ATP production, which is required for operation of pump and
concentration of ions in the cell. When sodium pump is impeded, sodium
accumulate in the cell. The cell becomes hypertonic. To counteract it water
enters the cell, which is enlarged and water-logged (hydropic).
• Abnormal accumulation of substance in the cell (e. g, lipid): Liver is a key
organ in fat metabolism. In addition to being able to manufacture fatty acids
themselves, the liver cells remove fatty acids from the blood stream and
utilize it in the production of phospholipids. These are bound to protein, and
returned to the blood as lipoproteins by an active transport mechanism. If
liver cells are damaged due to hypoxia and poisoning, protein synthesis is
impaired; lipoprotein manufacture is impeded. The fat taken up by the liver is
inadequately utilized and accumulates initially as small droplets in the RER
and sacs of Golgi complex and later fuse to form large globules.
Thank You