Pathology Introduction Cell Injury & Adoptation

PATHOLOGY INTRODUCTION
CELL INJURY & ADOPTATION
department of pathology 1
PATHOLOGY
• Pathology is the study of the structural
and functional causes of human
disease.
PATHOLOGY
• Definition of Pathology "Pathology is the
medical science and speciality practice that
deals with all aspects of disease, but with
special reference to the essential nature, the
causes, and development of abnormal
conditions, as well as the structural and
functional changes that result from disease
processes. “
• More simply it is the study of disease. The
literal translation of pathology from Greek
(pathos, -logos) is "the words of suffering."
Aspects of Disease
• Etiology (cause)
• Pathogenesis (physiologic mechanism)
• Pathologic anatomy (histopathology or
morphology)
• Functional derangement and clinical
significance (symptoms)
Disease etiology - VINDICATE
• Vascular (atherosclerosis, thrombosis)
• Infectious (viral, bacterial, mycobacterial,
spirochetal, fungal, protozoal, and
arthropod)
• Neoplastic (both benign and malignant
tumors)
• Drugs or toxins
• Inflammatory/idiopathic
• Congenital (chromosomal abnormalities, gene defects)
Disease etiology (continued)
• Autoimmune disorders (lupus,

rheumatoid arthritis)
• Trauma or environmental (heat, cold,
vitamin deficiencies, nutritional)
• Endocrine/Metabolic (diabetes,
acidosis)
Pathogenesis - Definition
• The sequence of events in response to
cell injury, from whatever etiology, that
leads to the ultimate expression of the
disease (symptoms)
• Many times the pathogenesis or

etiology is unknown, in which case we
say that the disease pathogenesis is
idiopathic
Pathologic Anatomy
• The morphologic changes in cell and

tissue structure may either be
characteristic or suggestive of the
disease process in question, or
they may be diagnostic of the disease, in
which case we say that they are
PATHOGNOMONIC
Cell Injury
Causes of Cell Injury
• Hypoxia and free-radical injury
• Physical agents (heat, cold, radiation, trauma)
• Chemical agents and drugs
• Infectious organisms
• Immunologic reactions
• Genetic derangements
• Nutritional imbalances
• Neoplasia
• Aging
• Causes
• Hypoxia
• ischemia (vascular obstruction-prevents O2 and nutrients)
• infarction
• anemia
• Methemoglobinemia (Ferrous to Ferric which alters the
binding of oxygen to hemoglobin),
carboxyhemaglobinemia( CO poisoning)
• metabolic impairment
• reduced production of ATP
• e.g. cyanide poisoning
• Causes
• physical injury
• trauma
• irradiation, including UV
• heat (beware heat pads)
• Cold
• pressure
• may be exacerbated by concurrent vascular
damage
• Causes
• biological agents
• virus induced cell damage
• bacterial toxins
• protozoa, fungi, algae
• host response
• inflammation
• immune reactions - immunopathology
common cause of cell injury
• A common cause of cell injury
• ischemia, which leads to infarction !!!
• reduced oxygen carrying capacity
• metabolic abnormalities
• tissues vary in susceptibility
• variable demands for energy
• ability to utilize anaerobic metabolism
• The brain is mostly affected because it uses glucose as
its only source of energy as compared to the skeletal
muscle which is anaerobic !!!
• Therefore, tissues using anaerobic resp. can withstand
hypoxia vs aerobic, since they don’t depend on
oxygen. department of pathology 13
Hypoxic Cell Injury
common cause of cell injury

*
Autolysis, since they brk

dwn whatever they contact
Ca+ is stored in the SR and the mitochondria.

Also, there is the Ca+ ATPase pump that pumps Ca+ into the mitochondria from the
cytosol.
Ca+ pumped from the SR and into the cytosol, increases enzyme activity with
regard to ATPase for the depletion of ATP, Protease for protein break down,
Phospholipases for cell membranedepartment of pathology
injury and Endonucleases for DNA damage.14
Cell Injury
Principles of Cell Injury
• Dependent upon the etiology, duration, and severity of the
injury
• Dependent upon cell type, stage of cell cycle, and cell

adaptability
• Cellular membranes, mitochondria, endoplasmic reticulum,

and the genetic apparatus are particularly vulnerable
• Injury at one focus often has a cascade effect
• Morphologic reactions occur only after critical biochemical

(molecular) damage
Mitochondria in Hypoxic
Injury
ATP depletion & mitochondrial
damage
• Hypoxia – decreased ATP synthesis
lipid peroxidation
• Increased Ca+ in the cytoplasm
• Release of cytochrome C – apoptosis
• Increased ATPase activity in the cytoplasm
• Inactivation of Na K ATPase pump
• Increased influx of Na+ and efflux of K+
• Cell swells
• Anaerobic metabolism – decreased glycogen
increased lactic acid
decreased pH
ER damage
Cell Membrane in Hypoxic
Injury
• Alterations occur early in injury
• blebbing
• loss of specialized structures – e.g. cilia
  Na:K, Ca pumps, influx of Na+, efflux of K+
• influx of water
• cell swelling
• what draws water into the cell?
• membrane disruption, loss of large
molecules
The ER in Hypoxic Cell
Injury
• Early water influx enters ER
• leads to distension and vacuolation
• disaggregation and detachment of
ribosomes
• reduced protein-synthetic capacity
• effects on protein production
• lipidosis
Lysosomes in Hypoxic Cell
Injury
• Contain potent hydrolytic enzymes
• “Suicide bag” hypothesis

• Lysosomal damage is typically a late
event
• thought not to be involved in causing cell death
• Important in autolytic breakdown of dead cells
• variable number of lysosomes in different tissues
• May be important in some forms of
injury
Cell Injury due to Membrane
Damage
• Causes
• irradiation
• chemical toxins and drugs
• reactive intermediates
• bacterial toxins – phospholipases
• complement
• nutritional
• vitamin E, selenium deficiency
• Ca+ is low in the intracellular region and
enzymatic reactions are lowered
Mechanisms of Membrane Injury
• Direct membrane injury

• certain chemicals (ccl4, mercuric chloride)
• complement
• phospholipases
• Free radicals
• lipid peroxidation
• Tissue targets
Lipid Peroxidation
• Initiated by free radicals

• unpaired electrons, highly reactive
• Sources
• metabolism by P-450 mixed function
oxidases
• reactive oxygen species
• from inflammatory cells – O2-, H2O2, ·OH
• Cellular metabolism
• need for free radical scavengers
Lipid Peroxidation
• Free radicals react with unsaturated lipids in cell

membranes
• Generate lipid radicals
• Combine with oxygen generating lipid peroxide

and another lipid radical
• lipid peroxides break down to form aldehydes

(malonaldehyde) and more organic radicals
Lipid Peroxidation
• Consequences
• membrane dysfunction
• plasma membrane and organelle membrane will blub, ie; a
part will bulge out due to swelling
• catalysis by metal ions – Fe, Cu
 protein synthesis
• ion fluxes
• DNA damage
• protein cleavage and cross linking
• aldehydes (cf fixation)
• enzyme dysfunction (since proteins are broken down)

Membrane Injury
• Functional and morphologic sequelae

• CCl4 model can be converted to CCL3 which
is toxic
• Early changes in RER – ribosome
disaggregation
• Distension of ER and cell swelling
• Hepatic lipidosis
  synthesis of apolipoprotein
• Otherwise many similarities to hypoxia
Lipid Peroxidation - Defenses
• Superoxide dismutase – O2-  H2O2
• catalases break down H2O2
• An accumulation of superoxide and hydrogen peroxide can
lead to cell and membrane damage !!!
• antioxidants
• vitamin E – membrane associated
• ascorbate (vit. C) – cytosolic associated
• glutathione – GSH  GSSH
• glutathione peroxidase – selenium containing. If absent, it
can lead to Lipid Peroxidation which will lead to free
radical injury to the cell
• quenching of lipid peroxidation
Reactive Oxygen Species and Hypoxic Cell
Injury
• Reperfusion injury
• increase in free radicals (this occurs as WBCs within
the blood becomes active when they enter a hypoxic
site and release the “free radicals”) and metabolites
following reperfusion
• free radical scavengers can limit infarct size
• Infiltrating leukocytes : Inflammatory cells in circulation

by the use of lipid Peroxidation.
• Xanthine oxidase
• derived from xanthine dehydrogenase
• species differencesdepartment
– dogs, cats, rats, cattle
of pathology 28
Xanthine Oxidase
Cell Injury - Targets
 Mitochondria, DNA and Membranes
as the targets
 (Primary VS Secondary)
 Hypoxia : Mitochondria
 Hyperoxia: Membranes & DNA
 Chemicals: Membranes and E.R. but DNA &
Mitochondria can be affected also.
Cell Injury
• Reversible
• Irreversible
Reversible injury
• Hydropic swelling (due to H20 filling)

• Plasma membrane blebs
• Dissociation of ribosomes
• Swollen mitochondria
• Aggregation of nucleolus
Irreversible
injury
• Denotes pathologic changes that are
permanent and cause cellular death.
• If ischemia persists, irreversible injury

ensues.
• Due to rupture of mitochondria, cell
membrane and lysosome and permanent
damage to the DNA.
Major Processes of Cell Injury
• 1. Decreased ATP because of decreased cellular
respiration is often caused by either ischemia or
toxins.
The reduction in ATP starts a cascade of other
effects which do further damage including failure to
maintain normal Na and Ca gradients.

• 2. Toxic oxygen radicals are formed normally
during respiration, but unless they can be scavenged
effectively, they may cause cellular damage.
• 3. Calcium regulation within the cell plays
an important role in cell homeostasis.
• Normal intracellular calcium in the cytosol is

less than 0.1 micromol and 1.3 mmol outside
the cell or in the mitochondria and ER.
• Gradients are maintained by ATPase pumps.

Influx of calcium into cytosol activates
phospholipases, proteases, ATPases and
Endonucleases which then act to further
cellular damage.
Major Types of Cell Injury
• Chemical Injury: some chemicals cause

direct cell injury through a variety of
mechanisms, e.g., cyanide works to disrupt
cytochrome oxidase.
• Indirectly, Carbon tetrachloride (CCl4)

poisoning occurs only after the P-450
oxidative enzymes convert it to the reactive
CCl3 activated species that causes lipid
peroxidation.
Hypoxic/Ischemic Injury
• 1) First consequence is loss of oxidative
phosphorylation and reduction in ATP
production. This causes effects on the
following:
a) failure of ATP dependent Na/K pumps
and Ca pump that normally maintains high cell
K and low cell Na and Ca. So now K decreases
and Na and Ca increase within the cell. Na
brings water and cell swelling. Ca causes many
effects including activation of phospholipases
that disrupt the membrane.
b) decrease in ATP increases glycolysis

and thus decreases pH from lactic acid buildup
within the cell and decreases glycogen stores
• 2) Disruption of organelle membranes
and loss of ATP needed for synthesis of
proteins results in ribosomes detaching
from RER and ER swells.
• This decreases protein synthesis, which

leads to membrane disruption,
decreased mitochondrial function, and
disruption of the cytoskeleton.
• 3) Ongoing hypoxia will eventually result in
formation of blebs and myelin figures (plasma
and organelle membranes in lamellar stacks),
swollen mitochondria, dilated ER.
• There is not some magical point at which
cell function is lost and cell is doomed for
destruction. The changes above are
reversible, but at some point, return of
oxygen will not lead to cell recovery.
ATP mechanism (if it recommences) and
cell membrane seem most important--
especially membrane integrity.
• Membrane function depends mostly on
mitochondrial function, phospholipid loss
of membrane components, mostly from
endogenous phospholipase activation, and
decreased synthesis of new phospholipids.
• Cytoskeleton attaches to plasma membrane

and strengthens it. Proteases may damage
this connection and the plasma membrane
is thus more susceptible to rupture.
Reactive oxygen species injure cell
membranes and lipid byproducts may have
a detergent effect on membranes.
• Irreversible injury is associated with massive
calcium influx which is further worsened when
perfusion is re-established.
• Morphologically, vacuolated mitochondria
with large calcium deposits and nuclear
changes (karyorexhis, etc.) illustrate
irreversible damage.
• Lysosomal membrane injury causes release
of enzyme contents that eventually lead to
irreversible nuclear damage. Myelin figures
are phagocytosed by other cells or calcified
into calcium soaps.
• Enzymes will be leaked to extracellular space
--i.e. CK-MB.
Reperfusion injury:
• Much of the damage from ischemia or

hypoxia occurs on the re-establishment
of circulation: reperfusion can help
restore health to reversibly damaged
cells, but can also lead to cell death
through apoptosis and necrosis.
• Causes:
• 1) circulation brings PMNs (neutrophils
especially) that release toxic oxygen radicals
that do damage to membranes.
Damaged cells may express cytokines that
attract PMNs to them and cause inflammation
with additional injury.
• 2) reperfusion brings a massive influx of Ca++

which leads to activation of phospholipases,
Endonucleases, proteases (cytoskeleton), and
DNAases
Oxygen radicals may be produced via :
• outside energy (radiation),
• metabolism of chemicals (CCL4),
• normal metabolic reduction of O2 to water,
• Lysosomal enzymes, and from
• iron or copper metals or nitric oxide.

• Oxygen radicals (free unpaired electron in
outer orbit) do three main things:
• 1. lipid peroxidation -- takes an unsaturated
fatty acid in membrane phospholipids and
crease a damaged lipid and peroxide, which is
autocatalytic and does more damage
• 2. promotes sulfhydryl mediated protein cross

linking that creates disulfide bonds which
inactivate enzymes
• 3. interact with DNA causing mutations,

especially with thymine causing single strand
breaks
• Note that these radicals are removed by
other mechanisms including
antioxidants, catalase (peroxisomes),
superoxide dismutase (cytosol),
glutathione peroxidase.
• Nucleotide Endonuclease Repair
Reperfusion Injury and
Activated Oxygen
• Toxic oxygen species are generated, not
during the ischemia itself, but during
reperfusion, hence the term reperfusion
injury
• This has clinical relevance, since reperfusion
of heart muscle is commonly achieved with
per-cutaneous angioplasty.
Patients more than 20 minutes post-infarction
are at risk for reperfusion injury.
• Cell Injury Caused by Oxygen Free Radicals
• Superoxide anion (O2-) – may be formed via the

cytochrome P450 system, which metabolizes many
drugs and toxins – removed by superoxide
dismutase
• Hydrogen peroxide (H2O2) – removed by catalase or

glutathione peroxidase
• Hydroxyl radical (.OH) – initiates lipid per-

oxidation and DNA damage
• Cell Injury
How Radiation Kills Cells
• Absorption of radiant energy with
sufficient energy to initiate the
radiolysis of water, i.e., “ionizing”
radiation, leads to the following
reaction:
• H2O  .H + .OH
• How Radiation Kills Cells
• Hydroxyl radical initiates lipid per-oxidation,
leading to severe damage to membranes
• Hydroxyl radical also damages DNA, which
leads to an inability to replicate, and
eventually apoptosis (in proliferating cells)
• Non-proliferating cells (nerve cells) may be
killed by radiation, but much higher absorbed
doses are required
• How Viruses Kill Cells
• Direct cytotoxicity
• Indirect cytotoxicity, via the immune system
(activated killer T cells identify viral proteins
on the cell surface and kill the cell)
• Cell Injury
• How Chemicals Kill Cells
• otransformation
• The cytochrome P450 system (a mixed-function oxidase) in

the liver converts toxins like carbon tetrachloride and
acetaminophen into much more toxic substances, either via
the production of toxic intermediates, or indirectly-
generated oxygen radicals. The end result is lipid per-
oxidation, and severe membrane damage.
• Cell Injury
Cell Injury
General Biochemical Mechanisms
• ATP depletion
• Oxygen free radicals
• Loss of calcium homeostasis
• Membrane defects
• Mitochondrial damage
Response to Injury
• Adaptations (reversible)
• Hydropic degeneration
• Hypertrophy, Hyperplasia, Atrophy( due to disuse,
nerve damage and diminish blood flow)
• Accumulations - hyaline, fat, etc.
• Cell death / Necrosis (irreversible)

• Coagulative – Infarction - Heart
• Liquifactive - Brain, abscess (pus)
• Caseous - Tuberculosis
• Gangrene - With infection – limbs.
Definition - Hypertrophy
• Hypertrophy is an increase in the size of
individual cells, in response to a stimulus or
injury. This usually results in increased size
and weight of an organ, plus (usually)
increased functionality. A good example would
be the hypertrophy of skeletal muscle myocytes
in body builders.
LEFT VENTRICULAR
HYPERTROPHY
Definition - Atrophy
• Atrophy is the opposite of hypertrophy, in that

individual cells decrease in size, and may lose
function, due to disuse, denervation or
interruption of trophic signals, ischemia, or
chronic injury.
Atrophy, heart - micro
ALZHEIMERS
RENAL ARTERY STENOSIS
Definition - Hyperplasia
• Hyperplasia is an increase in the
absolute number of cells, in response to
a stimulus or persistent cell injury. This
usually results in increased size and
weight of an organ. A good example
would be the enlargement of the breast
during pregnancy, due to the influence
of estrogen.
Hyperplasia – Normal breast (for
comparison)
Hyperplasia – Lactating breast
Definition - Metaplasia
• Metaplasia is an induced change in the type
of mucosal epithelium,
e.g., from ciliated columnar epithelium to
squamous epithelium, (which can withstand
stress) brought about by various forms of
chronic injury. Most commonly, this is seen
in the bronchi (due to cigarette smoke), or in
the uterine cervix (due to chronic
inflammation).
• Metaplasia can lead to Dysplasia which can
lead to cancer. department of pathology 66
Definition - Dysplasia
• Dysplasia means disordered growth, most
commonly seen in squamous epithelial cells
following chronic injury.
Morphologically, it is characterized by
variations in size and shape of the cell,
disorderly arrangement within the
epithelium, and nuclear changes, consisting
of enlargement, irregular borders, and
hyperchromasia of individual cell nuclei.
Normal Uterine Cervix (for
comparison)
Dysplasia – Uterine Cervix
Squamous metaplasia -
uterine cervix
Cell Injury
Dysplasia
• Dysplasia is the only one of the above
conditions that is considered pre-
malignant ( dysplasia often arises in
previously metaplastic epithelium), and
can progress to malignant squamous
cell carcinoma, unless treated.
Cell Injury
Intracellular accumulations
• Fat
• Triglycerides, cholesterol, and
phospholipids
• Glycogen
• Lysosomes
• Iron
• Lipofuscin
• Melanin
• "Hyaline"
• Exogenous pigments
Cell Injury
Irreversible Cell Injury
• “If the acute stress to which a cell must react
exceeds its ability to adapt, the resulting
changes in structure and function lead to the
death of the cell” .
Cell Injury
Irreversible Cell Injury
• “Cell injury is classified into two types,
depending on the underlying mechanisms
responsible for the loss of viability, namely
necrosis and apoptosis”
Apoptosis
• Occurs when a cell dies through the
activation of an internal suicide program.
• This is mainly useful in eliminating the
unwanted cells with minimal disruption of
the surrounding tissue.
• Can be seen mainly in the elimination of
unwanted cells during embryogenesis.
• It is activated by Cyt. C
Cell Injury
Apoptosis – definition
• “Apoptosis refers to a genetically
determined, internal, self-destruct
mechanism of cell death, which is activated
under a variety of conditions”
• Developmental morphogenesis
• Radiation
• Immune system regulation
• Viral infections
• Cancers
• Toxins
Cell Injury
Morphology of Apoptosis
• Similar or identical to necrosis at the light
microscopic level, EXCEPT
• Tends to affect individual cells, against a
background of viable ones
• Usually an absence of acute inflammatory cells
Apoptosis
• Programmed cell
death
• Normal
physiological death,
different from
accidental death
(myocardial
infarction).
• Various signals,
internal (genes) &
external initiate
apoptosis.
Steps in Apoptosis
• Condensation of chromatin (pyknosis)
• Fragmentation of DNA by enzymatic digestion
• Fragmentation of nucleus & dissolution of nuclear

envelope
• Loss of junctional complexes & cell shrinkage

• Fragmentation of the entire cell into membrane
bound fragments (apoptotic bodies)
• Removal of apoptotic bodies by macrophages &
surrounding cells department of pathology 80
Necrosis
• Pathologic death of one or more cells, or of
a portion of tissue or organ, resulting from
irreversible damage.
• Necrosis is the sum of the morphologic
changes that follow cellular death in the
tissue or organs.
• Mainly two processes cause the
morphologic changes of necrosis;
1. Denaturation of proteins
2. Enzymatic digestion of organelles and
other cytosolic components.
Types of Necrosis
• Autolysis:
• Cell digestion due to Hydrolytic enzymes
derived from dead cells.
• Heterolysis:
• Cell digestion due to enzymes derived from
invading inflammatory cells.
• pyknosis
• a degenerative state of the cell nucleus
• Nuclear shrinkage
• Increased Basophilia
• Karyorrhexis
• nuclear fragmentation
• With in 1 to 2 days nucleus disappears.
Nuclear changes
• karyolysis
• disintegration and dissolution of a cell
nucleus when a cell dies
• Due to DNAse activity,
• Basophilia of chromatin fade
Subtypes Necrosis
• Liquefactive necrosis
• Fat necrosis
• Caseous necrosis
• Coagulative necrosis
Cell Injury
Liquefactive necrosis
• Liquefaction necrosis occurs when the rate of
cell destruction exceeds the rate of repair.
• It is due to autolysis and heterolysis
• The necrotic area is soft and filled with fluid.

• Pyogenic (pus-forming) abscesses
• Brain
Liquefactive necrosis
Cell Injury
Definition - Fat necrosis
• Fat necrosis occurs only in adipose tissue,
usually in association with pancreatitis, which
releases numerous lipases and proteinases.
Liberated fatty acids become saponified to
form calcium soaps, which appear as
amorphous blue areas in H&E stained tissue
sections, often at the periphery of the necrotic
lesion.
Saponification Reaction
Triglyceride – (fat)
R-C-O-CH2
O
R-C-O-CH + lipase + Ca++ = (3) RCOO-Ca++ (soap)
O
R-C-O-CH2
O
Definition - Caseous necrosis
• Caseous (cheesy) necrosis is normally found
in association with Mycobacterium, and is
thought to be due to the presence of mycolic
acids within their cell membranes. When
seen by the pathologist, tuberculosis must be
ruled out clinically.
• Soft , friable & Cheesy material.
• Associated with TB
Extensive caseous necrosis:
Tuberculosis
Definition – Coagulation
necrosis
• Most common pattern of necrosis.
• Characterized by Denaturation of
cytoplasmic proteins.
• Commonly occurs in myocardium, kidney,

liver and lung( only if lung isn’t TB infected)
Coagulative necrosis
Sequels of Necrosis:
• Cell Death
• Necrosis
• Autolysis
• Phagocytosis
• Organization & fibrous repair.
Cell Injury
Pathologic calcification
• Dystrophic calcification
• May occur at any serum calcium level
• Usually occurs in previously injured tissue
• Metastatic calcification
• Occurs at high serum calcium levels
• Often related to bone metastases
• It can occur in any organ, even in normal tissue,
during periods of hypercalcemia (from whatever
cause)
STEATOSIS
yellow discoloration as a result of the
accumulation of certain fats (triglycerides) in the
liver; can be caused by alcoholic cirrhosis or
pregnancy or exposure to certain toxins
lipofuscin
• Brown pigment granules representing lipid-
containing residues of lysosomal digestion and
considered one of the aging or “wear and tear”
pigments; found in liver, kidney, heart muscle,
adrenal, and ganglion cells.

Lipofuscin
• The "aging" pigment.
• The ( wear and tear) pigment left over from
the breakdown and digestion of damaged
blood cells.
• Found in heart muscle and smooth muscles.

Lipofuscin
• As one ages, the amount of lipofuscin will
continue to increase, especially in the heart.
• One can determine whether a heart is
relatively young or old, as a direct reflection
of the amount of lipofuscin present

brown atrophy
• atrophy in which the affected viscus assumes
a brownish hue, due to intracellular
accumulation of lipofuscin; it is seen chiefly
in the heart, liver, and spleen of the elderly.

BRONZE DIABETES
• genetic disease of the liver in which the body
takes in too much iron from food. Also called
"hemocromatosis." A high level of heme can
lead to diabetes.

hemosiderin,
• granular brown substance composed of
ferric oxide; left from the breakdown of
hemoglobin; can be a sign of disturbed iron
metabolism

Dystrophic Calcification

Metastatic Calcification
• Calcium deposits, which occur commonly in
hypercalcemic states, are found in the kidney,
stomach, lung, brain, eyes, skin,
subcutaneous and periarticular (surrounding
a joint) tissues, and arterial walls.
This type of calcinosis is usually related to
other underlying conditions, such as
hyperparathyroidism, hypoparathyroidism or
renal disease.

Ageing

Ageing:
“Progressive time related loss of structural and
functional capacity of cells leading to death”
• Senescence, Senility, Senile changes.

• Ageing of a person is intimately related
to cellular ageing.
• Countdown starts with birth…!

Factors affecting Ageing:
• Genetic – Clock genes, (fibroblasts)
• Diet – malnutrition, obesity etc.
• Social conditions -
• Diseases – Atherosclerosis, diabetes etc.
• Genetic disease - Werner’s syndrome.

Cellular mechanisms of
ageing

Telomerase in ageing:
Germ
Cells
Somatic
Cells

Cell Injury
Theories of aging
• Genetic theory – cells have a predetermined

life span, which may be altered by
environmental factors
• Accumulated somatic damage
• Summary hypothesis

Cell Injury
Genetic theory
• This theory postulates that each
organism has a genetically
programmed finite life span. It can be
modified by environmental factors, but
not much, i.e., you are your genes. Pick
long-lived parents.

Cell Injury
Somatic damage theory
• lipid peroxidation is induced by oxygen
free radicals.
• Lipofuscin pigment contains products of
the peroxidation of fatty acids, and is
increased in aged cells (wear and tear
pigment).
• Presumably, its presence implies a
continuing deleterious effect on lipid
membranes by free radicals, as a result of
inadequate defenses.
Cell Injury
Theories of aging
• Summary hypothesis postulates that the

two previous theories are not mutually
exclusive, but allows for possible
alterations in your pre-determined
genetic aging through the use of anti-
oxidants, caloric restriction, exercise,
and possibly future bio-engineering of
senescence genes.
Cellular ageing mechanisms:
• Nuclear:
• Reduced synthesis of nucleic acids
• Telomere shortening
• Clock genes
• Metabolic:
• Reduced Mitochondrial oxidative reactions
• Reduced protein synthesis, Protein cross
linking.
• Decreased cell receptors, transcription factors.
• Oxidative peroxidation of organelles.
Ageing – Morphologic
changes:
• Loss of skin elasticity

• Easy bruising – fragile capillaries.
• Glycosylation of lens proteins –
• Accumulation of Lipofuscin pigment –
Brown atrophy.

Normal Brain surface:

Cerebral atrophy - Alzheimers:

Pathology
of Ageing

Pathology Introduction Cell Injury & Adoptation

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Pathology Introduction Cell Injury & Adoptation

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PATHOLOGY INTRODUCTION

CELL INJURY & ADOPTATION

• Autoimmune disorders (lupus,

• Many times the pathogenesis or

• The morphologic changes in cell and

common cause of cell injury

Autolysis, since they brk

Ca+ is stored in the SR and the mitochondria.

• Dependent upon cell type, stage of cell cycle, and cell

• Cellular membranes, mitochondria, endoplasmic reticulum,

• Injury at one focus often has a cascade effect

• Morphologic reactions occur only after critical biochemical

• “Suicide bag” hypothesis

• Direct membrane injury

• Initiated by free radicals

• Free radicals react with unsaturated lipids in cell

• Generate lipid radicals

• Combine with oxygen generating lipid peroxide

• lipid peroxides break down to form aldehydes

• enzyme dysfunction (since proteins are broken down)

• Functional and morphologic sequelae

• Infiltrating leukocytes : Inflammatory cells in circulation

• Hydropic swelling (due to H20 filling)

• If ischemia persists, irreversible injury

• Normal intracellular calcium in the cytosol is

• Gradients are maintained by ATPase pumps.

• Chemical Injury: some chemicals cause

• Indirectly, Carbon tetrachloride (CCl4)

b) decrease in ATP increases glycolysis

• This decreases protein synthesis, which

• Cytoskeleton attaches to plasma membrane

• Much of the damage from ischemia or

• 2) reperfusion brings a massive influx of Ca++

• outside energy (radiation),

• metabolism of chemicals (CCL4),

• normal metabolic reduction of O2 to water,

• Lysosomal enzymes, and from

• iron or copper metals or nitric oxide.

• 2. promotes sulfhydryl mediated protein cross

• 3. interact with DNA causing mutations,

• Nucleotide Endonuclease Repair

• Superoxide anion (O2-) – may be formed via the

• Hydrogen peroxide (H2O2) – removed by catalase or

• Hydroxyl radical (.OH) – initiates lipid per-

• The cytochrome P450 system (a mixed-function oxidase) in

• Cell death / Necrosis (irreversible)

• Atrophy is the opposite of hypertrophy, in that

• Usually an absence of acute inflammatory cells

• Fragmentation of DNA by enzymatic digestion

• Fragmentation of nucleus & dissolution of nuclear

• Loss of junctional complexes & cell shrinkage

• It is due to autolysis and heterolysis

• The necrotic area is soft and filled with fluid.

• Commonly occurs in myocardium, kidney,

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