Response To stress/ Injury

 Recovery

 Adaptation-Important before cell death

 Cell-Death- Apoptosis and Necrosis

 Depends on duration, severity and type of injury

 Cell injury

Stress/load

Irreversible
Reversible
Adaptation cell injury
cell injury

Cell Recovery
Atrophy, Hypertrophy
and return to Hyperplasia, Meta-plasia
Cell Death
normal

Apoptosis
Necrosis
 Reversible cell injury

Functional and morphologic changes are reversible if

the damaging stimulus is removed.

The features are: decreased oxidative

phosphorylation,
-ATP depletion and cellular swelling.
 Reversible Injury
2: Fatty change:
 accumulation of lipid droplets- vacuolation of cells
 Results due to disturbance of ribosomal function

 The liver is commonly affected

 Occurs in hypoxic injury, toxic-alcohol, metabolic-DM

 Moderate fatty changes are reversible, but sever changes

may not be
 Chronic alcoholism- Liver cirrhosis, NAH
 Pathologic calcification
Abnormal deposits of calcium salts occur in tissues

Two distinct types of pathologic calcification:

1. – Dystrophic calcification; characterised by deposition of calcium salts in dead
or degenerated tissues with normal calcium metabolism and normal serum
calcium levels.

2. Metastatic calcification:apparently normal tissues and is associated with

deranged calcium metabolism and hypercalcaemia

 Etio-pathogenesis of the two are different but morphologically the deposits in

both resemble normal minerals of the bone

 H and E stained sections, – Calcium salts appear as deeply basophilic, irregular

and granular clumps.clumps.

 Pathologic calcification is often accompanied by diffuse or granular deposits of

iron
1: Dystrophic calcification

May occur due to 2 types of causes:

 – Dead tissue
 Degenerated tissue.

Dead Tissue : Caseous necrosis in tuberculosis is the most common site

 Fat necrosis following acute pancreatitis or traumatic fat necrosis in the breast
results in deposition of calciumnecrosis in the breast results in deposition of
calcium soaps
 Thrombi, especially in the veins, may produce phleboliths

Degenerated tissue: Dense old scars -undergo hyaline degeneration and

subsequent calcification.
 Atheromas in the aorta and coronaries frequently undergo calcification

 Stroma of tumours such as uterine fibroids, breast cancer, thyroid adenoma,

goitre etc show calcification.
2: Metastatic calcification •

 Calcification in normal tissue whenever there is hypercalcemia.

 may be due to – Excessive mobilisation of ca2+ from the bone – Excessive

absorption of ca2+ from the gut

 Excessive mobilisation of ca2+ from the bone

 Hyperparathyroidism – Primary : parathyroid adenoma,

 – Secondary: parathyroid hyperplasia, chronic renal failure

 Hypervitaminosis D : Milk-alkali syndrome – Excessive oral intake of calcium in

the form of milk

 administration of calcium carbonate in the treatment of peptic ulce

 Irreversible injury:
It is suggested that cell membrane is the central factor in the
pathogenesis of irreversible cell injury
Also due to:
– sever mitochondrial dysfunction
– lysosomal rupture
Two patterns of cell death:

– Necrosis
– Apoptosis
CELLULAR ADAPTATION TO INJURY

1- Atrophy
2. Hypertrophy
3. Hyperplasia
4- Metaplasia.
5- Dysplasia
 ATROPHY: Shrinkage in the size or function of an organ
or decrease in cell size
 Cells are not dead

Hypertrophy: Increase in the sizes of cells

Physiological
Pathological

Hyperplasia: An increase in the number of cells in a

tissue or organ
Can be pre-cancerous

Metaplasia: substitution of one type of adult or fully

differentiated cell for another type of adult cells
 1- Atrophy
 When a sufficient no of cells is involved, entire tissue or organ
diminishes in size...

Probable Causes of atrophy include:

 Decreased workload –immobilization, Fractured
 Diminished blood supply- blockage/ischemia
 Inadequate nutrition
 Loss of endocrine stimulation
 Loss of innervations- Nervous system injury
 Aging.
In most of the cases reversible but -CNS

Poliomyelitis- virus infect a person's spinal cord, causing muscle weakness, paralysis-Limb
atrophy
Types of Atrophy
 Nutritional atrophy: Caused by malnutrition or inadequate
nutrient/starvation

 Vascular Atrophy: Caused by ischemia or partial loss of blood

supply

 Endocrine Atrophy: Due to hormones imbalance –decrease

seen in involution of thymus and mammary gland

 Pressure Atrophy: Due to mild, continuous pressure on cells and

tissues causing obstruction of blood supply or ducts-cancer or
tumor

 Nervous System: paralysis or nerve impairments

 Biochemical Mechanism:
May be due to imbalance between anabolism (Protein synthesis) and
catabolism due to metabolic disturbance .

An increased degradation of protein (proteolysis) plays a key role in

atrophy.
Two key mechanisms for proteolysis:
– lysosomal – pathway: contain proteases and other enzymes that
degrade molecules from old cytoplasmic organelles like (ER,
mitochondria, ribosomes.

– Ubiquitin – Proteosome Pathway: regulating the degradation

of proteins by the intracellular protease known as the 26S
proteasome, a large complex that breaks down proteins to their
constituent amino acids for reuse
 HYPERTROPHY

 An increase in the sizes of cells, and hence the size of the

organ, an adaptive response may be physiologic (normal)
or pathologic (abnormal).

may be caused by mechanical signals-stretch or trophic signals --

growth factors
E.g Muscle mass, cell or tissue is exposed to an increased
workload.
Occurs in tissues that cannot increase cell number as an adaptive
response
 Two types:
Physiologic hypertrophy is in skeletal muscle
- e.g: adipocytes (fat cells) may expand in size by depositing
more lipid within cytoplasmic vesicle

-increases in body fat tissue occurs mostly by increases-size of

adipocytes, not by increases in the number of adipocytes

Pathologic hypertrophy is in cardiac muscle as a result of hypertension.

LVH-caused by increased workload continuously
 or compensatory process, when one kidney is removed, for example, the
remaining kidney hypertrophies to increase its functional capacity

 Hypertrophy and hyperplasia can also occur together, and obviously both
result in an enlarged (hypertrophic) organ
 HYPERPLASIA
 "An increase in the number of cells in a tissue or organ.

 It occurs in cells/tissue that are capable of mitotic division "

 Physiologic hyperplasia:
- hormonal hyperplasia,
-compensatory hyperplasia,

 Most forms of pathologic hyperplasia are instances of excessive

hormonal or growth factor stimulation.

 Hyperplasia could be precancerous.

For example, increase in the size of the breasts during pregnancy,
-adrenal glans –during stress
increase in thickness of thyroid glands
-endometrium during menstrual cycle,
-milk-secreting glandular cells in breast as a response to pregnancy
-liver growth after partial resection.

Clinical usefulness:

 Wound Healing: Fibroblasts and angioblasts proliferate due

to stimulation by the growth factor and facilitate healing and
repair of wounds.
 Epithelial hyperplasia usually disappears when the cause is
removed
 METAPLASIA
 “ Irritation /injury -(Adaptive) substitution of (or fully one
type of adult or fully differentiated cell for another type of
adult differentiated cell"

 "A reversible change in which one adult cell type replaced by

another adult cell type.“

 It might be wisely adaptive-protective mechanism e.g.

cigarette smoking
-transformation represents a reactive or reparative response to
chronic injury or irritation.

In COPD: -chronic cigarette smokers, following years of exposure

to irritating cigarette smoke

the ciliated columnar epithelium lining the respiratory passages

gradually converts to stratified squamous epithelium which although be
better to survive to the cigarette smoke:

they lack the cilia of the columnar epithelial cells that are necessary
for clearing particulates from the surfaces of the respiratory passages

Sometimes may be a precancerous lesion-Intestinal metaplasia

DYSPLASIA
"Bad growth“: An abnormal/ derangement of cell growth that leads
to tissues with cells of varying size, shape and appearance,
May occurs in response to chronic irritation and inflammation

 A very abnormal epithelium with "loss of uniformity of the

individual cells, as well as a loss of their architectural orientation“,
Includes "atypical hyperplasia" and "atypical metaplasia“

 Fibrous dysplasia of bone: a disorder where normal bone

and marrow is replaced with fibrous tissue

 Myelodysplastic syndromes: a group of cancers in which immature

blood cells in the bone marrow do not mature
 Aplasia
 Failure of cells, tissues or organs to attain their mature size.

Occurs in the embryo or foetus during intrauterine development.

Causes:
– Congenital anomalies due to unknown causes.

– Intrauterine viral infections during early gestation.

 Hypoplasia/ Involution
Involution: Decrease in cell production
-at cellular level, involution is characterized
by the process of proteolysis of
the basement membrane,
-leading to epithelial regression
and apoptosis, with
accompanying stromal fibrosis.

Reduction in cell and reorganization of stromal tissue eventually -

reduction in the size of the organ
e.g: Thymus, Uterus , Mammary Glands

the shrinkage of an organ in old age or when inactive, e.g. of the

uterus after childbirth.
 Summary
Cells adapt to altered environment
Metabolic adaptation
Cell stress response
Changes in growth pattern
Hyperplasia, hypertrophy, atrophy, involution,
metaplasia
 Growth factors, controlling proliferation or cell death,
play a key role in cell adaptations in disease
 Causes of Cell injury
 Physical injury
Mechanical trauma
Thermal-burn injury, frostbite/Electrical current
 Chemical injury
Chemicals, toxins, heavy metals, solvents, smoke,
pollutants, drugs, gases

 Radiation injury
Ionizing radiation — gamma rays, X rays
Non-ionizing radiation — microwaves, infrared, laser
 Biologic agents/ Infectious agents
-Bacteria, viruses, parasites
 Nutritional injury
-Malnutrition
-Obesity
Metabolic disorders
WHAT HURTS CELLS?

Hypoxic cell injury

Free radical injury

Chemical cell injury

 HYPOXIA
loss of the ability to carry on sufficient aerobic oxidative respiration, is the
most common cause of cell injury and death

- a lack of oxygen in cells and tissues that generally results from ischemia.

The hypoxic cellular injury process is either:

reversible, if oxygen is quickly restored,

Or irreversible and lead to cell death, e.g -brain are particularly sensitive to
hypoxic injury.

Death of brain tissues can occur only 4 to 10 minutes after hypoxia begins
 CAUSES OF HYPOXIA
 Ischaemia
 Hypoxia/ Hypoxaemia
 Failure of the cytochromes
 Poor nutrition-
 Infectious agent- virus, bacteria
Genetic diseases:
Sickle cell anemia (substitution of one amino acid in Hb
structure) and muscular dystrophy (muscle tissue does not
function properly
WHAT HURTS CELLS?

Hypoxic cell injury

Free radical injury

Chemical cell injury

 HYPOXIA
loss of the ability to carry on sufficient aerobic oxidative respiration, is the
most common cause of cell injury and death

- a lack of oxygen in cells and tissues that generally results from ischemia.

The hypoxic cellular injury process is either:

reversible, if oxygen is quickly restored,

Or irreversible and lead to cell death. Certain tissues such as the brain are
particularly sensitive to hypoxic injury.

Death of brain tissues can occur only 4 to 6 minutes after hypoxia begins
 Hypoxic cell injury
Event-During hypoxia:
 Aerobic metabolism of the cells begins to fail, leads to drastic decreases in
energy production (ATP)
 Hypoxic cells begin to swell as energy-driven processes begin to fail, (such
as ATP-driven ion pumps).
 The pH of the extracellular / Intracellualar begins to decrease as waste
products
-begin to accumulate, such as lactic acid, a product of anaerobic metabolism.
 Accumulation of intracellular calcium-Calcium-dependent protease
enzymes
-present within cells that become activated in the presence of excess calcium and
begin to digest important cellular constituents
Ischemia : an inadequate blood supply to an organ/ Loss of arterial
blood flow
Local causes
– Occlusion of the arteries
– Occlusion of the veins which allow blood to leave, so that fresh
blood can flow in
– Shunting of arterial blood elsewhere ("steal syndromes"; "Robin
Hood" syndromes)
Systemic causes
– Failure of the heart to pump enough blood
– Kidney failure
Hypoxemia: very little available oxygen in the blood

Due to Oxygen problems

 little oxygen in the air

 Failure to properly ventilate the lungs –infection/COPD
 Failure of the lungs to properly oxygenate the blood
 Failure of the heart to pump enough blood through the lungs -CHF
 Tremendously increased dead space (i.e., pulmonary -thromboembolus)

Due to Hemoglobin problems

- Anemia- decrease RBC level

-Inability of hemoglobin to carry the oxygen (carbon monoxide -
poisoning, methemoglobinemia)
-Thallesmia /sickle cell anemia
-"High affinity" hemoglobins that will not give up their oxygen to the tissues
Failure of the cytochromes:
Mitochondrial oxidative phosphorylation accounts for more than 90% of the
cellular ATP production

Cytochrome c Oxidase (CcO) is the terminal oxidase of the mitochondrial

electron transport chain.

Inhibition of the electron-transport chain also inhibits ATP synthesis because

the proton-motive force can no longer be generated

Cyanide poisoning

Dinitrophenol poisoning

Other curious poisons:

- Warfare gases-Tabun, sarin , soman
 Infectious Injury

 Microorganism – gram neg or positive , fungi, virus

 Disease-producing potential
 Invasion and destruction
 Toxin production
 Production of hypersensitivity reactions

 COVID-19

 Ensure the most effective antibiotics that will work best – anti viral agents for viral
infecions
 Cellular Injury-Consequences

Cellular accumulations:
– Water
– Lipids and carbohydrates
– Glycogen
– Proteins

Cellular swelling is the Ist manifestation of almost all forms of

injury to cells.
 Cell Injury and Death

• Reversible Injury
o Cell swelling develops when cells are incapable of fluid an ion
homeostasis (↓ed function of ATP dependant pumps).
o Fatty change the accumulation of lipid vacuoles in the
cytoplasm.

• Irreversible injury
o Two basic processes underlie the morphologic changes of
necrosis
 Necrosis:Denaturation of protein
 Enzymatic digestion of cell components

 Apoptosis-Gene regulated
Necrosis-Cell Death
Irreversible injury
Necrosis:
 Denaturation of protein,
 Enzymatic digestion of cell components
 Necrotic cells, unable to maintain membrane integrity
-resulted their contents often leak out, which may elicit
inflammation/sweeling in the surrounding tissue.

The enzymes that digest the necrotic cell are derived from the
lysosomes of the dying cells themselves and from the
lysosomes of leukocytes that are called in as part of the
inflammatory reaction.
WHAT HURTS CELLS?

Hypoxic cell injury

Free radical injury

Chemical cell injury

 HYPOXIA
loss of the ability to carry on sufficient aerobic oxidative respiration, is the
most common cause of cell injury and death

- a lack of oxygen in cells and tissues that generally results from ischemia.

The hypoxic cellular injury process is either:

reversible, if oxygen is quickly restored,

Or irreversible and lead to cell death. Certain tissues such as the brain are
particularly sensitive to hypoxic injury.

Death of brain tissues can occur only 4 to 6 minutes after hypoxia begins
 CAUSES OF HYPOXIA

 Ischaemia
 Hypoxaemia
 Failure of the cytochromes
 Poor nutrition
 Infectious agent
 Immune injury
 Chemical agents
 Physical agents
 Hypoxic cell injury
During periods of hypoxia:
1. Aerobic metabolism of the cells begins to fail.
2. This leads to dramatic decreases in energy production (ATP) within the
cells.
3. Hypoxic cells begin to swell as energy-driven processes begin to fail,
(such as ATP-driven ion pumps).
4. The pH of the extracellular environment begins to decrease as waste
products begin to accumulate, such as lactic acid, a product of anaerobic
metabolism.
5.Accumulation of intracellular calcium, which is normally closely
regulated within cells.
6.There are a number of calcium-dependent protease enzymes present
within cells that become activated in the presence of excess calcium and
begin to digest important cellular constituents
• Ischemia : Loss of arterial blood flow
• Local causes
– Occlusion of the arteries that bring in fresh blood
– Occlusion of the veins which allow blood to leave, so that fresh
blood can flow in
– Shunting of arterial blood elsewhere ("steal syndromes"; "Robin
Hood" syndromes)

• Systemic causes
– Failure of the heart to pump enough blood
Hypoxemia: Too little available oxygen in the blood

Oxygen problems ("hypoxic hypoxia")

 Too little oxygen in the air

 Failure to properly ventilate the lungs
 Failure of the lungs to properly oxygenate the blood
 Failure of the heart to pump enough blood through the lungs
 Tremendously increased dead space (i.e., pulmonary thromboembolus)

Hemoglobin problems ("anemic hypoxia")

- Inadequate circulating red cell mass ("anemia")

- Inability of hemoglobin to carry the oxygen (carbon monoxide -
poisoning, methemoglobinemia)
-"High affinity" hemoglobins that will not give up their oxygen to the tissues
• Reversible hypoxic/ ischemic injury

Loss of ATP generation by mitochondria initially results in reversible

events:

o Na+/K+ ATPase membrane pump leads to a loss of ionic and osmotic

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

o ↑ed anaerobic glycolysis results in glycogen depletion and lactate

accumulation (↓ed pH).

o Reduced protein synthesis due to ribosome detachment from the RER

 Sequence of events in reversible injury

 reduced oxidative phosphorylation and ATP production in the mitochondria

 increased anaerobic metabolism (glycolysis)  reduced glycogen stores and

increased production of Lactic acid

 decreased intracellular pH - clumping of nuclear DNA

 decreased activity of Na+ pump (ATP-dependent)

 generalized edema (increased intracellular Na+ and H20)

 detachment of ribosomes from ER - reduced protein synthesis

 surface blebs, mitochondrial swelling

 Cell Injury and Death
Irreversible hypoxic/ ischemic injury
 -Denaturation of protein
 -Enzymatic digestion of cell components
These changes are reversible if O2 and flow are reinstated, the transition to
irreversible injury depends on the extent of ATP depletion and membrane
dysfunction especially of mitochondria.
• ATP depletion results in MTP with loss of the H+ gradient, releases
cytochrome c that can induce apoptosis

• ↑edCa+2 activates membrane phospholipases with resulting membrane

damage
• -Intracellular proteases leading to cytoskeletal degradation
• Phospholipid degradation products that accumulate are directly toxic to the
cell
 Possible Biochemical Mechanisms
of Cell Injury

1) ATP depletion.

2) Generation of reactive oxygen free radicals.

3) Loss of ca++ homeostasis.

4) Defect in plasma membrane permeability.

5) Mitochondrial damage.
 2-Free Radical Mediation of Cell Injury

Definition Of Free Radicals

Extremely unstable, highly reactive chemical species with a single
unpaired electron in an outer orbital

In cells they attack and degrade nucleic acids, proteins, lipids and
carbohydrates

They initiate autocalytic reaction, i.e. molecules that react with free
radicals are converted into free readicals

Examples Of Free Radicals

.
– Hydroxyl (OH )
.
– Hydrogen (H )
.-
– Superoxide (O2 )
2-Free Radical Mediation of Cell Injury
Free radicals constitutes an important mechanism of cell
injury

It Contributes To:
– Chemical and radiation injury
– Oxygen and other gaseous toxicity
– Cellular aging
– Microbial killing by phagocytic cells
– Inflammatory damage
– Tumor destruction by macrophages
– Others

Antioxidant enzymes: SOD, Glutathione, Catalase etc

3-Increased Cytosolic Calcium

Due to membrane disruption,sources:

mitochondria
endoplasmic reticulum
external to the cell

Consequences (activates enzymes)

-Protease
– disruption of membrane and cytoskeletal proteins
– Endonuclease-nuclear chromatin damage
Increased Cytosolic Calcium, source and consequences
 Sequence of events in reversible injury

 reduced oxidative phosphorylation and ATP production in the mitochondria

 increased anaerobic metabolism (glycolysis)  reduced glycogen stores and

increased production of Lactic acid

 decreased intracellular pH - clumping of nuclear DNA

 decreased activity of Na+ pump (ATP-dependent)

 generalized edema (increased intracellular Na+ and H20)

 detachment of ribosomes from ER - reduced protein synthesis

 surface blebs, mitochondrial swelling

 5-Mitochondrial damage

Mitochondrial integrity if cruicial for cell survival

Causes:
MTP formation: Increase Cytosolic calcium, free radicals

Effects:
No ATP generation
Release of cytochrome c into cytoplasm
Mechanism: Summary

1. Decreased oxidative phosphorylation

2. Increased anaerobic glycolysis
3. Detachment of ribosomes/reduced protein synthesis
4. Worsening mitochondrial function
5. Increasing membrane permeability
6. Cytoskeleton dispersion
7. Swelling of mitochondria, endoplasmic reticulum, and
entire cells followed by damage
 Reversible vs irreversible cell injury

• Reversible injury Irreversible injury

 Decreased ATP levels
 * Ion imbalance Amorphous densities in
 * Swelling mitochondria
• Decreased pH
Severe membrane damage
• Fatty change (liver)
• (Steatosis) Lysosomal rupture

• Glycogen  Extensive DNA damage

• Pigments: Lipofuscin
• Bilrubin, Hemosiderin
 Necrosis
 Necrosis is always pathologic.
 Denaturation of protein, severe membrane damage, lysosomal
enzymes enter cytoplasm & digest cell wall.
 Enzymatic digestion of cell:
-Autolysis: hydrolytic enzymes, derived from the dead cells themselves
-Heterolysis: hydrolytic enzymes, derived from invading inflammatory
cells
 When enzymes have digested the cytoplasmic organelles, the
cytoplasm becomes vacuolated
 Cellular contents leak out.
 Histologic changes -apparent after 4 to 12 hours.
 Followed by nuclear changes
Necrotic dead cells:
Cytoplasmic changes:
due to eosin binding to denatured proteins and loss of
cytoplasmic RNA - eosinophilia (pink) increased
Decreased basophilia (blue) – mainly imparted by
cytoplasmic RNA
Dead cells may be replaced by large, whorled
phospholipid masses called myelin figures
Clacification may occur late

Nuclear Changes: -breakdown of the DNA

Nuclear changes  due to break down of DNA

 Karyolysis: Nuclear dissolution and chromatin lysis, decrease

basophilia of chromatin,
 Pyknosis: nuclear shrinkage, clumping of the nucleus and increased
basophilia
 Karyorrhexis: fragmentation of nucleus,
Types and Morphologic Patterns of Necrosis
– Coagulative necrosis
– Liquefactive necrosis
– Gangrenous necrosis
– Caseous necrosis
– Fat necrosis
– Others (fibrinoid necrosis)
 COAGULATION NECROSIS
Death of groups of cells (most often from ischemia).
– Primarily found in Kidneys, heart, and adrenal glands
– Protein denaturation and increased intracellular level of Ca+2
– Architecture of dead tissues is preserved –couple of days.
– the dead area is likely to be soft and pale

 pale area of coagulative necrosis/

infarction in the renal cortex of the
kidney

 myocardial infarction: myocytes dye as

a result of ischemic injury from coronary
artery occlusion
 Liquefactive necrosis

 Digestion of the dead cells, transformation of the tissue into a liquid viscous
mass.

 The necrotic material is frequently creamy yellow because of the presence of

dead leukocytes and is called pus.

 common after ischemic events in CNS (stroke), Neurons and glial cells of
the brain die

 Leaked enzymes – hydrolytic, causes brain tissues to become soft and

liquefy
Caseous necrosis
Caseous” –cheeselike, friable white appearance
– Found in Tuberculous pulmonary infection
– Combination of coagulative and liquefactive necrosis
– Necrotic debris not completely digested thus tissues appear
granular like clumped cheese
– collection of fragmented or lysed cells and amorphous granular
debris enclosed within a distinctive inflammatory border-
Granuloma
Fat necrosis
Not majorly occur:Common in Breast, pancreas, and other
abdominal organs –
– Focal areas of fat destruction, typically resulting from release
of activated pancreatic lipases
– breakdown of fats to FA and glycerols -create soaps and
referred to as saponification
– and tissue is opaque or white chalky
GANGRENE
 Gangrenous necrosis" not a separate kind of necrosis at all, but a
term for necrosis that is advanced and visible grossly.
 Latin word gangraena, an eating sore, -death and decay of a body
part
 Generally the lower leg, that has lost its blood supply, undergone,
typically, coagulative necrosis
 gradual destruction of living tissue, due to an obstruction in the
supply of blood and oxygen to an area of the body

 Foul-smelling discharge
 Loss of feeling in the area
 Amputating the body part that has
gangrene
 An emergency operation to find and
remove dead tissue
 TYPES OF GANGRENE
 Dry gangrene
 Wet gangrene
 Gas gangrene
 Dry gangrene: is usually brought on by a blood clot, frostbite, or poor circulation:

 -that causes the tissues to become dry and shriveled

 WET GANGRENE
 Mostly liquefactive necrosis (i.e., the typical foul-smelling,
oozing foot infected with several different kinds of bacteria),
 or if it's in a wet body cavity
 Swelling, blistering and a wet appearance are common
features
 Common in Diabetic Patients-Toe
 Gas gangrene
Gas gangrene (also known as clostridial myonecrosis and myonecrosis) is a
bacterial infection that produces tissue gas in gangrene.
 is a deadly form of gangrene,
 fast-spreading and potentially life-threatening form of gangrene
 caused by Clostridium perfringens bacteria
 Fibrinoid Necrosis

Usually seen in immune rxn, involving blood vessels-dilation-leakage

-a specific pattern of irreversible, uncontrolled cell death that occurs

when antigen-antibody complexes are deposited in the walls along with
fibrin.

Bright pink and amorphous appearance in H&E stains, called “fibrinoid”

(fibrin-like).

Noma -is a rapidly progressive often

gangrenous infection of the mouth and face
 Apoptosis
 A programmed cell death- coordinated collapse of cell and its
elimination without releasing harmful subs into the surrounding
-protein degradation ,
-DNA fragmentation followed – engulfment

-Approx.50 - 70 billion cells die each day due to apoptosis

Inappropriate apoptosis: when it does not work?
-cells that should be eliminated- persist and may in turn -
cancer and leukemia.
- over activation- may kills too many cells and inflicts grave tissue
damage.
-strokes and neurodegenerative disorders- AD, PD and Huntington
Apoptosis- Process
Involves single cells or small clusters
– Cells shrink rapidly, retain intact plasma membrane
– Formation of cytoplasmic buds, fragmentation into apoptotic
bodies
– Apoptotic bodies- phagocytosed or rapidly degraded
– No inflammatory response, entire process from 5 to 30 min.
Apoptosis
Physiological processes:
during embryogenesis -implantation, organogenesis, developmental
hormone -dependent involution –MC, lactating breast after weaning
cell deletion in proliferating populations -intestinal crypt epithelium
deletion of autoreactive T cells in thymus

Pathological
pathologic atrophy-prostate after castration
Cell death – Cancer/Tumors- Treatement
Cell death induced by cytotoxic drugs and ionizing radiation
Councilman’s bodies/hyaline body- globule of cells that represents a
dying hepatocyte- due to viral hepatitis, yellow fever

Anoikis: Specific variant of intrinsic apoptosis initiated by-loss of integrin-

dependent anchorage.
Apoptosis-Mechanisms
Start when-negative signals recived
– increased levels of oxidants within the cell
– damage to DNA by oxidant,- X-ray or UV light, chemotherapeutic drugs

– death activators :
 Tumor necrosis factor alpha (TNF-)
 Lymphotoxin (TNF-β)
 Fas ligand (FasL)

 Steps in apoptosis:

-the decision to activate the pathway;

-the actual "suicide" of the cell;
-engulfment of the cell by specialized immune cells- phagocytes;
-degradation of engulfed cell.
APOPTOSIS
Apoptosis Triggered via Two Pathways

1: Intrinsic or mitochondrial pathway

- Cytochrome c is released from mitochondria

2: Extrinsic or death receptor pathway

-activated by extracellular ligands binding to cell-surface death

receptors
 Extrinsic or death receptor pathway
initiated by perturbations of the extracellular microenvironment

-detected by plasma membrane receptors,-ligand-TNF-α/Fas-Fas

- propagated by CASP8 and precipitated by executioner caspases, mainly CASP3.

 Intrinsic or mitochondrial pathway
The critical step for intrinsic apoptosis is irreversible and widespread
mitochondrial outer membrane permeabilization
-Cytochrome C

Intrinsic Pathway

Mitochondria

Cytochrome C

Apoptosome Complex
v
Caspases

Cell Death
 Necrosis Vs Apoptosis
Apoptosis:
Necrosis  Single cell death in living
 Grp of cells or part of tissue tissue
 passive process  Active process
 Always pathologic  Physiologic or pathologic
 Mechanism is ATP  Endonucleases
depletion, mb damage  Apoptotic bodies
 Histology: coagulation/liq
 inflammation  No inflammation
 Cell -swelling  shrinkage