Cell Injury:

Cellular Injury (year 2010 )

Dr. Huda M.Zahawi, FRC.Path.

Cell Injury:

Topic Outline

Causes of cell injury Types of Injury Priciples & Mechanisms of cell injury Outcome : ?Reversible ? Irreversible Morphology Adaptation to Injury Patterns & types of Cell Death Process of Aging

Cell Injury:

Cellular Injury & Adaptation

Normal cell is in a steady dynamic state “Homeostasis” :

The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes.

Cell Injury: Cells are constantly exposed to

stresses.

Normal physiologic stress Severe stresses: injury results, and

alters the normal steady state of the cell, consequently,

It can survive in a damaged state and adapt to the injury

(reversible injury or adaptation) It can die (irreversible injury or cell death).

NORMALCELL

STRESS INJURY

AtrophyHypertophyHyperplasiaMetaplasia

Cellular swellingVacuolar change

Fatty change

Necrosis

Apoptosiss

IrreversibleIrreversibleinjuryinjury

ReversibleReversibleinjuryinjury

AdaptationAdaptation

Cell Injury:

Causes of Cell Injury

Hypoxia and ischemia Free radicals Chemical agents Physical agents Infections Immunological reactions Genetic defects Nutritional defects Aging

Cell Injury:

TYPES OF INJURY

Cell Injury:

Causes of Hypoxia

low levels of oxygen in the air poor or absent Hemoglobin function decreased erythropoiesis respiratory or cardiovascular

diseases, or ischemia (reduced supply of blood)

1- Hypoxia & Ischemia

Cell Injury:

Ischemia & Hypoxia induce mitochondrial

damage.

This results in decreased ATP which in turn reduces energy for all cell functions

!

If persistent CELL DEATH

Cell Injury:

Hypoxia is a common cause of cell injury Result : Cell resorts to anaerobic glycolysis Ischemia is the commonest cause of hypoxia,

& injures the cells faster than pure hypoxia Why ?? Restoration of blood may lead to recovery OR

Ischemia/ Reperfusion injury Progressive cell damage Examples : Myocardial & Cerebral infarction

Cell Injury:

Ischemia/Reperfusion Injury Restoration of blood flow influx of high

levels of calcium Reperfusion increases recruitment of

inflammatory cells free radical injury Damaged mitochondria induce free

radical production & compromise antioxidant defense mechanisms

Dead tissue becomes antigenicAB activation of complement immune

response

Cell Injury:

Recommendation :

In some cases , high oxygen therapy to improve hypoxia is NOT given because

it generates oxygen derived FREE

RADICALS ( Reactive Oxygen Species ROS)

Cell Injury:

2- Free Radicals

Free radicals are chemical species with a single unpaired electron in an outer orbital, they are chemically unstable and therefore readily react with other molecules, resulting in chemical damage.

To gain stability, the radical gives up or steals an electron.

Radicals can bind to proteins, carbohydrates lipids, producing damage.

Cell Injury:Sources of Free Radicals in pathology

Chemical injury Physical injury Inflammation Oxygen toxicity Reperfusion injury Malignant transformation Aging

Cell Injury:

Formation of Free Radicals :

Endogenous from normal metabolism

Reduction Oxidation reaction (REDOX) in mitochondria

Transition metals (Copper, Iron) catalyze Free Radicals formation by donating or accepting free electrons

(Fenton reaction)

Ferric iron Ferrous iron

superoxide

Cell Injury:

Exogenous formation : Ionizing radiation Drug metabolism

Cell Injury:

Free Radicals (Examples) Reactive Oxygen Species (ROS)

generated

by mitochondrial respiration : Oxygen Superoxide H2O2 (Hydrogen peroxide)

OH (hydroxyl group) Inflammation :

Accumulation of leucocytes NO (Nitric oxide) reactive nitrite

Cell Injury:Mechanism of injury by Free Radicals

1-Lipid peroxidation (oxidative degradation of lipids):

Destruction of unsaturated fatty acids by binding to methylene groups (CH2)

that posses reactive hydrogen molecules

Cell Injury:

2-Protein destruction: By cross linking proteins forming

disulfide bonds (S-S) → inactivate enzymes, & polypeptide degradation

3- DNA alteration: By producing single strand breaks in

DNA Induce mutation that interfere with

cell growth

Cell Injury:

Inactivation Free Radicals

Spontaneous decay Enzymes

Superoxide dismutase, glutathione peroxidase, and catalase

Antioxidants Block synthesis or inactivate free radicals

Include Vitamin E, Vitamin C, albumin, ceruloplasmin, and transferrin

Cell Injury:

3- Chemical Agents Chemical agents can cause cellular

injury by:

direct contact of the chemical with molecular components of the cell.

Indirect injury formation of free radicals, or lipid

peroxidation.

Cell Injury:

Examples of injurious chemicals

Cyanide disrupts cytochrome oxidase. Mercuric chloride binds to cell

membrane in cell resulting in increased permeability.

Chemotherapeutic agents & antibiotics may act in the same way.

Carbon Monoxide (CO) Ethanol Lead

Cell Injury:

Action of Carbon Monoxide :

Has a very high affinity to hemoglobin (carboxyhemoglobin: COHb) The effect of large quantities of

COHb is death (carbon monoxide poisoning).

Smaller quantities of COHb leads to tiredness,dizziness & unconsciousness.

Cell Injury:

Action of Ethanol :

The conversion of ethanol to acetaldehyde leads to formation of free radical.

Acetaldehyde initiates changes in liver Fatty change Liver enlargement Liver cell necrosis.

Cell Injury:liver enlargement with deposition of fat

Cell Injury:

Action of Lead :

Mimics other metals (calcium, iron and zinc) which act as cofactors in many catalyzing enzymatic reactions.

Acts on the CNS by interfering with neurotransmitters, blocking glutamate receptor.

(May cause wrist, finger,&foot paralysis).

Affects hemoglobin synthesis

Cell Injury:

Indirect injury of some chemicals :

Activation in the liver by the P- 450 mixed function oxidases in SER . CCL4 CCL3 (FR) membrane

phospholipid peroxidation & ER destruction:

↓ protein ↓ lipid No apoproteins for lipid transport Fatty liver

Mitochondrial injury ↓ATP Failure of cell function increased cytosolic Ca+ cell death

Acetaminophen may act similarly

Cell Injury:

4- Physical agents

Mechanical injury resulting in tearing, or crushing of tissues.

e.g.: blunt injuries , car accidents….

Ionizing Radiation Water and DNA are the most

vulnerable target

Cell Injury:

Physical agents (cont……) Extreme temperatures

Hypothermia Hyperthermia

Atmospheric Pressure Blast injuries Water pressure – increased or

decreased

Cell Injury:

5-Infectious Agents Bacteria: produce toxins

Endotoxin Exotoxin

Viruses : Decrease the ability to synthesize

proteins Change host cell’s antigenic

properties

Cell Injury:

5-Immunological reactions

Cell membranes are injured by contact with immune components such as lymphocytes, macrophages….etc

Exposure to these agents causes changes in membrane permeability

Cell Injury:

6- Genetic Diseases

Genetics play a substantial role in cellular structure and function.

A genetic disorder can cause a dramatic change in the cell’s shape, structure, receptors, or transport mechanisms.eg : Enzyme deficiencies Sickle Cell Anemia

Cell Injury:

7- Nutritional Imbalances Adequate amounts of proteins, lipids,

carbohydrates are required. Low levels of plasma proteins, like

albumin, encourages movement of water into the tissues, thereby causing edema.

Hyperglycemia, hypoglycemia, Vitamin deficiencies (vitamins E, D, K,

A, and folic acid) Excess food intake is also classified as

a nutritional imbalance

Cell Injury:

Mechanism of cell injury & sites of damage

Cell Injury:

Function is lost before morphological changes occur

EM changes Microscopic changes Gross changes

General Considerations:

Cell Injury:

Result of injury depends on : Injury : Type

Duration Severity

Type of cell: Specialization Adequacy of blood supply,

hormones, nutrients Regenerative ability or adaptability Genetic make up

Cell Injury:

Steps & Cellular targets in Injury :

Cell Injury:

1- Mitochondria: Interruption of oxidative

metabolism Loss of energy due to formation of mitochondrial permeability transition pore (MPT) loss of membrane potential prevents ATP generation (ATP depletion)

Cytochrome c released into cytosol activates apoptosis.

O2 depletion ROS

Cell Injury:

2- Cell Membranes

Important sites of damage : Mitochondrial membrane ATP Plasma membrane failure of Na

pump leads to cellular amounts of water

Lysosomal membrane enzyme release,

activation & digestion of cell components

Cell Injury:

3- Influx of Calcium:

Ca stability is maintained by ATP Loss of Ca homeostasis cytosolic

Ca+ activation of:

phospholipases proteases ATPases Endonucleases

Cell Injury:

4-Protein synthesis:

High fluid levels cause ribosomes to separate from the swollen

endoplasmic reticulum protein synthesis, glycolysis Metabolic acidosis

5- Genetic apparatus DNA defects & mutations

Cell Injury:

Injury at one locus leads to wide ranging secondary effects

Cascading effect

Cell Injury:

Subcellular response to injury

Cell Injury:

1- Hypertrophy of Smooth Endoplasmic Reticulum in liver induced by some drugs

e.g. barbiturates , alcohol…. etc.2-Mitochondrial alterations in size &

number e.g. in atrophy, hypertrophy, alcoholic

liver3-Cytoskeletal abnormalities

e.g. microtubule abnormality involved in cell mobility

Cell Injury:

4- Lysosomal Catabolism: Enzymatic digestion of foreign

material (Heterophagy / pinocytosis & phagocytosis) or intracellular material (Autophagy).

Persistent debris → residual body (Undigestible lipid peroxidation products → Lipofuscin pigment.

Cell Injury: Morphology of reversible cell injury:

Ultrastructurally :• Generalized swelling of the cell and

its organelles • Blebbing of the plasma membrane• Detachment of ribosomes from the endoplasmic reticulum• Clumping of nuclear chromatin.

Cell Injury:Transition to irreversible cell injury :

• Increasing swelling of the cell• Swelling and disruption of lysosomes• Severe swelling & dysfunction of

mitochondria with presence of large calcium rich densities

in swollen mitochondria• Disruption membranes→ phospholipase• Irreversible nuclear changes

Ultra structural changes in irreversible injury

mitochondria

Breaks in cell & organelles membranes

Nucleus

Cell membrane

Endoplastic retic

lysosomes

Amorphous density,bizarre forms,calcification

rupture

fragmentation

See by light mic

Nuclear changes in irreversible changesby light microscopy

Pyknosis

Nuclear shrinkage+Increasedbasophilia

Pyknotic nucleus

karyolysis karyorrhexis

Anucleated cell

Cell Injury:

After death Cellular constituents are digested by

lysosomal hydrolases → enzymes & proteins leak into

extracellular space → useful in diagnosis Myocardial Infarction ( creatine kinase &

troponins) Liver injury (biliary obstruction): Alkaline

phosphatase Dead cells converted to phospholipid masses (Myelin Figures) → Phagocytosis or degraded

to fatty acids → calcification

Summary

Cell Injury:

IF INJURED CELLS DON’T DIE, THEY MAY ADAPT TO PROTECT

THEMSELVES !

Cell Injury:

Cellular Adaptations

Cells change to Adapt to a new environment Escape from injury Protect themselves

Cell Injury:

Cellular Adaptations: Growth adaptations:

Hyperplasia, Hypoplasia, Hypertrophy, Atrophy, Metaplasia , Dysplasia.

Degenerations: (Accumulations) Hydropic change (water collection in cell

/edema) Fatty Change Hyaline Change Pigment storage – wear & tear..

Cell Injury:Cellular Adaptation to Injury

The most common morphologically apparent adaptive changes are

– Atrophy (decrease in cell size)– Hypertrophy (increase in cell size)– Hyperplasia (increase in cell number)– Metaplasia (change in cell type)

Cell Injury:

Atrophy

Decrease in cell size due to loss of cell

substance (protein degradation & lysosomal

proteases digest extracellular endocytosed

molecules )

Often hormone dependent (insulin, TSH,

etc…).

Atrophic cells have diminished function.

Cell Injury:

Atrophy

Physiologic: Uterus following parturition Pathologic:

Decreased workload (Disuse atrophy) Loss of innervation (Denervation

atrophy) Decreased blood supply (Brain atrophy) Malnutrition (Marasmus). Lack of hormonal stimulation.

Ageing: Senile atrophy

Cell Injury:

Disuse atrophy of muscle fibers

Cell Injury:

Atrophy of frontal lobe

Cell Injury: Atrophy: Undescended testes

Cell Injury:

Hypertrophy

Hypertrophy is an increase in cell size by gain of cellular substance

With the involvement of a sufficient number of cells, an entire organ can become hypertrophic

Hypertrophy is caused either by increased functional demand or by specific endocrine stimulations

With increasing demand, hypertrophy can reach a limit beyond which degenerative changes and organ failure can occur

Cell Injury:

Hypertrophy

Physiological & Pathological

Skeletal muscles in manual workers & athletes

Smooth muscles in pregnant uterus (Hyperplasia accompanies hypertrophy

here) Cardiac muscles in hypertension Remaining kidney after

nephrectomy

Cell Injury:Left ventricle hypertrophy -

HPTN

Compare normal & pregnant uterus

Cell Injury:

Hyperplasia

Hyperplasia is an increase in the number of cells of a tissue or organ, from an increased rate of cell division.

If cells have mitotic ability and can synthesize DNA, both hyperplasia and hypertrophy can occur.

Hyperplasia may be a predisposing condition to neoplasia

Cell Injury:

Cells differ in their capacity to divide :

High capacity: Epidermis, intestinal epithelium hepatocytes, bone marrow, fibroblasts.

Low capacity: Bone cartilage, smooth muscles

Nil capacity: Neurons, cardiac muscle, skeletal muscle….

Cell Injury:

Types of Hyperplasia

Physiological Hyperplasia (hormonal or compensatory),

Examples:

Uterine enlargement during pregnancy

Female breast in puberty & lactation Compensatory hyperplasia in the

liver

Cell Injury:

Pathological

Hyperplasia of the endometrium (excessive hormone stimulation).

Wound healing (Effects of growth factors). Infection by papillomavirus

Cell Injury:

Endometrial Hyperplasia

Cell Injury:

Metaplasia Metaplasia is a “reversible” change

(adaptation ) in which one adult cell type is replaced by another adult cell type that are better suited to tolerate a specific abnormal environment.

May occur in epithelial or mesenchymal tissue. e.g. Bronchial , gastric, & cervical epith., and bone in injured soft tissue

Cell Injury:

Some disadvantages occur :

Because of metaplasia, normal protective mechanisms may be lost.

Persistence of signals that result in metaplasia often lead to progression from metaplasia to dysplasia and possibly to adenocarcinoma.

Cell Injury:

Example of Metaplasia Replacement of ciliated columnar

epithelium with stratified squamous epithelium in respiratory tract of a smoker.

Cell Injury:Columnar (gastric) metaplasia in esophageal squamous epithelium

Cell Injury:

Dysplasia

Abnormal changes in size, shape, appearance, and organizational structure of the cells

Sometimes atypical hyperplasia can progress to neoplasia

Caused by persistent injury or irritation

Cervix, oral cavity, gallbladder, and respiratory tract“Cells having disordered arrangement”

Cell Injury:

Cervical dysplasia

Cell Injury:

Intracellular Accumulations & Deposits

Cell Injury:May occur in any one of the following ways :

Excessive production of a normal product

but metabolic function is inadequate

Normal or abnormal substance accumulates but there is genetic or acquired defective enzyme mechanism for removal

Abnormal exogenous substance accumulates because the cell does not possess a mechanism for removal

Cell Injury:

Accumulations include

Water ( Hydropic degeneration/cloudy swelling)

Fatty change Cholestrol & cholestrol esters Proteins Glycogen Pigments Calcium Amyloid deposition

Cell Injury:

Hydropic degeneration

Cell Injury:

1- Fatty change

Accumulation of excessive lipid in cells

The liver is the main organ involved, to lesser extent heart and kidney

Fatty acids → hepatocytes → triglyceride + apoproteins → lipoprotein → exit liver

Excess accumulation may result from defect in any of the above steps

Cell Injury: Causes of fatty change :

Toxins including alcohol Starvation and protein malnutrition Diabetes mellitus Oxygen lack (anemia & ischemia ) Drugs, Complicate pregnancy &

Obesity

Cell Injury:

Morphology of fatty liver

Gross appearance in liver depends on severity Normal to large size, looks yellow and

greasy when severe Histology

Fat accumulates in hepatocytes as small vacuoles in cytoplasm with nucleus in the center (Microvesicular fatty change ).

The whole cytoplasm is replaced by fat and nucleus is pushed to one side of the cell (Macrovesicular fatty change).

Cell Injury:

Fatty Liver (Alcoholism)

Cell Injury:2- Cholestrol & Cholestrol esters

Accumulate in macrophages ( foam cells ) & in foreign body giant cells : Atherosclerosis Hereditary & Acquired

hyperlipidemia → Xanthomas (a yellow nodule or plaque, especially of the skin, composed of lipid-laden histiocytes).

Cell Injury:

3- Protein accumulation:

kidney in the nephrotic syndrome. Plasma cells as immunoglobulins. Mallory Bodies: Alcoholic liver

disease as (Eosinophilic intracellular hyaline body)

Glycogen accumulation in Glycogen Storage Diseases.

Liver - Mallory hyaline - Alcoholism

Cell Injury:

4- Pathologic Calcification

A- Dystrophic calcification : Abnormal deposition of calcium

phosphate in dead or dying tissue Dystrophic calcification is an

important component of the pathogenesis of atherosclerotic disease and valvular heart disease.

Areas of caseous, coaggulative or fat necrosis.

Dead parasites & their ova

Cell Injury:

cont… B- Metastatic calcification : Calcium deposition in normal tissues

as a consequence of hypercalcemia: Increased PTH with subsequent

bone resorption Bone destruction: METASTATIC

BONE CANCERS Vitamin D disorders Renal failure

Organs affected: Kidney, stomach, lungs….

Cell Injury:

Dystrophic calcification - Stomach.

Cell Injury:

5-Pigments

Pigments

EXOGENOUS

Hb-derived Non Hb -derived

ENDOGENOUS

Bilirubin

IronTattooing

Anthracosis

Lipofuscin

Melanin

Cell Injury:

Exogenous pigment :

Anthracosis :

Accumulation of carbon, black pigment Smokers Tatooing

Cell Injury:Exogenous pigment : Anthracosis

Cell Injury:

Endogenous pigments : 1- Melanin pigment : Brown pigment synthesized in

melanocytes. Melanin protects the nuclei of cells in

basal layer of epidermis against effects of UV light

Lesions associated with melanocytes Moles (nevi)…..benign Melanoma…….malignant

Lesions can occur anywhere e.g.rectum,eye.

Cell Injury:

2- Lipofuscin pigment Brown pigment in cytoplasm of cells,

represents residue of oxidized lipid derived from digested membranes of organelles.

It is called “wear and tear”pigment accumulates as a part of the aging process and atrophy, in which lipid peroxidation take part in it.

It is harmless to the cell. Large amounts in atrophic organs

gives rise to “Brown atrophy” e.g brown atrophy of the heart.

Cell Injury:

Lipofuscin

Cell Injury:

3- Bile pigment (Bilirubin ) Derived from heme of Hb from destroyed

RBC in reticuloendothelial system. Conjugated in hepatocytes with glucuronic

acid and excreted as bile. Hyperbilirubinemia may present clinically

as jaundice Causes may be hemolysis, liver diseases or

obstruction to the outflow of bile

Cell Injury:

4- Excess iron accumulation Total body iron….. 2 - 4gm. Functional pool

Hb, myoglobin, cytochromes & catalase Storage pool

in macrophages of RES in the ferric form as ferritin & / or hemosiderin which is golden brown.

Potasium ferrocyanide + hemosiderin = ferric ferrocyanide. This is known as ” Prussian Blue reaction” or Perl`s reaction.

Cell Injury: Iron overload: Localized or systemic

Local increase of iron in tissues Localized hemorrhage in tissues Chronic venous congestion of lung in

heart failure Systemic increase of iron

Hemosiderosis ….. Iron in RES without much damage

Occurs in: Excessive hemolysis Multiple blood transfusions Intravenous administration of iron

Cell Injury:Hemosiderin granules in liver cells. A- H&E section showing golden-brown, finely granular pigment. B- Prussian blue reaction, specific for iron.

Cell Injury:

Idiopathic Hemochromatosis

Abnormality is lack of regulation of iron absorption & defect in the monocyte - macrophage system.

Iron accumulates in liver, pancreas, other parenchymal cells & to lesser extent in RES.

Induce fibrosis, secondary diabetes, cirrhosis & liver cancer

Cell Injury:

5- Amyloidosis

Extracellular deposition of an abnormal fibrillar proteins in various tissues and organs (kidney, heart, brain, liver…etc.)

The abnormal protein is called Amyloid. Many types associated with different

diseases or primary forms H & E … Hyaline-like acellular eosinophilic

material Congo red stains amyloid pink or red and

under polarizing microscopy gives apple green birefringence .

Cell Injury:

Amyloid deposition in kidney

Cell Injury:

Congo Red Stain

Cell Injury:

Classification of amyloidosis Localized amyloid deposition

larynx,lungs,urinary bladder,etc.. Systemic amyloidosis

multiple myeloma associated …. AL amyloid Reactive (secondary amyloidosis) … AA amyloid

RHEUMATOID ARTHRITIS, INFLAMMATORY BOWEL DISEASE, OSTEOMYELITIS, HODGKIN’S DISEASE AND RENAL CELL

CARCINOMA. Hereditary amyloidosis

Cell Injury:

CELL DEATH

Cell Injury:

CELL DEATH

Ultimate result of injury, following ischemia, infection, toxins, immune reactions……

Physiologically seen in embryogenesis, lymphoid tissue development, hormonally induced involution.

Therapeutically in cancer radiotherapy and chemotherapy.

Cell Injury:

Types :

Necrosis: Morphologic changes seen in dead cells within living tissue.

Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen)

Apoptosis: Programmed cell death. Physiological, cell regulation.

Cell Injury:

NECROSIS

Irreversible

Necrosis is local cell death and cellular dissolution in living tissues.

Necrosis involves the process of self/auto digestion and lysis.

Cell Injury:

Morphologic changes :

Increased eosinophilia of cells Pyknosis of nuclei Karyorrhexis Karyolysis: dissolution of the

nucleus from hydrolytic enzymes Release of catalytic enzymes from

lysosomes cause either autolysis or heterolysis

Cell Injury: Morphologic appearance of necrosis

is due to: Enzymic digestion of the cell Denaturation of proteins

Types: coagulative, liquefactive, caseous, fat necrosis, gummatous necrosis and fibrinoid necrosis.

Sequels of Necrosis: Autolysis Phagocytosis Organization & fibrous repair Dystrophic calcification

Cell Injury:

1- Coagulative necrosis

Commonest type of necrosis, usually ischemic Infarction specially in heart (Myocardial

Infarction) Also in kidney & in adrenals…. Variable appearance mostly firm texture. It is suspected that high levels of intracellular

calcium plays a role in coagulative necrosis. Results from denaturation of all proteins

including enzymes .

Cell Injury:

Histology:

Preservation of the tissue architecture & cellular outlines.

The necrotic area stains more eosinophilic, often devoid of nuclei.

Cell Injury:

Renal Infarction: Coagulative Necrosis

Cell Injury:

2- Liquefactive Necrosis Autolysis predominates and results in

liquefied mass e.g. hypoxia in brain, bacterial infections (abscess). Brain cells have a large amount of

hydrolytic digestive enzymes (hydrolases). These enzymes cause the neural tissue to become soft and liquefy.

Liquefactive necrosis is what causes pus to form.

Hydrolytic enzymes are released from neutrophils to fight an invading pathogen.

E. Coli, Staphylococcus, and Streptococcus

Cell Injury:

Stroke- Liquifactive necrosis

Cell Injury:

Lung abscess: Liquefactive necrosis

Cell Injury:Liver abscess: Liquefactive necrosis

Cell Injury:

3- Caseous Necrosis

Grossly “cheese-like”, appearance, being soft and white.

Histology: Central cheesy material , rimmed by chronic

inflammatory cells, epitheloid cells & Langhans giant cells ( GRANULOMA)

Typical of tuberculosis, may be seen in others Is a distinctive form of coagulative necrosis

modified by capsule lipopolysacchride of TB bacilli

Cell Injury:

Caseous necrosis in Tuberculosis

Cell Injury:

Caseous necrosis - Tuberculosis

Cell Injury:

4- Fat Necrosis Two types :

Traumatic fat necrosis → foreign body giant cells → calcification → hard lump

Enzymatic fat necrosis due to acute pancreatitis

Acute Pancreatitis : Medical emergency Enzymes released, digests fat

Adipose tissues → triglycerides & fatty acids → saponification & calcification

Cell Injury:

Foci of fat necrosis with saponification in the mesentery

Cell Injury:

Fat Necrosis - Peritoneum.

Cell Injury:

Gangrene Necrosis plus putrefaction (rotting) by

saprophytes. Wet gangrene: Coagulative necrosis due to

ischemia and liquifactive necrosis due to superimposed infection.

Dry gangrene: Drying of dead tissue, is a form of coagulative necrosis, applied to necrosis of the lower limbs distally, associated with peripheral vascular disease.

Necrosis is separated by a line of demarcation from viable tissue.

Gas gangrene: This caused by wound contamination by anaerobic bacteria (Clostridia perfringes)

Cell Injury:

Toes - Dry Gangrene

Cell Injury:

Wet Gangrene Amputated Diabetic foot

Cell Injury:

APOPTOSIS Programmed cell death by suicide The cell’s membrane remains intact Apoptosis is characterised by death of

single cells or clusters and results in cell shrinkage, not lysis and swelling without an inflammatory reaction, unlike necrosis where there is death of

large amounts of the tissue and there is an associated inflammatory reaction.

Cell death involved in normal and pathologic conditions.

Cell Injury:

APOPTOSIS Apoptosis depends on cellular signals, these

signals cause protein cleavage (proteases) within the cell, causing cell death.

Programmed and energy dependent process designed to switch cell off and eliminate them Cell shrinkage Chromatin condensation- most characteristic Formation of cytoplasmic blebs and

apoptotic bodies Phagocytosis of apoptotic cells or bodies

Cell Injury:

Two main pathways

Intrinsic ‘mitochondrial’ pathway: Increased permeability of mitochondrial

membrane results in release of pro-apoptotic factors (cytochrome c and AIF) that activate downstream caspases death .

Extrinsic ‘death receptor pathway’: FAS and TNF1 receptor families with death

domain.

Cell Injury:

Cell Injury:

Physiologic apoptosis

During development, embryogenesis. Homeostatic mechanism to maintain cell

population(Cell turnover in intestinal crypts).

Immune reaction - defense mechanism. In aging. Shedding of menstrual endometrium. Involution of breast after weaning.

Cell Injury:

Pathologic apoptosis Prostatic ‘atrophy’ after castration. Death of inflammatory cells after

inflammation When cells are damage by disease or

injurious agents DNA damage e.g. radiation,

chemotherapy, Cytotoxic drugs Viral infections e.g. viral hepatitis Neoplasia: tumours that regress or

involution Deletion of autoreactive T cells in thymus Others including rejection of transplants

Cell Injury:

A, Apoptosis of epidermal cells in an immune-mediated reaction. The apoptotic cells are visible in the epidermis with intensely eosinophilic cytoplasm and small, dense nuclei. H&E stain. B, High power of apoptotic cell in liver in immune-mediated

hepatic cell injury.

Cell Injury:Comparison of apoptosis with necrosis

Apoptosis Active process

Occur in single cells

Physiological & pathological

No inflammatory reaction

Necrosis Passive process

Affects mass of cells

Always pathological

stimulates Inflammation

Cell Injury:

Aging and Cellular Death Theories

Aging is caused by accumulations of injurious events

Aging is the result of a genetically controlled developmental program.

Mechanisms Genetic, environmental, and behavioral Changes in regulatory mechanisms Degenerative alterations

Cell Injury:

Cellular aging Genetic e.g. failure of repair mechanisms ,

Clock genes overexpression of antioxidative enzymes Telomerase activity …….etc

Telomerase activity stops in somatic cells, but

continues in stem cells & germ cells Environmental: generation of FR, diet Accumulation of multiple defects Aging Aged cells show Lipofuscin pigment ,

abnormally folded proteins & advanced glycosylation end products ( AGES’s)