Cell Injury. Why is it important? Cellular injury appears to be the common denominator in almost all diseases.

Cell Injury

Why is it important?

• Cellular injury appears to be the common denominator in almost all diseases.

The Cell and the Environment

Stimuli Stimuli [[Causes of Cell Injury]

Cell AdaptationAdaptation

Cell Injury

ReversibleIrreversible (cell death)

apoptosis necrosis

تكيف

Causes of Cell Injury1.1. Hypoxia: Hypoxia: (Oxygen deficiency) Mainly due to:

ischemia (impaired blood supply) most commonmost common inadequate oxygenation of blood (cardio-respiratory failure) loss of oxygen carrying capacity (anaemia) Carbon monoxide poisoning

2.2. Physical AgentsPhysical Agents Trauma, radiation, extremes of temperatures, electric shock

3.3. Chemicals and DrugsChemicals and Drugs Wide variety

4. Microbiologic Agents Viruses, worms, bacteria …..

5. Immunologic Reactions Allergic reactions, autoimmune diseases

6. Genetic Defects Obvious congenital malformations (Down syndrome) Subtle single amino acid substitution (hemoglobin S of sickle cell anemia)

7. Nutritional Imbalances Deficiency of nutrients/ or excess

8. Aging

The Cell and the Environment

StimuliStimuli [Causes of Cell Injury]

Cell AdaptationAdaptation

Achieving a new steady state and preserving viability

تكيف

ADAPTATION1. Atrophy:

decrease in size or number of cells leading to reduction in tissue mass

2. Hypertrophy:increase in size of cells leading to increase

in size of organ

3. Hyperplasia:increase in number of cells leading to

increase size of organ

4. Metaplasia:Is the replacement of one type of cells by

another

ADAPTATION

Atrophy: causes

Decreased workload Loss of innervation Diminished blood supply Inadequate nutrition Loss of endocrine stimulation Aging

ADAPTATION

Hypertrophy:

increase in size of cells leading to increase in size of organ Increased functional demand

skeletal muscle in exercise myocardium in hypertension

Specific hormonal stimulation uterus in pregnancy

Heart, left ventricular hypertrophy

Heart, normal

ADAPTATION

Hyperplasia:

increase in number of cells leading to increase size of organ Physiologic

Hormonal (breast during pregnancy) Compensatory (partial hepatectomy

Pathologic Excessive hormonal / growth factor

absolute or relative increase in estrogen over progesterone--endometrial hyperplasia

ADAPTATION

Metaplasia:

• Is the replacement of one type of cells by another Squamous Metaplasia

Respiratory epithelium cigarette smoking vitamin A deficiency

Intestinal Metaplasia Lower esophageal epithelium

chronic gastric reflux

Osseous metaplasia: it is the formation of new bone at sites of tissue injuryMyeloid metaplasia (extramedullary hematopoiesis): is the proliferation of hematopoietic tissue in sites other then the bone marrow such as liver or spleen

Aplasia

• Defective development resulting in the absence of all or part of an organ or tissue

Aplasia Cutis Congenita

Hypoplasia

• Incomplete or arrested development of an organ or a part

• It may be hereditary or acquired. Enamel hypoplasia

The Cell and the Environment

StimuliStimuli

Cell AdaptationAdaptation

Cell Injury

Reversible

Atrophy HypertrophyHyperplasiametaplasia

Reversible Injury

1. Cellular swelling 2. Fatty change

– Also called hydropic change or vacuolar degeneration

– Earliest change– Grossly: organ pallor,

increased weight

– Microscopy: small, clear cytoplasmic vacuoles

• Adenosine triphosphate (ATP) depletion• water influx ---Cellular swelling

Normal kidney tubules

Rversible cell injury

1. Cellular swelling Reversible Injury

• Lipid vacuoles in the cytoplasm. • In cells participating in fat metabolism (e.g.,

hepatocytes and myocardial cells).

2. Fatty change

Normal liver Fatty liver

Reversible Injury

The Cell and the Environment

StimuliStimuli

Cell AdaptationAdaptation

Cell Injury

ReversibleIrreversible (cell death)

apoptosis necrosis

Atrophy HypertrophyHyperplasiametaplasia

Reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletionwater influx ---Cellular swelling

Irreversble Cell Injury

• Necrosis– Definition--sequence of morphologic changes that

follow cell death in living tissue.– Enzymatic digestion of cells

• The enzymes derived from the lysosomes of the dead cells themselves, [autolysis], • The enzymes derived from the lysosomes of immigrant leukocytes, [heterolysis].

Patterns of Acute Cell Injury

• Necrosis: morphology

– Cytoplasmic eosinophilia (pink)– Nuclear changes

• Pyknosis --karyorrhexis --karyolysis

Normal kidney tubules Irrversible cell injuryRversible cell injury

NECROSIS

• Morphologic Patterns of Necrosis1. Coagulative necrosis2. Liquefactive necrosis3. Caseous necrosis4. Fat necrosis5. Gangerene 6. Fibrinoid necrosis

Patterns of necrosis

– Coagulative necrosis

• Preservation of structural outlines for days• Characteristic of hypoxic cell death except in the brain

Normal kidney tubules Coagulative necrosisCoagulative necrosis in kidney

Patterns of necrosis

– Liquefactive necrosis

• complete digestion of the dead cells1.bacterial and some fungal infection, 2.hypoxic cell death in brain

Patterns of necrosis

– Caseous necrosis

• cheesy, white• amorphous granular debris in a ring of granulomatous

inflammation• characteristic of tuberculous infection

Patterns of necrosis

– Fat necrosis

• fatty acids combine with calcium to produce grossly visible chalky white areas

• On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells with basophilic calcium deposits

• It occurs in:1.Breast trauma 2.Acute pancreatitis ---pancreatic lipases

Patterns of necrosis

• Gangrene• Necrosis with putrefaction of the tissues, sometimes as a

result of the action of certain bacteria, notably clostridia.• The affected tissues appear black

Dry gangreneWet gangrene

Patterns of necrosis

• Fibrinoid necrosis • Necrosis of the smooth muscle wall of arterioles in

malignant hypertension . • Also seen in immune vasculitis

The Cell and the Environment

StimuliStimuli

Cell AdaptationAdaptation

Cell Injury

ReversibleIrreversible (cell death)

apoptosis necrosis

Atrophy HypertrophyHyperplasiametaplasia

Reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletionwater influx ---Cellular swelling

Patterns of Acute Cell Injury

• Apoptosis (a falling away from)Apoptosis is programmed cell death. It is a pathway of cell death that is induced by a tightly

regulated intracellular program in which cells destined to die activate their own enzymes to degrade their own nuclear DNA, nuclear proteins and cytoplasmic proteins.

The cell's plasma membrane remains intact, but its structure is altered in such a way that the apoptotic cell sends signal to macrophages to phagocytose it.

Apoptosis is a complicated process Apoptosis is programmed process

Apoptosis

– Involves single cells– Eosinophilia, condensed

chromatin with peripheral aggregation

– karyorrhexis

Regulation of apoptosis

• It is mediated by a number of genes and their products :

• - bcl-2 gene inhibits apoptosis• - bax genes facilitates apoptosis• - p53 facilitates apoptosis by inhibiting bcl2

and promoting bax genes.

Two types of cell death

Necrosis• Large No. of cells

• Invariably (always ) pathologic

• Disrupted Plasma membrane

• Inflammation

Apoptosis• Single cells or small clusters

• Often physiologic; may be pathologic

• Intact Plasma membrane

• No inflammation , • phagocytes to eleminate it

The Cell and the Environment

StimuliStimuli

Cell AdaptationAdaptation

Cell Injury

ReversibleIrreversible (cell death)

apoptosis necrosis

Atrophy HypertrophyHyperplasiametaplasia

Mechanisms of cell injury• Depletion of ATP • Damage to Mitochondria • Influx of Calcium • Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) • Defects in Membrane Permeability • Damage to DNA and Proteins

Free radicals

• are atoms with an unpaired electron [odd number of electrons in its outer ring]

• They are highly reactive, chemically unstable,

• Generally present only at low concentrations, and tend to participate in, or initiate, chain reactions.

Free Radical-Induced Cell Injury

Generation of reactive oxygen free radicals

SMOKING

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

Free Radical-Induced Cell Injury

Free Radicals may be generated Free Radicals may be generated within the cells by:

1. Hydrolysis of water into hydroxyl (OH. ) and hydrogen (H. ) free

radicals by ionizing radiation (e.g. ultraviolet, x-ray)

2. Reduction-oxidation (Redox) reactions in normal cell physiology

Respiration generates (O.), (H2O2), (OH

.)

intracellular oxidases action (xanthine oxidase)

transition metal reactions (Fenton reaction)

3. Metabolism of exogenous chemicals

e.g. carbon tetrachloride

4. Macrophages and inflammatory reactions (e.g. Nitric oxide, & others)

Free Radicals

As Free radicals are produced in radiation and chemical cell injury, they are also generated normally during respiration and cell activities

Therefore cells should have mechanisms to degrade free radicals to minimize the damage

Antioxidant defenses 1. detoxifying enzymes 2. scavengers (vitamins E, C, A).

Cellular Accumulations

Intracellular Accumulations

– Endogenous• normal substance produced at normal or increased

rate/rate of metabolism inadequate for removal (fatty liver)

• normal or abnormal substance cannot be metabolized (storage diseases)

– Exogenous– cell cannot degrade substance (carbon)

Intracellular Accumulations

• Fatty Change (Steatosis)

• Any abnormal accumulation of triglycerides within parenchymal cells.

• It is most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in heart, skeletal muscle, kidney, and other organs.

• Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations.

Intracellular Accumulations

• Fatty Change (Steatosis)– Liver

• increased weight, yellow color

fat vacuoles within cytoplasm of hepatocytes

Intracellular Accumulations

• Exogenous Pigments

– Carbon (anthracosis)• When inhaled, it is phagocytosed by alveolar

macrophages and transported by lymphatics to lymph nodes

• mild accumulations usually are of no consequence--heavy accumulations may induce a fibroblastic response

Intracellular Accumulations

• Endogenous Pigments– Lipofuscin (“wear and tear pigment)

• insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) as a function of age or atrophy.

• It is not injurious to the cell but is important as a marker of past free-radical injury.

Intracellular Accumulations

• Endogenous Pigments– Melanin

• brown-black pigment produced in melanocytes

• It is synthesized exclusively by melanocytes located in the epidermis and acts as a screen against harmful ultraviolet radiation

Intracellular Accumulations• Endogenous Pigments

– Hemosiderin• iron containing golden-yellow pigmen• Local or systemic• Local excesses of iron and hemosiderin result from hemorrhages

or vascular congestion, eg hemosiderosis is the common bruise. With lysis of the erythrocytes, the hemoglobin eventually undergoes transformation to hemosiderin.

hemosiderin• hemosiderosis • systemic overload of iron, hemosiderin is deposited in many organs and tissues [ liver, bone

marrow, spleen, and lymph nodes • occurs in 1. increased absorption of dietary iron, 2. impaired utilization of iron, 3. hemolytic anemias, 4. transfusions

• hemochromatosis • hereditary more extensive accumulations of iron with tissue injury including liver fibrosis,

heart failure, and diabetes mellitus.

PATHOLOGIC CALCIFICATION

• dystrophic calcification • deposition occurs in dead or dying tissues, • normal serum levels of calcium.

• metastatic calcification • deposition in normal tissues• almost always reflects some derangement in calcium

metabolism (hypercalcemia).

Match A and B

A1) Increase in size of skeletal

muscle in exercise2) increase in number of

hepatocytes after partial hepatectomy

3) The replacement of respiratory epithelium to sequamous epithelium

4) Loss of innervation

Ba) Atrophyb) Hypertrophyc) Hyperplasiad) Metaplasia

Match A and B

A1. Pyknosis2. fragmentation of the cell

membrane3. Hydropic change, vacuolar

degeneration4. Necrosis5. Apoptosis

Ba. reversible cell injury b. irreversible cell injury

Match A and B

A1. Enzymatic digestion of cell by

the dead cells themselves2. Enzymatic digestion of cell by

the inflammatory cells

Ba. Autolysisb. Heterolysis

Match A and B

A1. The affected tissues appear black2. hypoxic cell death in brain3. Autoimmune vasculitis4. hypoxic cell death but not in brain5. malignant hypertension6. Breast trauma7. Diabetes mellitus 8. tuberculous infection9. Immune vasculitis

Ba. Coagulative necrosisb. Liquefactive necrosisc. Caseous necrosisd. Fat necrosise. Gangerene f. Fibrinoid necrosis

Match A and B

A1. programmed cell death2. Large no. of cells3. always pathologic4. Intact Plasma membrane5. No inflammation6. Can be physiological 7. Inhibited by bcl-2 gene8. Gangrene

Ba. Necrosisb. Apoptosis

Match A and B

A1. systemic overload of iron2. abnormal accumulation of

triglycerides within parenchymal cells

3. Present in old hemorrhage4. carbon dust5. Inactivated by [ antioxidants]

vitamin E, C, A

Ba. Steatosisb. Anthracosisc. Free radicals d. Hemosiderosis

Match A and B

A1. Acts as a screen against

harmful ultraviolet radiation

2. vacuoles within cytoplasm of hepatocytes

3. May indicate old hemorrhage

4. wear and tear pigment and a sign of free radical injury

Ba. Fatty Changeb. Lipofuscinc. Iron [ hemosidren ]d. Melanin

Match A and B

A1. deposition of calcium salts

in dead or dying tissues2. deposition of calcium salts

in normal tissues 3. normal serum levels of

calcium4. hypercalcemia

B a. dystrophic calcificationb. metastatic calcification