Cell Injury Robert Low MD PhD. sites within cells that are easily injured reversibility of injury...

Cell InjuryCell Injury

Robert Low MD PhDRobert Low MD PhD

•sites within cells that are easily injured

•reversibility of injury and complete recover

•adaptation to chronic injury

•cell death-necrosis vs apoptosis

Hypoxic injury-starving cells/tissues for oxygen; problems of too much oxygen and cell damage from oxygen radicals

Cell and tissue injury produce human diseaseInjury-acute vs chronic

#1

• Human disease occurs because of injury to cells/tissue

Cell Injury– Cell Injury– Damage or alteration Damage or alteration of one or more cellular of one or more cellular components components

1.1.Many types of injury we incur are tissue specific Many types of injury we incur are tissue specific because of anatomic relationships and the because of anatomic relationships and the tissue tropism of chemical and infectious agents.tissue tropism of chemical and infectious agents.

2.2.Cell injury perturbs cell physiology; the cell does Cell injury perturbs cell physiology; the cell does not function at full capacity. not function at full capacity.

Basic Types of TissuesBasic Types of Tissues

1.1. EpitheliumEpithelium

2.2. Muscle (skeletal, smooth, cardiac)Muscle (skeletal, smooth, cardiac)

3.3. Nerve (CNS, PNS)Nerve (CNS, PNS)

4.4. Connective (bone, cartilage, soft Connective (bone, cartilage, soft tissue, adventitia, ligaments, blood tissue, adventitia, ligaments, blood and lymph, etc)and lymph, etc)

#2

• Most human disease results from injury to Epithelium

Epithelium arises from each of Epithelium arises from each of three germ layersthree germ layers

1.1. Cells cover external surfaces (skin); line Cells cover external surfaces (skin); line internal closed cavities, secretory glands internal closed cavities, secretory glands and tubes- -GI, respiratory, GU tracts- -that and tubes- -GI, respiratory, GU tracts- -that communicate with external surfacescommunicate with external surfaces

2.2. Also includes liver, exocrine pancreas, Also includes liver, exocrine pancreas, parotid glands, thyroid, parathyroid, parotid glands, thyroid, parathyroid, epithelium of kidneyepithelium of kidney

3.3. Also: vascular endothelium, mesotheliumAlso: vascular endothelium, mesothelium

#3

• Injury to one tissue usually affects the adjacent or underlying tissue as well

Cell Injury Produces:Cell Injury Produces:

1.1. SignsSigns- abnormal physical findings- abnormal physical findings

2.2. SymptomsSymptoms- complaints experienced - complaints experienced

by the patientby the patient

Cell Injury Produces: (cont)Cell Injury Produces: (cont)

3.3. Morphologic changeMorphologic change- A visual - A visual change in the cell shape or appearance, change in the cell shape or appearance, seen when cells are stained and viewed seen when cells are stained and viewed by light microscopy; or examined by by light microscopy; or examined by E.M. in the injured tissue; or seen E.M. in the injured tissue; or seen “grossly” with the naked eye.“grossly” with the naked eye.

Outcomes from cell injury Outcomes from cell injury depend upon:depend upon:

1.1. Type of injuryType of injury

2.2. Severity of the injurySeverity of the injury

3.3. Duration of the damageDuration of the damage

4.4. Type of cell being injured- Some cell Type of cell being injured- Some cell types sustain injury better than others; types sustain injury better than others; some tissues (e.g. liver) have a some tissues (e.g. liver) have a capacity to regenerate.capacity to regenerate.

Cell Injury: Vulnerable SitesCell Injury: Vulnerable Sites

1.1. Cell membranesCell membranes

2.2. MitochondriaMitochondria

3.3. Endoplasmic reticulumEndoplasmic reticulum

4.4. NucleusNucleus

Cell Membrane- Cell Membrane- why so easily injuredwhy so easily injured

1.1. Membrane faces the external environment: Membrane faces the external environment: sustains “trauma”, extracellular oxidants, sustains “trauma”, extracellular oxidants, proteases, etc.proteases, etc.

2.2. Requires a constant supply of ATP for Requires a constant supply of ATP for normal function (ion pumps).normal function (ion pumps).

3.3. Lipid molecules in the membrane are easily Lipid molecules in the membrane are easily oxidized and support and oxidative chain oxidized and support and oxidative chain reaction called lipid peroxidation.reaction called lipid peroxidation.

Consequences of InjuryConsequences of Injury

1.1. No long term effects- - the cell No long term effects- - the cell damage is repaired, the effects of the damage is repaired, the effects of the injury are reversible.injury are reversible.

2.2. The cell ”adapts” to the damaging The cell ”adapts” to the damaging stimulus.stimulus.

3.3. The cell dies, undergoing necrosis. The cell dies, undergoing necrosis. The damage is irreversible.The damage is irreversible.

Reversible Cell InjuryReversible Cell Injury

Examples:Examples:1.1. Cell swelling – usually accompanies all Cell swelling – usually accompanies all

types of injury. Results from an increase in types of injury. Results from an increase in water permeability. Reverses once water permeability. Reverses once membrane function is restored.membrane function is restored.

2.2. Increase in extracellular metabolite Increase in extracellular metabolite because of a biochemical derangement. because of a biochemical derangement. Ex.: Increase in extracellular glycogen in Ex.: Increase in extracellular glycogen in diabetes.diabetes.

Reversible Cell Injury (cont)Reversible Cell Injury (cont)

Examples:Examples:3.3. Fatty change in liver. Vacuoles of fat Fatty change in liver. Vacuoles of fat

accumulate within the liver cell following many accumulate within the liver cell following many types of injury: alcohol intoxication, chronic types of injury: alcohol intoxication, chronic illness, diabetes mellitus, etc.illness, diabetes mellitus, etc.

Due to: An increase in entry of free fatty acids.Due to: An increase in entry of free fatty acids. An increase in synthesis of free fatty An increase in synthesis of free fatty

acids. acids. A decrease in fatty acid oxidation.A decrease in fatty acid oxidation.

Adaptation-Adaptation- the cell responds the cell responds successfully to the injurious stimulus successfully to the injurious stimulus

Examples:Examples:

1.1. Hypertrophy- the cell increases in Hypertrophy- the cell increases in size.size. Ex.: cardiac myocytes of the left Ex.: cardiac myocytes of the left ventricle increase in size from ventricle increase in size from essential hypertension.essential hypertension.

2.2. Atrophy- the cell decreases in size Atrophy- the cell decreases in size because of a loss of cell substance.because of a loss of cell substance.

Causes of Cell AtrophyCauses of Cell Atrophy

1.1. Loss of blood supply or innervationLoss of blood supply or innervation

2.2. Loss of endocrine factors (ex. TSH)Loss of endocrine factors (ex. TSH)

3.3. Decrease in the workloadDecrease in the workload

4.4. Aging, chronic illnessAging, chronic illness

Cell Death

• Necrosis

• Apoptosis

Morphology of NecrosisMorphology of Necrosis

Coagulative NecrosisCoagulative Necrosis

• Dead cell remains a ghost-like Dead cell remains a ghost-like remnant of its former self-classically remnant of its former self-classically seen in an MI.seen in an MI.

PyknosisPyknosis

Intensely dark staining and shrunken Intensely dark staining and shrunken nucleus, seen in a necrotic (dead) cell.nucleus, seen in a necrotic (dead) cell.

KaryorrhexisKaryorrhexis

Fragmentation of pyknotic nucleus.Fragmentation of pyknotic nucleus.

KaryolysisKaryolysis

Extensive hydrolysis of the pyknotic Extensive hydrolysis of the pyknotic nucleus with loss of staining. nucleus with loss of staining. Represents breakdown of the Represents breakdown of the denatured chromatin.denatured chromatin.

Liquefactive NecrosisLiquefactive Necrosis

The dead cell undergoes extensive The dead cell undergoes extensive autolysis, caused by the release of autolysis, caused by the release of lysosomal hydrolases (proteinases, lysosomal hydrolases (proteinases, DNases, RNases, lipases, etc.) DNases, RNases, lipases, etc.)

Seen classically in the spleen and Seen classically in the spleen and brain following infarction.brain following infarction.

Caseous NecrosisCaseous Necrosis

Seen in Tuberculosis (mycobacterium Seen in Tuberculosis (mycobacterium tuberculosis). tuberculosis).

Type of necrosis seen within infected Type of necrosis seen within infected tissues characterized as soft, friable, tissues characterized as soft, friable, whitish-grey (resembles the milk whitish-grey (resembles the milk protein casein).protein casein).

Fat NecrosisFat Necrosis

Leakage of lipases from dead cells attack Leakage of lipases from dead cells attack triglycerides in surrounding fat tissue and triglycerides in surrounding fat tissue and generate free fatty acids and calcium soaps.generate free fatty acids and calcium soaps.

These soaps have a chalky-white These soaps have a chalky-white appearance.appearance.

Seen in the pancreas following acute Seen in the pancreas following acute inflammation.inflammation.

Causes of Cell and Tissue InjuryCauses of Cell and Tissue Injury

1.1. Physical agentsPhysical agents

2.2. Chemicals and drugsChemicals and drugs

3.3. Infectious pathogensInfectious pathogens

4.4. Immunologic reactionsImmunologic reactions

5.5. Genetic mutationsGenetic mutations

6.6. Nutritional imbalancesNutritional imbalances

Causes of Cell and Tissue Injury Causes of Cell and Tissue Injury (cont)(cont)

7.7. Hypoxia and Ischemia-Hypoxia and Ischemia-cell injury resulting from inadequate levels cell injury resulting from inadequate levels of oxygen.of oxygen.

Many important causes:Many important causes:A.A. Inadequate blood supply Inadequate blood supplyB.B. Lung disease Lung diseaseC.C. Heart failure Heart failureD.D. Shock Shock

Why So Important?Why So Important?

All cells in the body require a continuous All cells in the body require a continuous supply of oxygen in order to produce ATP supply of oxygen in order to produce ATP via oxidative phosphorylation in via oxidative phosphorylation in mitochondria.mitochondria.

ATP is absolutely critical for life.ATP is absolutely critical for life.

Susceptibility of specific cells to Susceptibility of specific cells to ischemic injury- -ischemic injury- -

Neurons: Neurons: 3 to 5 min.3 to 5 min.

Cardiac myocytes, hepatocytes, renal Cardiac myocytes, hepatocytes, renal epithelium: epithelium: 30 min. to 2 hr.30 min. to 2 hr.

Cells of soft tissue, skin, skeletal muscle: Cells of soft tissue, skin, skeletal muscle: many hoursmany hours

Hypoxic Injury- Hypoxic Injury- changes which changes which

are are reversiblereversible

1.1. Decrease in extracellular ATP levelsDecrease in extracellular ATP levels

2.2. Decrease in the Na pump, with cell Decrease in the Na pump, with cell swellingswelling

3.3. Increase in glycolysis, with a Increase in glycolysis, with a decrease in intracellular pHdecrease in intracellular pH

4.4. Decrease in protein synthesisDecrease in protein synthesis

Hypoxic Injury- Hypoxic Injury- changes which changes which

are are irreversibleirreversible

1.1. Activation of lysosomal enzymes. Activation of lysosomal enzymes. (recall that lysosomal enzymes are (recall that lysosomal enzymes are active at low pH, ca. pH 4-5)active at low pH, ca. pH 4-5)

2.2. Degradation of DNA and protein.Degradation of DNA and protein.

3.3. Influx of calcium. (recall that calcium Influx of calcium. (recall that calcium activates many lipases and activates many lipases and proteases)proteases)

Hypoxic cells are exposed to Hypoxic cells are exposed to damage from oxygen radicals-damage from oxygen radicals-

1.1. Hypoxic patients are given high levels Hypoxic patients are given high levels of oxygen. This oxygen is toxic to the of oxygen. This oxygen is toxic to the cells lining the alveolar spaces in the cells lining the alveolar spaces in the lung because the high 0lung because the high 022 produces produces

oxygen radicals.oxygen radicals.

Hypoxic cells are exposed to Hypoxic cells are exposed to damage from oxygen radicals- damage from oxygen radicals-

(cont)(cont)

2.2. Hypoxic tissues are often infiltrated Hypoxic tissues are often infiltrated with PMNs. PMNs have enzymes, with PMNs. PMNs have enzymes, myleoperoxidases, which produce myleoperoxidases, which produce activated oxygenactivated oxygen

Hypoxic cells are exposed to Hypoxic cells are exposed to damage from oxygen radicals- damage from oxygen radicals-

(cont)(cont)

3.3. Hypoxic tissues are often reperfused Hypoxic tissues are often reperfused once the blood supply is restored. once the blood supply is restored. Xanthine oxidase, produced from Xanthine oxidase, produced from proteolysis during hypoxia, generates proteolysis during hypoxia, generates free radicals when the 0free radicals when the 022 is brought is brought

back to normal levels.back to normal levels.

0022-- + 0 + 022

-- + 2H + 2H++ HH220022 + 0 + 022

SODSOD

GOOD/BAD REACTIONGOOD/BAD REACTION

BAD REACTIONSBAD REACTIONS

1

2

3

HH220022 H H.. + 0H + 0H.. (very reactive)(very reactive)

FEFE++++ + H + H220022 FE FE ++++++ + 0H + 0H.. + +

0H0H--

HH220022 + 0 + 022-- 0H 0H.. + 0H + 0H-- + 0 + 022

FENTON REACTIONFENTON REACTION

HABER-WEISS REACTIONHABER-WEISS REACTION

GOOD REACTIONSGOOD REACTIONS

1

2

GLUTATHIONE PEROXIDASEGLUTATHIONE PEROXIDASE

2 H202 02 + 2H20

2 0H. + 2 GSH 2 H20 + GSSGH202 + 2 GSH 2 H20 + GSSG