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Anat Path > Cell Injury, Necrosis And Apoptosis > Flashcards

Cell Injury, Necrosis And Apoptosis Flashcards

1
Q

Causes of Cell Injury

A

•Oxygen deprivation
•Physical agents
•Chemical agents and drugs
•Infectious diseases
•Immunologic reactions
•Nutritional imbalance
•Genetic derangements

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2
Q

Hypoxia

A

It refers to inadequate oxygenation of tissue. It is the most common cause of cell injury.

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3
Q

Causes of hypoxia:

A

•Decreased blood flow is called ischemia. It may be due to thrombosis, embolism, atherosclerosis or external compression of vessel.

••• Inadequate oxygenation of the blood (hypoxemia)
•–– Due to pulmonary disease
•–– Decreased perfusion of tissues: e.g. cardiac failure, hypotension shock
•–– Decreased oxygen-carrying capacity of the blood: e.g. anemia
•–– Severe blood loss.

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4
Q

Mechanism and outcome of hypoxic injury

A

•Mechanism of hypoxic injury:
Hypoxia causes cell injury by reducing aerobic oxidative respiration and decreasing the synthesis of adenosine triphosphate (ATP).

•Outcome: Depending on the severity of the hypoxia, cells may adapt, undergo injury, or die.

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5
Q

Physical agents causing cellular injury

A

•B. Physical Agents:
••• Mechanical trauma: e.g. blunt/penetrating/crush injuries, gunshot wounds
••• Thermal injury: Extremes of temperature (burns and deep cold)
••• Radiation (ionizing radiation and non-ionizing radiation)
••• Electric shock
••• Pressure changes: Sudden changes in atmospheric pressure.

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6
Q

Chemical agents causing cellular injury

A

Chemical Agents:
••• Heavy metals and poisons: e.g. arsenic, mercuric salts or cyanide
••• Simple chemicals: e.g. hypertonic concentrations of glucose or salt
••• Strong acids and alkalis
••• Oxygen at high concentrations is toxic
••• Environmental and air pollutants: e.g. insecticides, and herbicides
••• Industrial and occupational hazards (carbon monoxide and asbestos)
••• Social/lifestyle choices: Addiction to drugs and alcohol, cigarette smoking
••• Therapeutic drugs.

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7
Q

Infectious agents causing cellular injury

A

Infectious Agents: Viruses, bacteria, fungi, rickettsiae and parasites. The mechanism by which these infectious agents cause injury varies.

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8
Q

Immunologic Reactions causing cellular injury

A

E. Immunologic Reactions
••• Autoimmunity: Immune reactions to endogenous self-antigens are responsible for
autoimmune diseases.
••• Hypersensitivity reactions and other immune reactions: Heightened immune reactions to

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9
Q

Genetic Derangements causing cell injury

A

Genetic Derangements: Genetic defects may cause cell injury because of
••• Deficiency of functional proteins (e.g. enzyme defects in inborn errors of metabolism)
••• Accumulation of damaged DNA or misfolded proteins
••• Variations in the genetic makeup.

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10
Q

Nutritional Imbalances causing cell injury

A

G. Nutritional Imbalances:
••• Nutritional deficiencies:
•–– Protein-calorie deficiencies
•–– Deficiencies of specific vitamins.

• Nutritional excesses:
• –– Excess of cholesterol predisposes to atherosclerosis
• –– Obesity is associated with increased incidence of several important diseases, such as diabetes and cancer
• –– Hypervitaminosis

• H. Idiopathic: Cause is not known

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11
Q

Cellular response to injury depends on:

A

•1) type of injury,
•2) duration of injury and
•3) severity of injury.

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12
Q

Consequences of injury depends on:

A

•1) type of cell involved
• 2) adaptability of cell
•3) status of cell and
•4) genetic makeup of the cell.

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13
Q

Targets and biochemical mechanism of cell injury include (structures and mechanisms more likely to be affected by cell injury)

A

• 1) mitochondrial damage/dysfunction
• 2) disturbance of calcium homeostasis
• 3) damage to cellular membranes and
• 4) damage to DNA and misfolding of proteins.

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14
Q

Principal mechanisms/Pathogenesis of Cell Injury

A

•Depletion of ATP
•Mitochondrial damage
•Loss of calcium homeostasis
•Accumulation of free radicals
•Defects in membrane permeability
•Damage to DNA and proteins
●Ischaemia-Reperfusion Injury

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15
Q

Important mechanism of cell injury include

A

•1. Damage to DNA, proteins, lipid membranes, and circulating lipids (LDL) by peroxidation caused by oxygen-derived free radicals, e.g. O2.- , OH. , H2O2
• 2. Adenosine triphosphate (ATP) depletion
•3. Increased cell membrane permeability
4. Influx of calcium
5. Mitochondrial dysfunction

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16
Q

How does Influx of calcium cause cell injury

A

Influx of calcium:
•Second messenger
•Activates a wide spectrum of enzymes
•Proteases protein breakdown
•ATPases contributes to ATP depletion
•Phosphatases DNA damage
•Endonucleases DNA damage

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17
Q

How does Mitochondrial dysfunction cause cell injury

A
  1. Mitochondrial dysfunction:
    •Decreased oxidative phosphorylation
    •Formation of mitochondrial permeability transition (MPT) channels
    •Release of cytochrome c is a trigger for apoptosis
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18
Q

REVERSIBLE CELL INJURIES include

A

•A. Decreased synthesis of ATP by oxidative phosphorylation
•B. Decreased function of Na+ K+ ATPase membrane pumps
•C. Switch to glycolysis
•D. Decreased protein synthesis:
•E. Plasma-membrane blebs and intracytoplasmic myelin figures may be seen.

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19
Q

How does Decreased function of Na+ K+ ATPase membrane pumps cause reversible cell injury

A

•-Influx of Na+ and water
•-Effux of K+
•- Cellular swelling (hydropic swelling)
•-Swelling of endoplasmic reticulum

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20
Q

How Switch to glycolysis cause reversible cell injury

A

Switch to glycolysis
• - Depletion of cytoplasmic glycogen
•- Increased lactic acid production
•- Decreased intracellular pH

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21
Q

How Decreased protein synthesis cause reversible cell injury

A

Decreased protein synthesis:
•- Detachment of ribosomes from the rough endoplasmic reticulum

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22
Q

IRREVERSIBLE CELL INJURIES include

A

•A. Severe membrane damage
•B. Marked mitochondrial dysfunction
•C. Rupture of lysosomes:
•D. Nuclear changes:

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23
Q

How does Severe membrane damage: cause irreversible cell injury

A

*-Massive influx of calcium
*-Efflux of intracellular enzymes and proteins into the circulation

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24
Q

How does Marked mitochondrial dysfunction cause irreversible cell injury?

A

B. Marked mitochondrial dysfunction:
- Mitochondrial swelling
•- Large densities are seen within the mitochondrial matrix
•-irreparable damage of the oxidative phosphorylation pathway
•-inability to produce ATP

25
Q

How does the Rupture of lysosomes cause irreversible cell injury?

A

•C. Rupture of lysosomes:
•- Release of lysosomal digestive enzymes into the cytosol
•-Activation of acid hydrolases followed by autolysis

26
Q

What Nuclear changes cause irreversible cell injury?

A

•D. Nuclear changes:

Pyknosis; degeneration and condensation of nuclear chromatin

Karyorrhexis: nuclear fragmentation

Karyolysis: dissolution of the nucleus.
Schematic illustration of the morphologic chang

27
Q

Discuss Ischaemic-Reperfusion Injury

A

•This is a process by which reperfused tissues sustain loss of cells in addition to the cells that are irreversibly damaged at the end of ischemia.

•It’s clinically important because it contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow

•Ischaemic-reperfusion injury occur due to the new damaging processes that are set in motion during reperfusion, causing the death of cells that might have recovered

28
Q

Pathogenesis of Ischaemic-Reperfusion Injury

A
  1. Oxidative stress
  2. Intracellular calcium overload
  3. Activation of the complement system
29
Q

What is Oxidative stress?

A
  1. Oxidative stress: Free radicals may be produced in reperfused tissue as a result of incomplete reduction of oxygen by damaged mitochondria or because of action of oxidases in leukocytes, endothelial cells or parenchymal cells.
30
Q

Intracellular calcium overload

A

Intracellular calcium overload: influx of calcium resulting from cell membrane damage and ROS mediated injury to sarcoplasmic reticulum **opening of the mitochondrial permeability pore with resultant depletion of ATP

31
Q

Intracellular calcium overload

A

influx of calcium resulting from cell membrane damage and ROS mediated injury to sarcoplasmic reticulum **opening of the mitochondrial permeability pore with resultant depletion of ATP

32
Q

Activation of the complement system:

A

Some IgM antibodies have a propensity to deposit in ischemic tissues, for unknown reasons, and when blood flow is resumed, complement proteins bind to the deposited antibodies, are activated and cause more injury and inflammation

33
Q

Two main types of cell death

A

Necrosis and apoptosis.

34
Q

Difference between apoptosis and necrosis

A

*Necrosis: Always a pathologic process

  • Apoptosis: May be physiological or pathological
35
Q

Describe NECROSIS

A

•Definition: Morphological changes indicative of cell death in a living tissue following harmful injury.

•The necrotic cells bring out acute inflammatory reaction in the surrounding tissue.

36
Q

NECROSIS: MORPHOLOGY

A

•The general changes occurring in necrotic cell:
••• Cytoplasmic changes: Increased eosinophilia.
••• Nuclear changes: These may take up one of three patterns.
•–– Pyknosis: Shrinkage of nucleus which appears shrunken and deeply basophilic (similar to ink drop).
•–– Karyolysis: Progressive fading of basophilic staining of the nuclei and leads to a ghost nuclei.
•–– Karyorrhexis: Nucleus breaks up into many smaller fragments

37
Q

MORPHOLOGIC PATTERNS OF NECROSIS

A

➢Coagulative
➢Liquefactive
➢Caseous
➢Gangrenous
➢Fat
➢Fibrinoid

38
Q

Discuss COAGULATIVE NECROSIS:
(Causes, mechanism, gross, microscopy)

A

Common type, outline of dead tissues is preserved (at least for few days). Infarct is a localized area of coagulative necrosis. With ghost cells
** Causes: Ischemia caused by obstruction in a vessel.
*** Mechanism: Ischemia denatures and coagulates structural proteins and enzymes.

** Gross:
*–– Organs affected: All organs except the brain. More frequent in heart, kidney, spleen and limb (dry gangrene).
–– Appearance: Involved region appear dry, pale, yellow and firm. It is wedge shaped in organs like kidney and spleen.
** Microscopy : Indistinct outline of dead tissue. Nucleus may be either absent or show karyolysis.

39
Q

Discuss LIQUEFACTIVE NECROSIS (COLLIQUATIVE NECROSIS)
(Causes, mechanism, gross, microscopy)

A

LIQUEFACTIVE NECROSIS (COLLIQUATIVE NECROSIS)
•Dead tissue rapidly undergoes softening and transforms into a liquid viscous mass.
••• Causes:
•–– Ischemic injury to central nervous system (CNS)
•–– Suppurative infections: Infections by bacteria which stimulate the accumulation of leukocytes.

••• Mechanism: Liquefaction is due to digestive action of the hydrolytic enzymes released from
•dead cells (autolysis) and leukocytes (heterolysis).
••• Gross: Organs affected are:
•–– Brain: Necrotic area is soft and center show liquefaction
•–– Abscess anywhere: Localized collection of pus.
•–– It is also seen in wet gangrene and pancreatic necrosis
••• Microscopy: Pus consists of liquefied necrotic cell debris, dead leukocytes and macrophages (scavenger cells).

40
Q

Discuss CASEOUS NECROSIS
(Causes, mechanism, gross, microscopy)

A

•Caseous Necrosis is a distinctive type of necrosis which shows combined features of both coagulative and liquefactive necrosis.
••• Cause: Characteristic of tuberculosis and is due to the hypersensitivity reaction.
••• Gross:
•–– Organs affected: Tuberculosis may involve any organ, most common in lung and lymph node.

◆◆ Necrotic area appears yellowish white, soft, granular and resembles dry, clumpy cheese, hence the name caseous (cheese-like) necrosis.
••• Microscopy:
•–– Focal lesion of tuberculosis is a granuloma which may be caseating (soft granuloma) or noncaseating (hard granuloma).
•◆◆ Caseous necrosis appears as eosinophilic, coarsely granular material.
•◆◆ Caseous necrotic material may undergo dystrophic calcification

41
Q

Discuss types of FAT NECROSIS and define (Causes, mechanism, gross, microscopy)

A

•Fat Necrosis refers to focal areas of fat destruction, which affects adipose tissue.
•Types:
•1. Enzymatic fat necrosis: Occurs in adipose tissue around acutely inflamed pancreas (in acute pancreatitis).
••• Mechanism: In pancreatitis, the enzymes (one of them is lipase) leak from acinar cells and causes tissue damage. Lipase destroys fat cells and liberates free fatty acids which combine with calcium and form calcium soaps (fat saponification).

••• Gross: Appears as chalky-white areas
••• Microscopy: The necrotic fat cells appear pale with shadowy outlines surrounded by an inflammatory reaction

•2. Traumatic fat necrosis: Occurs in tissues with high fat content (like in breast and thigh)
following severe trauma.

42
Q

Discuss FIBRINOID NECROSIS
(Causes, mechanism, gross, microscopy)

A

FIBRINOID NECROSIS
•Fibrinoid Necrosis is characterized by deposition of pink-staining (fibrin-like) proteinaceous material in the tissue matrix with a staining pattern reminiscent of fibrin).
•It obscures the underlying cellular detail.
••• Causes: Usually seen in immune mediated diseases with deposition of antigen-antibody complexes in the wall of vessels,

43
Q

Examples of fibrinoid necrosis

A

•1. Vascular injury/vasculitis (e.g. polyarteritis nodosa),
•2. Malignant hypertension,
•3. Aschoff bodies in rheumatic heart disease,
•4. Placenta in pre-eclampsia,
•5. hyperacute transplant rejection.
•6.. Autoimmune disorder-SLE

44
Q

Discuss GANGRENOUS NECROSIS,
(Causes, types, mechanism, gross, microscopy)

A

•Gangrene (Gangrenous Necrosis) is massive necrosis with superadded putrefaction.

•Types: Two types, namely dry and wet gangrene.
•A variant of wet gangrene known as gas gangrene is caused by clostridia (gram-positive anaerobic bacteria).

•1. Dry Gangrene:
••• Causes: Arterial occlusion (e.g. atherosclerosis).
••• Sites: It is usually involves a limb, generally the distal part of lower limb (leg, foot, and toe).
••• Gross: Affected part is dry, shrunken (shriveled) and dark brown or black resembling the foot of a mummy. The black color is due to the iron sulfide. A line of demarcation is seen between gangrenous and adjacent normal area

Microscopy: The necrosis (coagulative type) shows smudging of soft tissue and overlying skin. The
•line of demarcation consists of granulation tissue with inflammatory cells.

•2. Wet Gangrene:
••• Causes: Due to the venous blockage (e.g. strangulated hernia, intussusception or volvulus).
••• Sites: Occurs in moist tissues or organs (e.g.

45
Q

Discuss APOPTOSIS

A

•A programmed cell death that occurs when a cell dies through activation of a tightly regulated internal suicide program.
•It is characterized by activation of cell enzymes that degrade its own nuclear DNA and proteins (nuclear and cytoplasmic).
•The cause of apoptosis can be either physiologic or pathologic.

46
Q

PHYSIOLOGIC CAUSES of apoptosis

A

➢Programmed destruction of cells during embryogenesis
➢Hormone-dependent involution of tissues (e.g., endometrium, prostate) in adult
➢Cells deletion in proliferating cell population (e.g., intestinal epithelium to maintain a constant cell number.
➢Death of cells that have served their purpose (e.g., neutrophils following an acute inflammatory response)
➢Death of potentially harmful self-reactive lymphocytes

47
Q

PATHOLOGIC CAUSES of apoptosis

A

➢DNA damage (e.g. due to hypoxia, radiation or cytotoxic drugs).
➢Accumulation of misfolded proteins (e.g. due to inherited defects or due to free radical damage)
ER STRESS.
➢Cell death in certain viral infections (e.g. hepatitis).
➢Cytotoxic T cell causing apoptotic cell death in tumours and in rejection of transplanted tissues.
➢Pathologic atrophy in parenchymal organs after duct obstruction (e.g. pancreas).

48
Q

APOPTOSIS: MORPHOLOGY under an electron microscope

A

•A. Electron Microscope:
•The ultrastructural features of apoptosis are:
••• Cell shrinkage: Cytoplasm becomes dense.
••• Nuclear condensation and fragmentation
••• Formation of cytoplasmic blebs and apoptotic bodies

49
Q

APOPTOSIS: MORPHOLOGY under a Light Microscopy

A

B. Light Microscopy:
•The apoptotic cells appear as round or oval mass having intensely eosinophilic cytoplasm.
•The nuclei appear as fragments of dense nuclear chromatin and shows pyknosis.
•Apoptosis does not elicit an inflammatory reaction in the host.
•Phagocytosis of apoptotic cells/bodies: The apoptotic bodies are rapidly ingested/phagocytosed by adjacent healthy cells or phagocytes (usually by macrophages) and degraded by the lysosomal enzymes of phagocytes.

50
Q

BIOCHEMICAL CHANGES IN APOPTOSIS

A

•Activated caspases (proteases) break down cell components

•Internucleosomal cleavage of DNA into fragments of 180 to 200 base pairs in size give rise to characteristic ladder pattern of DNA bands on agarose gel electrophoresis

•Plasma membrane alteration (e.g., flipping of phosphatidylserine) allow recognition of apoptotic cells for phagocytes

51
Q

Which signals control APOPTOSIS? And which group of enzymes control apoptosis?

A

•The survival or apoptosis of many cells depends upon balance between two opposite sets of signals namely
• 1) death signal (pro-apoptotic) and
•2) pro-survival (anti-apoptotic) signals.
•Unlike necrosis, apoptosis engages the cell’s own signaling cascades and results in its own death (suicide).
•Apoptosis results from activation of enzymes called as caspases.

52
Q

Phases of Apoptosis

A

A) initiation phase
B) execution phase (common to the two pathways)

53
Q

Initiation Phase of apoptosis

A

•Apoptosis is initiated by signals derived from two distinct pathways activated by distinct stimuli
•namely: 1) intrinsic or mitochondrial pathway and 2) extrinsic or death receptor pathway.

54
Q

Intrinsic (Mitochondrial)Pathway in apoptosis

A

•Regulated by BCL2 family of proteins
➢Anti-apoptotic members– BCL2, BCL-XL and MCL1
➢Pro-apoptotic members – BAX, BAK
➢Sensors (BH3-only proteins) – Bim, Bid, Bad, Puma and Noxa
•Release of Cytochrome C
•Binding of cytochrome c to APAF1(Apoptotic activating factor 1) apoptosome
•Leads to activation of initiator caspase(caspase9)
which further activate executioner caspase(caspase3)

55
Q

Extrinsic (Death receptor initiated) Pathway

A

•TNF receptor family – TNFR1 and Fas (CD95)
•They have intracytoplasmic death domain
•FasL binds to Fas and activates it
•Adaptor protein FADD is bound
•Caspase 8 or 10 is activated
•FLIP proteins inhibit procaspase 8

56
Q

Disorders associated with dysregulated apoptosis

A

•Defective apoptosis and increased cell survival
➢Tumor arising from TP53 mutation
➢B-cell lymphomas

•Disorders resulting from excessive apoptosis
➢Neurodegenerative diseases
➢Ischaemic injury – myocardial infarction and stroke
➢Death of virus infected cells

57
Q

Necroptosis

A

Necroptosis: Form of cell death which shares features of both necrosis and apoptosis.
•It is caspase-independent. It resembles morphologically necrosis and mechanistically apoptosis.

58
Q

Pyroptosis

A

•Pyroptosis: A form of programmed cell death associated with the release of fever inducing
•cytokine IL-1 and has some biochemical similarities with apoptosis.

Anat Path (26 decks)

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