Unit 1: Cell Injury and Necrosis I and II

Question 1

Cell injury occurs when?

Answer 1

• cell is unable to adapt to environmental changes and unable to return to full function
• can be reversible, but can also result in death (apoptosis or necrosis)

Question 2

Cell types and injury (how long can they go without O2?)

Answer 2

• Neurons= minutes
• heart/renal epithelial= 30mins-2 hours
• soft tissue/skeletal muscle= hours

Question 3

What is involved in cellular injury (what parts of the cell?)

Answer 3

membranes, mitochondrial function, protein synthesis, nuclear components, enzymatic processes

Question 4

Signs of REVERSIBLE cell injury (x6)–4 visible with LM

Answer 4

1. cellular swelling*
2. cell membrane blebs
3. detached ribosomes
4. chromatin clumping*
5. lipid deposition (fatty change)*
6. vacuole formation (hydropic change)*

**Can be seen with LM

Question 5

causes of IRREVERSIBLE cell injury (x6)

–8 total, 5 visible with LM

Answer 5

1. lysosomal rupture
2. dense bodies in mitochondria
3. cell membrane rupture
4. nuclear condensation= Karyolysis* Karyorrhexis* Pyknosis*
5. vacuolization *
6. calcification*
7. increased eosinophilia *
8. hyalinazation*

**visible with LM

Question 6

Primary causes of cell injury (x6) and consequence of the injury….

(see pathway of cell injury in notes-Cell injury and necrosis #1)

Answer 6

1. ATP depletion [damages cell membranes]
2. irreversible mitochondrial damage [causes free radicals to leak out, less ATP synthesis]
3. Ca⁺² homeostasis disrupted [activate degradative enzymes]==>cytoskeletal damage==>nuclear disassembly]
4. free radical formation [damages membranes]
5. defect in cell membrane permeability [cause electrolyte imbalance]
6. DNA/ Protein damage [can lead to cell death]

(Also: pH, physical disruption)

Question 7

Causes of Cell death

Answer 7

1. Inability to form ATP
2. Physical disruption of cell membranes (mitochondrial or plasma)
3. activation of self-digestion enzymes

Question 8

What can cause ATP to be depleted?

Answer 8

1. Lack of O2 (hypoxia<==ischemia)
2. lack of substrates
3. mitochondrial dysfunction

Question 9

Explain how ATP depletion affects the cell

(ATP depletion results in 3 big things, that then cause more things..)

Answer 9

1. ATP dep Na/K pump not feuled= high Na inside cell==>
   
   • swelling, blebbing and dilation of membranes, loss of microvilli
   • loss of Ca⁺² homeostasis==> activaiton of digestive enzymes
2. Anaerobic glycolysis for energy==> acidosis==>low pH= chromatin clumping
3. damage to protein synthesis apparatus ==>
   
   • ribosomes detach, less protein synthesis ==> lipid deposition (no more lipoprotein)
   • low O2 and glucose==> misfolded proteins (can cause apoptosis)

Notice difference between ATP depletion =cell injury vs interruption of ATP synthesis (damage to mitochondria)= cell death

Question 10

What damages the mitochondrial membrane?

Answer 10

Low O2, high cytosolic calcium, lipase activation, free radical damage

Question 11

Mitochondrial membrane damage leads to….

Answer 11

1. decreased phospholipid synthesis==> plasma membrane damage
2. less ATP synthesis==> high Ca==> phospholipase activation==>phospholipid degradation ==> lipid breakdown products have detergent effect==> more membrane damage

Question 12

1. What can cause high Ca in cells
2. What does calcium do?

Answer 12

1. Low ATP (causing pumps to stop working) or physical damage to membranes/organelles (mitochondria and ER)==>Calcium accumulation in cell
2. high intracellular calcium:
   
   • activates enzymes: phospholipases, ATPases, proteases, endonucleases
   • induce mitochondrial permeability==> Apoptosis

Question 13

What is the permeability transition pore? What does it signify

Answer 13

disruption of the mitochondrial membrane ==> no electrochemical gradient/ETC==> no ATP production

POINT OF NO RETURN==> CELL DEATH

Question 14

What can cause increased free radical formation?

Answer 14

1. Infection: neutrophil oxidative burst,
2. radiation,
3. chemical exposure (CCl4),
4. chronic inflammation (ROS, NO)
5. reperfusion injury,
6. aging
7. oxygen toxicity

Question 15

What specifically do free radicals do to

1. DNA?
2. Lipids
3. Proteins

Answer 15

1. DNA: thymidine dimer formation, single strand breaks
2. Lipids: peroxidation
3. Proteins: oxidative modification
   
   • sulfhydryl x-linking of sulfur AA (cysteine, methionine)
   • polypeptide fragmentation

Question 16

Protective measures against free radicals

Answer 16

1. Mitochondria: Superoxide dismutase and glutathione peroxidase, catalase,
2. Membranes: Vit E, A, beta carotene,
3. ascorbic acid (donno where this chills)
4. Fenton reaction + glutation peroxidase
5. transport molecules (Cu, Fe)

Question 17

DNA/protein damage

1. Etiology
2. effect

Answer 17

DNA/Protein damage

1. Etiology: free radicals, enzymatic digestion
2. impaired cellular function==> toxic accumulation in cell and abnormal growth

Question 18

Is ischemia or hypoxia worse—why?

Answer 18

Ischemia is worse.

• Ischemia: hypoxia (low O2), lack of substrates for glycolysis, lactic acid and metabolic waste accumulation
• Hypoxia: low O2

Question 19

What are causes of hypoxia?

Answer 19

1. ischemia
2. low SaO2 (oxygen tension
3. CO poisoning
4. anemia

Question 20

Chronic inflammation can lead to cancer…How? Examples?

Answer 20

1. chronic inflammation= increased free radical formation= DNA damage==> Dysplasia==> neoplasia
2. Chronic hep C, smoking, GERD, gastritis

Question 21

Hemochromatosis

1. Defect
2. Pathophysiology
3. Associated diseases

Answer 21

1. Hereditary disease with defect leading to Fe deposition in tissues (heart, liver, pancreas)
2. Fe causes damage via Fenton reaction= formation of free radicals
3. Damage results in liver cirrhosis (and cancer), diabetes, heart failure

Question 22

Types of changes that occur in cell within minutes

Answer 22

1. Biochemical = functional loss, arrythmias

Question 23

Changes that occur in hours

Answer 23

Ultrastructural- HOURS–need Electron Microscope

• membrane changes- blebbing, swelling, microvilli distortion, myelin figures
• mitochondrial- swelling, amourphous densities (phospholipids)
• ER- detachment of ribosomes, swelling
• nuclear alterations

Question 24

Changes that occur hours-days

Answer 24

Microscopic (light microscope) -hours-days

• cytoplasmic swelling and pallor
• hydropic changes (ER swelling and pinching off into small vacuoles)
• ballooning degeneration= swollen eosinophilic cytoplasm without vacuoles
• chromatin clumping

Question 25

Changes that occur days- weeks following necrosis

Answer 25

**Gross changes** * pallor (can occur in minutes if caused by ischemia) * soft= tissue disruption (4 days) * raised or depressed * Scar= 2+ weeks

Question 26

Alcoholic hepatitis shows

Answer 26

* ballooning degeneration * mallory bodies

Question 27

**Light microscopy/morphological** hallmarks of cell injury (x4)

Answer 27

1. cytoplasmic swelling, pallor (and turgor) 2. cytoplasmic vacuolization 3. chromatin clumping 4. Fatty change (if tissue is involved in lipoprotein synthesis)

Question 28

**MORPHOLOGICAL** hallmarks of cell death (necrosis)

Answer 28

1. disintegration of nucleus 2. disruption of cell membranes 3. digestion of cellular enzymes ==\> **EOSINOPHILIA and HYALINIZATION of cell==\>tissue becomes soft and structure is disrupted**

Question 29

Most important feature for identifying necrosis? How does this occur?

Answer 29

**_Loss of nucleus from pyknosis, karyorrhexis, karyolysis_**

Question 30

Define 1. Pyknosis 2. Karyorrhexis 3. Karyolysis

Answer 30

Nuclear changes that indicate NECROSIS 1. **Pyknosis**-solid, shrunken basophilic mass. Chromatin is more basophilic 2. **Karyorrhexis-** [basophilic] nucleus fragments 3. **Karyolysis-**nucleus dissolves into amorphic mass, less basophilic. DNAase activated= dissolution of DNA

Question 31

**Autolysis**

Answer 31

* **autolysis:** release of enzymes from lysosomes--activated by calcium * irreversible injury that causes morphological change

Question 32

**Coagulative Necrosis** 1. LM characteristics 2. Mechanism

Answer 32

1. LM charactertics of coagulative necrosis * karyorrhectic (fragmented) or absent nucleus, * eosinophilic cytoplasm, * cell outlines preserved, * firm tissue (days)==\>then softens 2. **Hypoxic cell death (in all tissues but brain)**

Question 33

**Liquefactive necrosis** 1. **LM characteristics** 2. **Gross** 3. **mechanism**

Answer 33

**liquefactive necrosis** 1. **LM changes** * neutrophils, * destructive enzymes from PMNs, * tissue architecture destroyed, * pus 2. **Gross changes:** softening (malacia) yellow/tan color 3. **Causes:** G- abscess, ischemia of brain

Question 34

Gangrenous necrosis * define * causes * wet gangrene

Answer 34

* type of coagulative necrosis of multiple tissue layers in limbs * Causes: loss of blood supply, frost bite * can become wet gangrene if secondary bacterial infection

Question 35

Caseous Necrosis * general features * gross appearance * Light microscope

Answer 35

Caseous necrosis * type of coagulative necrosis associated with m. tuberculosis. * caseating (necrotic center) * non caseating (non necrotic center) * gross appearance: yellow-white cheese-like material, nodules * LM: central area of amorphous eosinophilic granular matter surrounded with epithelioid histiocytes and a lymphocytic mantle. Less distinct cell borders than coag, but more clear than liquefactive.

Question 36

Potts diesease

Answer 36

TB in the spine

Question 37

Fat necrosis 1. features 2. Light microscope 3. Gross appearance

Answer 37

Fat necrosis- type of coagulative necrosis 1. soaponifaction from calcium combining with degrading fats and proteins (breast trauma or pancreatitis) 2. eosinophilic ghost outline of dead adipocytes with basophilic calcium deposits. surrounded by inflammation 3. white, chalky firm areas--soaponifcation

Question 38

Fibrinoid Necrosis 1. features 2. histological appearance 3. causes?

Answer 38

Fibrinoid necrosis- Type III HS reaction. 1. immune complex depositions within walls of blood vessels with fibrin 2. looks like fibrin--bright pink hyalinization 3. polyarteritis nodosa

Question 39

Contraction bands

Answer 39

speficif pattern of cardiac myocyte damgage caused by ROS (following repurfusion)