Lecture 1-3: Intro/Cell Injury (Castleman)

Question 1

pathology*

Answer 1

study of dz; branch of med. focused on the essential nature of dz, esp. the structural, biochemical and functional changes in tissues and organs of the body that result in or are the result of dz

Question 2

general pathology*

Answer 2

basic reactions of cells and tissues to injury that underlie all diseases. Involves degen, cell necrosis, edema, etc.

Question 3

systemic or special pathology*

Answer 3

specific responses of organs and tissues to more or less well defined stimuli or in well-defined dzs

Question 4

6 Basic Reactions of Cells and Tissue to Injury**

Answer 4

1) cell injury/death
2) tissue depositions and pigments
3) circulatory disturbances
4) inflammation and repair
5) disturbances of growth/neoplasia
6) neoplasia

Question 5

anatomical path*

Answer 5

focuses on tissue changes at the gross, microscopic, ultrastructural, and molecular lvls to identify lesions and to make dx to understand dz and to aid tx and prevention. Includes surgical and necropsy path

Question 6

necropsy path*

Answer 6

exam of animal post-mortem to identify pathologic processes and lesions present at the time of death and to provide info for better future disease treatment and control

Question 7

surgical path*

Answer 7

study changes in samples collected by biopsy procedures

Question 8

infarct*

Answer 8

small localized area of coag. necrosis resulting from failure of blood supply

Question 9

infarct in dogs most likely caused by:*

Answer 9

bacterial endocarditis

Question 10

deprivation of blood supply to tissue in artery w/o a collateral blood supply –>*

Answer 10

coagulation necrosis

Question 11

how does bacterial dissemination to the kidney result in thrombosis?*

Answer 11

via coag. and platelet aggregation

Question 12

disease*

Answer 12

abnormal body process with a char. set of signs/symptoms and lesions that may affect the whole body or any of its parts. Begins with injury at the molecular and cellular level

Question 13

cell injury*

Answer 13

damage or pathologic alterations in cell molecules or cell structures

Question 14

lesion*

Answer 14

cell alteration assoc. with disease

Question 15

Causes of cell injury (8)*

Answer 15

1) hypoxia/hypoxemia
2) physical agents
3) chemicals/drugs
4) infectious agents
5) immunologic rxns
6) genetic defects
7) nutritional imbalances
8) aging

Question 16

3 Main responses to cell injury**

Answer 16

1) Adaptation
2) Reversible cell injury
3) Irreversible cell injury (from necrosis to apoptosis)

Question 17

necrosis*

Answer 17

pattern of cell death that often follows hypoxic, toxic and microbial injury and is char. by cell swelling with nuclear changes such as pyknosis and karyorrhexis. Requires biochem. changes and time to occur

Question 18

pyknosis*

Answer 18

irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis (web)

Question 19

karyorrhexis*

Answer 19

destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distr. irregularly throughout the cytoplasm (web)

Question 20

apoptosis*

Answer 20

pattern of cell death that is induced by a tightly reg. intracellular program in which cells induced to die activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins leading to nuclear frag. w/o loss of PM integrity

Question 21

reversible cell injury*

Answer 21

• cell injury w/ loss of cell fx and structural changes
• cell CAN revert to normal if insult removed
• char. by cell swelling, chromatin clumping, lipidosis

Question 22

cell swelling caused by:*

Answer 22

abnormality in the membrane’s ion/water transport mech. so that cell accumulates water (loss of ATP-dependent Na transport system in the plasma membrane causes Na, Ca, H2O influx). Ca influx increases intracellular protease activity and “poisons” mitochondria.

Question 23

chromatin clumping*

Answer 23

chromatin becomes markedly coarse as a result of degen. changes. Decreased oxidative phosphorylation –> increased anaerobic glycolysis –> dec. cell glycogen –> inc. lactic acid –> dec. cell pH –> chromatin clumping

Question 24

lipidosis*

Answer 24

accum. of lipid. Due to decreased protein synthesis leading to decreased lipid transport out of hepatocytes

Question 25

ultrastructural changes of reversible cell injury*

Answer 25

1) dilation of ER 2) ribosomal detachment from RER 3) loss of microvilli/cilia 4) mitochondrial swelling 5) chromatin clumping 6) membrane blebs 7) lipid accum.

Question 26

consequence of decreased protein synthesis*

Answer 26

accumulation of neutral triglycerides

Question 27

Irreversible cell injury*

Answer 27

- cell passes point of no return/can't recover - nuclear changes (hallmark) ie. nuclear condensation, fragmentation, dissolution: - pyknosis - karyorrhexis - chromatolysis - high amplitude mitochondrial swelling - membrane defects - lysosomal membrane rupture

Question 28

chromatolysis*

Answer 28

DNA broken down enzymatically and loses ability to be stained by various dyes such as hematotoxylin. Char. by loss of basophilic stain and increased eosinophilia

Question 29

kidney convoluted tubules undergo ____ when blood supply is interrupted*

Answer 29

coagulation necrosis

Question 30

EXAM Q: Which of the following are changes seen in reversible cell injury?***

Answer 30

A: mitochondrial swelling and swelling of ER. NOT pyknosis/karyorrhexis

Question 31

EXAM Q: Which of the following are defining chars. of necrotic cells?***

Answer 31

A: pyknosis/karyorrhexis and nuclear chromatolysis

Question 32

Chars. of coagulative necrosis*

Answer 32

- nuclear changes - pyknosis - karyorrhexis - chromatolysis - increased eosinophilia of cytoplasm - cell borders still visible** - cooked appearance grossly - calcification may occur - vacuolization (moth-eaten appearance)

Question 33

Patterns of necrosis*

Answer 33

``` coagulative liquefactive caseous gangrenous fat fibrinoid ```

Question 34

Chars. of liquefactive necrosis*

Answer 34

- loss of cell borders - granular basophilic and eosinophilic debris with nuclear fragments - tissue structure obliterated - often occurs in tissues with high fat content

Question 35

Liquefactive necrosis pathogenesis*

Answer 35

- high neutrophil influx (protease destruction) | - high fat content of tissue (i.e. brain)

Question 36

chars. of caseous necrosis*

Answer 36

- "cheese-like" quality grossly - loss of cell borders - tissue structure obliterated - center of lesions homogeously eosinophilic with scattered nuclear basophilia - hallmark: recruits macrophages, rather than neutrophils**

Question 37

pathogenesis of caseous necrosis*

Answer 37

- recruitment of macrophages with persistence of stimulus and inflammatory cell component breakdown - common in mycobacterial infections

Question 38

pathogenesis of gangrenous necrosis *

Answer 38

- loss of blood supply to distal extremities | - hypoxia-induced necrosis

Question 39

apoptosis*

Answer 39

specialized form of cell death that is often triggered by specific receptor-mediated stimuli or by loss of signals on well differentiated cells. Occurs both physiologically and pathologically. Cell breaks up into smaller fragments and then phagocytized

Question 40

Physiologic examples of apoptosis*

Answer 40

- embryogenesis - hormone-dependent physiologic involution and cycling - cell depletion in proliferating populations during tissue repair - deletion of autoreactive T cells in thymus - death of virus-infected cells induced by cytotoxic T cells

Question 41

Pathologic examples of apoptosis*

Answer 41

- DNA damage - accum. of misfolded proteins - drug/cytokine induced cell death - viral induced cell death - pathologic atrophy of organs after duct obstruction

Question 42

Examples of pathologic inhibition of apoptosis*

Answer 42

- neoplasm (i.e. p53 mutation) | - viral-induced proliferative diseases

Question 43

Cell functions that may be critical to tissue function and organismal survival

Answer 43

- contractility - communication - absorption - secretion of glycosaminoglycans - secretion of proteolytic enzymes - nutrient storage - defense against microbial and parasitic invaders

Question 44

adaptation

Answer 44

changes in function and structure that maintain a homeostatic state and maintain cell viability. Cells may revert to previous structure and fx when the stress or injury is removed

Question 45

karyolysis

Answer 45

dissolution of chromatin

Question 46

Extrinsic pathway of apoptosis (6 steps)*

Answer 46

In general: FAS-Fas-ligand, TNF-TNF receptor interactions activate caspases 1) stim. of receptor by ligand 2) alteration in second signals 3) activation of capsases 4) activation of endonucleases and cytoskeleton breakdown 5) nuclear and cytoplasmic fragmentation 6) phagocytosis of apoptotic bodies * no swelling/inflammation*

Question 47

What are caspases?*

Answer 47

enzyme cascade system

Question 48

withdrawal of growth factors initiates stim. of membrane pro-apoptotic molecules -->*

Answer 48

activates caspases --> apoptosis

Question 49

cytotoxic T-cells initiate necrosis by:*

Answer 49

bringing FAS ligand to FAS receptor. They help kill cells that become targeted by the cellular or adapted immune response

Question 50

what does granzyme B do?*

Answer 50

activates apoptotic pathway

Question 51

What does Bcl-2 do?*

Answer 51

inihibit mitochondrial permeability and therefore inhibits apoptosis

Question 52

Intrinsic (mitochondrial) pathway of apoptosis*

Answer 52

loss of stimuli or positive stimuli induce increased mitochondrial permeability and release of cytochrome c or other activators of the caspase system. *mitochondrial permeability a critical event*

Question 53

What circumstances can induce intrinsic pathway of apoptosis?*

Answer 53

- mitochondrial injury/dysfunction - increased cytosolic Ca2+ - oxidative stress - lipid peroxidation

Question 54

Does apoptosis have gross changes? Microscopic?*

Answer 54

RARELY gross. (i.e. lymphoid atrophy). Detectable microscopically

Question 55

Clicker Q: Mitochondrial release of cytochrome c contributes to the initiation of:*

Answer 55

apoptosis

Question 56

Clicker: Cell death is rarely assoc. with inflammation in: *

Answer 56

apoptosis

Question 57

Mitochondrial and ER swelling often accompanies:*

Answer 57

necrosis

Question 58

T/F: some injuries can induce both apoptosis and necrosis*

Answer 58

True. Dominance depends on severity/duration of injury

Question 59

Pyroptosis*

Answer 59

microbial products induce activation of inflammasome and apoptotic-like changes (i.e. activation of caspase 1 or IL-1)

Question 60

T/F: apoptosis and necroptosis can be regulated or programmed*

Answer 60

T

Question 61

activation of caspase 1 results in*

Answer 61

cell death with cell swelling due to membrane pores that are induced

Question 62

activation of IL-1 results in:*

Answer 62

fever and leukocyte recruitment

Question 63

post-mortem autolysis*

Answer 63

"self-digestion" after somatic death. Char. by diffuse gross changes (i.e. pale tissue) and NO tissue response microscopically

Question 64

Mechanisms of cell injury*** (7)

Answer 64

``` ATP depletion mitochondrial damage/dysfunction influx of calcium oxygen-derived free radicals membrane permeability defects DNA damage protein misfolding ```

Question 65

Common pathways in cell death (4)*

Answer 65

- ischemic/hypoxic injury - free radical injury - chemical injury - injury by infectious agents

Question 66

what is the result of Ca intracellular release? What do these results lead to? (4 things)*

Answer 66

Activation of enzyme systems including: - ATPase --> decreased ATP - Phospholipase --> decreased phospholipids - Protease --> disruption of membrane and cytoskeletal proteins - Endonuclease --> chromatin clumping * protease and phospholipase ultimately lead to membrane damage*

Question 67

Describe the flow of events resulting from hypoxic damage in REVERSIBLE injury?*

Answer 67

ischemia --> decreased mitochondrial ox. phos. --> decreased ATP --> decreased Na/K pump, increased glycolysis, detachment of ribosomes

Question 68

decreased Na/K pump function --> ??*

Answer 68

influx of Ca H2O, Na into cell. Efflux of K. Results in cell swelling, loss of microvilli, membrane blebs ER swelling, myelin figures

Question 69

increased glycolysis --> ??*

Answer 69

decreased pH/glycogen in the cell. Results in chromatin clumping, intracellular release and activation of lysosomal enzymes, decreased basophilia, nuclear changes, and protein digestion

Question 70

detachment of ribosomes --> ??*

Answer 70

decreased protein synthesis--> lipid deposition

Question 71

At what point does reversible cell injury from hypoxia become irreversible?*

Answer 71

Once membrane injury, intracellular release/activate of lysosomal enzymes, and/or influx of Ca occurs

Question 72

*Review green star slide flow chart slide 22 and practice drawing on whiteboard*

Answer 72

:)

Question 73

Free radical*

Answer 73

a chemical species that has a single unpaired electron in an outer orbital. I.e. OH, O2-

Question 74

Sources of free radicals*

Answer 74

- absorption of radiant energy - redox rxns (i.e. Fenton rxn) - exposure to toxins - inflammation - aging - repurfusion injury

Question 75

Fenton rxn*

Answer 75

generates ferric iron and hydroxyl radical from ferrous iron and hydrogen peroxide. *anything that leads to an abundance of ferrous iron will eventually kill cell via Fenton rxn due to generation of free radicals*

Question 76

superoxide dismutase (SOD)*

Answer 76

breaks down superoxides into hydrogen peroxide and oxygen

Question 77

Damage induced by free radicals*

Answer 77

- lipid peroxidation of membranes --> increased permeability and lipid autoperoxidation rxn - DNA damage leading to mutations and death - cross linking of proteins (esp. sulfhydryl rich proteins) - interaction with cytosolic molecules such as Hb *free radicals propagate more free radicals!*

Question 78

fxn of catalase*

Answer 78

breaks down hydrogen peroxide to H2O and O2

Question 79

Common antioxidants, and their mech. of action*

Answer 79

- sulfhydryl rich molecules (free radical scavengers) - Vitamin E (terminate lipid peroxidation) - Ceruplasmin and transferrin (bind copper and Fe+2, preventing Fenton rxn)

Question 80

glutathione peroxidase*

Answer 80

catalyzes conversion of hydroxyl free radicals to water

Question 81

most free iron in the body is in what state?

Answer 81

ferric iron (Fe+3)

Question 82

Reperfusion Injury is a combo of:*

Answer 82

hypoxic and free radical damage. Tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen (web)

Question 83

Series of events in reperfusion injury*

Answer 83

- reduced blood flow --> hypoxic damage - increased xanthine oxidase activity - re-est. of blood-flow brings O2, Ca, inflammatory cells - O2 converted to superoxide anion and OH - inflamm. cells generate oxygen free rads - membrane damage, increased Ca, cell death

Question 84

2 examples of toxin-induced cell injury*

Answer 84

CCl4, Cyclophosphamide

Question 85

CCl4 effects*

Answer 85

activation of free-radical intermediate, lipid peroxidation, necrosis

Question 86

Cyclophosphamide effects*

Answer 86

(a chemo drug) induces apoptosis via caspases

Question 87

2 methods of bacterial-induced cell injury*

Answer 87

1) exotoxin (i.e. by Clostridia) --> indirect membrane damage 2) endotoxin --> direct membrane damage, apoptosis, indirect membrane damage via TNF-alpha

Question 88

Clicker: Which of the following contribute to formation of free radicals that initiate cell injury?**

Answer 88

UV radiation, Fenton rxn, and CCl4 metabolism in the liver (all of the above)

Question 89

Clicker: Which of the following mechs. contributes most to cell death in hypoxic tissue injury?**

Answer 89

ATP depletion

Question 90

Clicker: Ischemia reperfusion injury is characterized by which of the following mechs. of injury?**

Answer 90

ATP depletion and free radical injury. (NOT protein misfolding and apoptosis)