Path - Cell Injury And Adaptation

Front 1

what causes cell injury to be irreversible? (2)

Back 1

persistent injurious stimulus
severe enough stimulus from the beginning

Front 2

what are the three possible consequences of cell injury?

Back 2

adaptation
reversible injury
cell death

Front 3

what are the two principle pathways of cell death?

Back 3

necrosis
apoptosis

Front 4

what can cause cell injury?

Back 4

O(h)xygen deprivation eg cardiac ischaemia

P(lease)hysical agents eg mechanical trauma

C(an)hemical agents eg insecticide

Infectious agents

I(mmunize)mmunological eg autoimmune disease

G(od)enetic derangement eg sickle cell - single aa substitution decreases life of RBCs

N(ow)utritional imbalance - protein calorie imbalance in underdeveloped, obesity & atherosclerosis in developed world

Front 5

what is the cellular response to increased demand or stimulation?

Back 5

hyperplasia/hypertrophy

Front 6

what is the cellular response to decreased nutrients/stimulation?

Back 6

atrophy

Front 7

what is the cellular response to chronic physical/chemical irritation?

Back 7

metaplasia

Front 8

what are possible responses to acute and transient reduced O2 supply/chemical injury/microbial infection?

Back 8

acute reversible injury
cellular swelling
fatty change

Front 9

what are possible responses to progressive and severe reduced O2 supply/chemical injury/microbial infection?

Back 9

irreversible injury -> cell death

Front 10

what are the cellular responses to metabolic alterations and chronic injury?

Back 10

intracellular accumulations, calcification

Front 11

? do we need to know hyperplasia, metaplasia and atrophy??

Back 11

...

Front 12

what are the hallmarks of reversible cell injury? (3)

Back 12

reduced oxidative phosphorylation & depletion of ATP (energy) stores

cellular swelling

alterations in intracellular organelles (eg mitochondria, cytoskeleton)

Front 13

what causes cell swelling in reversible cell injury?

Back 13

changes in ion concentrations & H20 influx

Front 14

distinguish how necrosis and apoptosis differ in distinguishing cause of cell death?

Back 14

necrosis is always pathological

apoptosis also serves many normal functions and is not necessarily due to cell injury

Front 15

what is the general mechanism behind necrosis?

Back 15

severe damage to cell membranes causes lysozomal enzymes to enter cytoplasm & digest cell, with cellular contents leaking out

Front 16

what is the general mechanism behind apoptosis?

Back 16

cell's DNA/proteins are damaged beyond repair

Front 17

what characterises apoptosis?

Back 17

nuclear dissolution
fragmentation of cell without complete loss of membrane integrity
rapid removal of cellular debris

Front 18

what are the physical agents capable of causing cell injury? (5)

Back 18

mechanical trauma
extremes of temperature
sudden changes in atmospheric pressure
radiation
electric shock

Front 19

how does oxygen deprivation cause cell injury?

Back 19

reducing aerobic oxidative respiration

Front 20

what are the general causes of hypoxia?

Back 20

ischaemia (reduced blood flood)
cardioresp failure -> inadequate oxygenation of blood
decreased O2 carrying capacity (eg anaemia, CO poisoning)
severe blood loss

Front 21

what is an example of adaptive cell change to hypoxic insult?

Back 21

tissue supplied may atrophy

Front 22

what are the two features of reversible cell injury recognisable under the light microscope?

Back 22

cellular swelling
fatty change

Front 23

what is the first manifestation of almost all forms of injury to cells?

Back 23

cellular swelling

Front 24

what morphological changes characterise reversible injury?

Back 24

generalised swelling of cell & organelles

clumping of nuclear chromatin

blebbing of plasma membrane

detachment of ribosomes from ER

Front 25

what causes cellular swelling in reversible cell injury?

Back 25

failure of energy dependent ion pumps in plasma membrane -> failure to maintain ion/fluid homeostasis

Front 26

when does fatty change occur in reversible cell injury?

Back 26

hypoxic injury

various forms of toxic/metabolic injury

Front 27

what part of the cell manifests fatty change?

Back 27

lipid vacuoles in cytoplasm

Front 28

which cells manifest fatty change?

Back 28

those involved in and dependent on fat metabolism (hepatocytes & myocardial cells)

Front 29

distinguish the following characteristics in necrosis vs apoptosis

cell size
nucleus
plasma membrane
cellular contents
adjacent inflammation
physio/pathological role

Back 29

robbins table 1-2 & fig 1-8 p13

Front 30

what feature of cell necrosis may elicit inflammation in surrounding tissue?

Back 30

leakage of cell contents due to loss of membrane integrity

Front 31

what is the time frame for histologic evidence in tissue necrosis?

Back 31

usually hours as digestion of cellular contents & host response may take hours to develop

Front 32

explain in terms of time frames and mechanism of cell necrosis the process in biochemically & histologically detecting myocardial necrosis

Back 32

since the cell membrane loses integrity as is classic to necrosis, the cardiac specific enzymes are released relatively rapidly (as early as 2 hours)

since the digestion of cell contents and host response takes hours to develop, there is no histological evidence of necrosis until 4-12 hours after the event

Front 33

a localized area of coagulative necrosis is called an...

Back 33

infarct

Front 34

what are the morphological categories of necrosis? (6)

Back 34

coagulative
liquefactive
gangrenous (clinical, typically coagulative)
caseous
fat (typically pancreas)
fibrinoid (typically vascular)

Front 35

?? need to know detailed morphology of necrotic cell ??

Back 35

.

Front 36

ischaemia caused by obstruction in a vessel can lead to which kind of necrosis? what is the exception

Back 36

coagulative necrosis of supplied tissue in all organs except brain

Front 37

what distinguishes coagulative necrosis

Back 37

tissues remain firm (vs liquefactive) as presumably enzymes are denatured which delays proteolysis of dead cells

(which are ultimately removed by phagocytes and lysozomal enzymes of leucocytes)

Front 38

when & why is liquefactive necrosis seen?

Back 38

focal bacterial & occ fungal infections as microbes stimulate accumulation of leukocytes & liberation of enzymes fromthese cells.

Front 39

what kind of tissue typically presents with liquefactive necrosis following hypoxic injury

Back 39

CNS

Front 40

what kind of necrosis occurs and what is the mechanism in acute pancreatitis?

Back 40

fat necrosis

focal areas of fat destruction following release of pancreatic lipase into pancreatic tissue & peritoneum

peritoneal fat membranes are liquefied and triglyceride esters are split which then combine with calcium to form visible chalky white regions (fat saponification)

Front 41

?? need to know fibrinoid necrosis or will cover in more detail in vascular path section??

Back 41

..

Front 42

how are necrotic cells removed from the body?

Back 42

enzymatic digestion from leukocytes

phagocytosis of debris

Front 43

what happens if there is not prompt destruction & reabsorption of necrotic cells?

Back 43

dystrophic calcification - attraction of Ca and mineral salts and subsequent calcification

Front 44

what changes in ATP are frequently associated with hypoxic and chemical injury?

Back 44

ATP depletion and decreased ATP synthesis

Front 45

what are the two ways in which ATP is produced?

Back 45

major pathway - oxidative phosphorylation of adenoside diphosphate (requires O2 to reduce by mitochondrial electron transfer system)

glycolytic pathway - ATP generated in absence of O2 from body fluids or glycogen hydrolysis

Front 46

what are the major causes of ATP depletion? (3)

Back 46

reduced supply O2 and nutrients
mitochondrial damage
actions of some toxins (eg cyanide)

Front 47

which tissues survive loss of oxygen (& decreased oxidative phosphorylation) best?

Back 47

those w a greater glycolytic capacity (eg liver) vs those with limited capacity eg brain

Front 48

how much ATP depletion is required to have widespread effects on critical cellular functions?

Back 48

5-10%

Front 49

outline the consequences of decreased ATP during cell injury

Back 49

robbins fig 1-17 p18

Front 50

what are the two main consequences of mitochondrial damage?

Back 50

opening of the mitochondrial permeability transition pore -> loss of membrane potential -> unable to generate ATP -> necrosis

pro-apoptotic proteins sequestered between mitochondrial membranes may be released with increased permeability of outer mitochondrial membrane -> apoptosis

Front 51

what can damage mitochondria?

Back 51

increased cytosolic Ca++
oxygen depravation

ie virtually all types of injurious stimuli including hypoxia & toxins

some inherited mutations in mitochondrial genes

Front 52

where is most intracellular Ca sequestered?

Back 52

mitochondria & ER

Front 53

how does cytosolic Ca levels compare with extracellular?

Back 53

normally extremely low 0.1micromole vs 1.3mmol extracellular

Front 54

which ions are important mediators of cell injury

Back 54

Ca

free radicals

Front 55

how does increased intracellular Ca++ cause cell injury

Back 55

robbins fig 1-19 p19

Front 56

what causes increased intracellular Ca++?

Back 56

ischaemia & certain toxins
later increased influx across plasma membrane

Front 57

what is oxidative stress?

Back 57

accumulation of oxygen derived free radicals

Front 58

what is a free radical?

Back 58

chemical species with a single unpaired electron in an outer orbit which release energy by reacting with adjacent molecules; many of these are cell membrane and nuclei components eg proteins, lipids, carbohydrates, nucleic acids

Front 59

how do free radicals propagate the chain of damage?

Back 59

by converting molecules they react with into free radicals themselves

Front 60

what are reactive oxygen species?

Back 60

oxygen derived free radicals which are normally produced in cells during mitochondrial respiration and energy generation but are normally degraded & removed in the cell ie cell can maintain steady state of transient free radicals without damage

Front 61

which immune cells produce reactive oxygen species? what kinds of reactions do ROS typically accompany

Back 61

neutrophils and macrophages (as mediators for destroying microbes and dead tissue)

therefore ROS typically accompanies inflammatory reactions & causes injury

Front 62

?? do we need to know how free radicals are removed & produced??

Back 62

..

Front 63

what are the three reactions of reactive oxygen species (free radicals) particularly relevant to cell injury?

Back 63

lipid peroxidation in membane (peroxides unstable & propagate further membrane damage)

oxidative modification of proteins - damage active site of enzymes, disrupt confirmation of structural protein ie "wreack havoc throughout the cell"

cause breaks in DNA

Front 64

what is the consistent feature of most forms of cell injury?

Back 64

early loss of selective membrane permeability leading ultimately to overt membrane damage

Front 65

draw the mechanisms of membrane damage in cell injury?

Back 65

robbins p 22 fig 1-21

Front 66

what are the most important sites of membrane damage during cell injury? (3)

Back 66

mitochondrial membrane
plasma membrane
lysosomal membranes

Front 67

how does mitochondrial membrane injury cause cell death?

Back 67

opening of mitochondrial permeability transition pore -> decreased ATP -> release of proteins triggering apoptosis

Front 68

how does plasma membrane injury cause cell death?

Back 68

loss of osmotic balance
influx fluids/ions
loss of cell contents

Front 69

how does lysosomal injury cause cell death?

Back 69

leaking of enzymes in cytoplasm results in digestion of proteins, DNA, RNA, glycogen -> necrosis

Front 70

what happens if DNA damage is too great to be repaired by normal cell process? how about improperly folded proteins?

Back 70

apoptosis triggered for both

Front 71

what defines "the point of no return" for cell injury?

Back 71

current undefined, no reliable morphologic/biochemical correlates of irreversibility

Front 72

give 4 examples of proteins leaked through a damaged cell membrane which would provide a means for detecting tissue-specific injury?

Back 72

creatine kinase - specific form in cardiac muscle
troponin - cardiac contractile protein
alkaline phosphatase - liver, esp bile duct epithelium
transaminases - hepatocytes

Front 73

why does ischaemia cause more rapid and severe cell/tissue injury than hypoxia in the absence of ischaemia?

Back 73

aerobic metabolism compromised in both

but in ischaemia, there is no blood flow for delivery of substrates of glycolysis & metabolites which inhibit glycolysis accumulate which would normally have been washed away with blood flow

Front 74

what are the mechanisms of early ischaemic cell injury?

Back 74

loss of oxygen tension
-> loss of oxydative phosphorylation
-> decreased generation ATP
-> failure of sodium pump
-> ionic balance loss
-> cell swelling

Front 75

what happens to the ischaemically injured cell if hypoxia continues?

Back 75

further deterioration from ongoing ATP depletion
- marked cell swelling
- loss of cytoskeletal features -> blebs
- swolled mitochondria

Front 76

what are the morphological associations with irreversible ischaemic cell injury?

Back 76

severe mitochondrial swelling
extensive plasma membrane damage (myelin figures)
lysosomal swelling

Front 77

what ion is massively influxed into the irreversibly ischaemically damaged cell under what conditions?

Back 77

Ca++

especially if ischaemic zone reperfused

Front 78

what kind of cell death occurs in ischaemic cell injury?

Back 78

mostly necrosis
some apoptosis (likely from pro apoptotic contents of leaky mitochondria)

Front 79

what effect does transient induction of hypothermia have on stressed ischaemic/traumatically injured brain/spinal cord cells?

Back 79

reduces metabolic demands of stressed cells
decreases cell swelling
suppresses formation free radicals
inhibits host inflammatory response

Front 80

what is ischaemia-reperfusion injury?

Back 80

when blood flow is restored to cells that have been ischaemic but not died, injury is paradoxically exacerbated & accelerated

Front 81

how does reperfusion injury occur?

Back 81

likely that new damaging processes (eg increased reactive oxygen species, inflammation or complement activation) are set in motion during reperfusion

Front 82

what tissues are especially susceptible to reperfusion injury?

Back 82

brain & heart

Front 83

which organ is a frequent target of drug toxicity & why?

Back 83

liver, since it metabolises many drugs

Front 84

what is the most frequent reason for terminating therapeutic use/development of a drug?

Back 84

toxic liver injury

Front 85

what are the two general mechanisms of toxic cell injury?

Back 85

direct cell injury (by combining w critical metabolic components)

membrane damage & cell injury by free radicals or covalent binding of metabolites of the toxin

Front 86

??HOW MUCH DETAIL DO WE NEED FOR APOPTOSIS???

Back 86

.

Front 87

what pathologic conditions stimulate apoptosis? (4)

Back 87

dna damage
accumulation misfolded protein
certain infections (esp viral egHIV & viral hepatis)
pathologic atrophy following duct obstruction (eg pancreas, parotic, kidney)

Front 88

what are the two main categories of intracellular accumulations?

Back 88

normal cellular constituents

abnormal substance (exogenous eg mineral/infectious product; endogenous eg product of abnormal synthesis/metabolism)

Front 89

what are the four main mechanisms of intracellular accumulations?

Back 89

normal substance produced at increased rate with inadquate rate of removal (eg fatty liver)

abnormal endogenous substance (usually mutated gene) folds abnormally & is unable to be removed (eg alpha 1 - antitrypsin in liver)

normal endogenous substance cannot be metabolised (usually genetic defect) - eg those genetic carbo/lipid metabolism diseases

abnormal exogenous substance deposited & accumulated because cell can't degrade or trasnport it
eg accumulation of carbon & silica

Front 90

which classes of lipids can accumulate in cells?

Back 90

all main classes
triglycerides
cholesterols
phospholipids

Front 91

what kind of lipids are found in necrotic cells?

Back 91

phopholipids are components of the myelin figures found in necrotic cells

Front 92

what does the term steatosis/fatty change refer to?

Back 92

abnormal accumulations of triglycerides in parenchymal cells

Front 93

where is fatty change most often seen & why? where else is it seen

Back 93

liver,since it is the major organ of fat metabolism

also heart, muscle & kidneys

Front 94

what is steatosis?

Back 94

fatty change

Front 95

what are the causes of steatosis? (5)

Back 95

toxins
protein malnutrition
diabetes mellitus
obesity
anoxia

Front 96

what are the commonest causes of fatty liver in the developed world?

Back 96

EtOH abuse
non Etoh fatty liver (diabetes/obesity)

Front 97

?? do we need to know robbins fig 1-30 fatty liver??

Back 97

..

Front 98

give four examples of defective metabolism and export of lipids in the liver?

Back 98

- EtOH is a hepatotoxin leading to increased synthesis/decreasedbreakdown of lipids

- CCl4 & protein malnutrition cause fatty change by reducing synthesis of apoproteins

- hypoxia inhibits fatty acid oxidation

- starvation increases fatty acid mobilisation from peripheral stores

Front 99

what effect does mild fatty change have on cell function

Back 99

may have none

Front 100

how does fatty change manifest itself morphologically in cells? what can this be confused by? how can we distinguish?

Back 100

clear vacuoles within parenchymal cells

but this can also be mimicked by water or polysaccharides (eg glyocgen)

distinguish by preparing frozen sections & then staining

Front 101

how many times its normal weight can a progressively fatty liver become?

Back 101

2-4 times normal

Front 102

what are the morphological signs of early fatty liver change?

Back 102

minute, membrane bound inclusions closely bound to ER

Front 103

what are progressive morphological changes in fatty liver?

Back 103

vacuoles in the cytoplasm around the nucleus coalesce, creating cleared spaces that displace the nucleus to the cell's periphery

Front 104

what are the two patterns of lipid in cardiac muscle?

Back 104

intracellular deposits of fat -> striped bands of yellowed myocardium alternating w normal darker red/brown myocardium (tigered effect)

uniformly affected myocytes is a hallmark of some myocarditis & profound hypoxia

Front 105

how do normal cells use normal amounts of cholesterol?

Back 105

use for synthesis of cell membranes without intracellular accumulation of cholesterol or cholesterol esters

Front 106

what is the hallmark of pathologic cholesterol accumulation?

Back 106

intracellular vacuoles

Front 107

what are foam cells? in which disease are they seen?

Back 107

in ATHEROSCLEROSIS, smooth muscle & macrophages in intimal layer of aorta/large arteries filled with lipid vacuoles with a foamy appearance

Front 108

what causes atheroma?

Back 108

aggregates of foam cells in the intima

Front 109

what are xanthomas?

Back 109

foam cells in the subepithelial connective tissue of skin & tendons

Front 110

what is cholesterolosis?

Back 110

focal accumulations of cholesterol laden macrophages in lamina propria of gallbladder

Front 111

what is niemann-pick disease (type C)

Back 111

lysosomal storage disease caused by mutations in enzyme involved in cholesterol trafficking -> cholesterol accumulates in multiple organs

Front 112

how do intracellular protein accumulations usually manifest?

Back 112

as rounded eosinophilic droplets, vacuoles or aggregates in the cytoplasm

Front 113

what is an example of a disease where abnormal proteins deposit primarily in extracellular spaces?

Back 113

amyloidosis

Front 114

what are some examples of diseases causing protein accumulation?

Back 114

- renal diseases assoc w proteinuria -> reabsorption droplets in proximal tubule

- alpha1-anytrypsin deficiency - protein folding slowed & partially folded intermediates build up in liver ER & not secreted -> not available to circulation -> emphysema

- neurofibrillary tangle in Alzheimers

- alcoholic hyaline is eosinophilic cytoplasmic inclusion composed predom of keratin

Front 115

when are excessive intracellular deposits of glycogen seen?

Back 115

patients with abnormality in either glucose or glycogen metabolism

Front 116

what do glycogen masses look like histologically?

Back 116

clear vacuoles in the cytoplasm

Front 117

in what tissues are intercellular glycogen deposits found in diabetes?

Back 117

renal tubular epithelium
liver cells
B cells of islets of langerhans
heart muscle

Front 118

what is teh most common exogenous pigment?

Back 118

carbon (coal dust)

Front 119

what is anthracosis?

Back 119

accumulation of coal pigment blackening the tissues of the lungs

Front 120

what is the "wear and tear" pigment called & what does it herald?

Back 120

lipofuscin

not injurious to cell but is telltale sign of free radical injury & lipid peroxidation

Front 121

what is haemosiderin?

Back 121

haemoglobin derived
major storage form of iron

Front 122

when is haemosiderin formed?

Back 122

when there is a local or systemic excess of iron

Front 123

what is the best example of localised haemosiderosis?

Back 123

a bruise

Front 124

what is haemosiderosis?

Back 124

systemic overload of iron, leading to haemosiderin deposit in many organs and tissues

Front 125

what are the 3 main causes of haemosiderosis?

Back 125

1. increased absorption of dietary iron
2. haemolytic anaemias (abnormal quantities of iron released from erythrocytes)

3. repeated blood transfusions

Front 126

what are the two forms of pathologic calcification?

Back 126

dystrophic
metastatic

Front 127

what is dystrophic calcification?

Back 127

Ca deposition occurs locally in dying tissues

Front 128

where does dystrophic calcification occur? (3)

Back 128

areas of necrosis

atheromas of advanced atherosclerosis

aging/damaged heart valves

Front 129

what does bone formation and dystrophic calcification have in cmomon?

Back 129

final common pathway of dystrophic calcification is formation of CaPO4 in an apatite similar to hydroxyapatite of bone

Front 130

what is metastatic calcification? what is it almost always due to?

Back 130

deposition of Ca salts in otherwise normal tissues

hypercalcaemia secondary to some Ca metabolic disturbance

Front 131

what are the four main causes of hypercalcaemia?

Back 131

1. increased secretion of PTH
2. destruction of bone tissue
3. vit D related disorders
4. renal failure -> 2ndary hyper PTH

Front 132

what feature do the tissues which are affected by metastatic calcification have in common?

Back 132

all excrete acid & so have an internal alkaline compartment which predisposes them to metastatic calcification

Front 133

what are the gross changes that occur with aging?

Back 133

decreased cellular replication & senescence (cells stop dividing)

accumulation of metabolic and genetic damage

Front 134

define necrosis

Back 134

from greek nekros (dead)
pathological process of cell death characterised by enlarged cells whose membranes break down & concomitant inflammation