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GSSE > Cell injury and death > Flashcards

Cell injury and death Flashcards

1
Q

What are the 3 responses to cell damange

A

Adaptation
Degenerate
Die

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2
Q

What is sublethal injury

A
  • Atrophy
  • Loss of volume (Na & H2O) control, swelling
  • Intracellular accumulation (e.g. fat, iron, etc…)
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3
Q

What is lethal injury

A
  • necrosis > always pathological
  • apoptosis > mostly physiological, sometimes pathological, BUT NEVER (+) INFLAMMATORY RESPONSE
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4
Q

What are the 7 ways cells can be injured

A
  1. Hypoxia > ischaemia, anaemia, impaired lung function, CCF, CO poisoning
  2. physical > trauma, heat, cold, radiation, electric shock
  3. chemical > alcohol, paracetamol (acetaminophen), cyanide, CCL4, lead, paraquat
  4. infection > viruses, bacteria, rickettsiae, fungi, parasites
  5. genetic derangements > chromosomal alterations, gene mutations
  6. nutritional
  7. immunological
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5
Q

List 7 mechanisms implicated in cell injury

A
  • Mitochondrial damage
  • Cell membrane damage
  • Damage to DNA
  • Oxidative stress
  • Disturbance in calcium homeostasis
  • Accumulation of misfolded proteins
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6
Q

What does loss of calcium homeostasis promote and how does it occur

A

Ischaemia and toxins release calcium from cells.

  • increase in Ca, increases the permeability of mitochondria.
  • (+) phopholipases > degrade membrane phospholipids
  • (+) proteases > break down membrane & cytoskeletal proteins
  • (+) ATPases > exacerbate ATP depletion
  • (+) Endonucleases > DNA fragmentation
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7
Q

Explain necrosis with respect to
- Cell size
- Cell target zone
- Injury
- Mechanism
- Degradation
- Reaction
- Cellular contents
- Nucleus

A

Enlarged (swelling)
Membrane
Membrane disruption
ATP, phospholipase etc
Autolytic (lysosomal)
Acute inflammation
Enzymatic digestion, may leak out of cell
Pykinosis, karyorrhexis, karyolysis

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8
Q

Explain apoptosis with respect to
- Cell size
- Cell target zone
- Injury
- Mechanism
- Nucleus
- Reaction
- Cellular contents
- Plasma membrane

A
  • Reduced (shrinkage)
  • Nucleus
  • DNA denaturation
  • Endonuclease (endogenous)
  • Fragmentation
  • Phagocytosis (receptors)
  • Intact; may be released by apoptotic bodies
  • Inatact; altered structure, especially orientation of lipids
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9
Q

Ultra structural changes indicating REVERSIBLE cell injury (6)

A
  1. Plasma membrane alterations
    - Blebbing, blunting and loss of microvilli
  2. Mitochondrial changes, swelling and the appearance of amorphous densities
  3. Accumulation of myelin figures (phospholipids from damaged cellular membranes) - pre necrosis
  4. Dilation of the ER with detachment of of polysomes
  5. Nuclear alterations, disaggregaion of granular and fibrillar elements

6 Eosinophilia.

The generalised swelling is due to influx of water from failure of the Na/ K ATPase (due to depletion of ATP from hypoxia)

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10
Q

Two features consistently seen in early stages of injury

A
  1. Generalised swelling (Hydropic change or vaculoar degeneration)
    - dis-regulated ATP dependent Na/K pump, blebbing of membrane, detachment of ribosomes, clumping of nuclear chromatin.
  2. Fatty change
    - Metabolic pathways disrupted, accumulation of triglyceride filled vacuoles
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11
Q

What is necrosis characterised by

A

Denaturation of cellular proteins
leakage of cellular contents through damaged membranes
enzymatic digestion of the lethally injured cell.

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12
Q

What are the sequelae of hypoxia (5)

A
  1. impaired respiration and ATP formation
  2. imbibition of water
  3. impaired synthesis of protein in membrane
  4. change from aerobic to anaerobic glycosis
  5. karyolysis (faint, dissolved nucleus)
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13
Q

Describe (in detail) the events of reversible cell injury

A

Hypoxia > loss of oxidative phosphorylation > decrease ATP synthesis by mitochondria, which causes the following
1. Na/K ATPase slow down/stop > Na pump out of cell > increase intracellular Na! swelling of cell and organelle
2. change of metabolism > anaerobic glycolysis ( decrease glycogen store) > accumulation of lactic acid, decrease intracellular pH
3. detachment of ribosomes from rER > decreased protein synthesis > increase lipid deposition

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14
Q

Morphology indicating necrosis

A

-
- Ruptured/breakdown membrane
- Nuclear changes (shrinkage, fragmentation and dissolution)
- Abundant myelin figures
- Leakage/ enzymatic digestion of cellular contents

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15
Q

Morphology indicating apotosis

A
  • Cell shrinkage
  • Chromatin condensation (MOST CHARACTERISTIC)
  • Formation of cystoplasmic bleb and apoptotic bodies
  • Phagocytpsos of apoptotic bodies by macrophages
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16
Q

Nuclear changes consistent with necrosis

A
  • pyknosis (small, dense nucleus) > nuclear shrinkage and chromatin condensation (also seen in apoptosis)
  • karyorrhexis (nucleus broken up into many clumps)
  • karyolysis (faint, dissolved nucleus)
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17
Q

What cellular events are typically associated with necrosis

A
  • Severe mitochondrial damage with depletion of ATP
  • Rupture of lysosomal and plasma membranes
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18
Q

Why is it currently accepted that cell membrane damage is a central factor in the pathogenesis of irreversible cell injury from many causes

A

Loss of regulation of cell volume and ionic gradients, plus cell membrane ultrastructural defects, occur in the earliest stages of irreversible injury

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19
Q

What are free radicals

A

Chemical species with unpaired electron in outer orbit, highly unstable and able to attack, CHO, lipids, proteins.
Some of these reactions are autocatalytic - i.e molecules that react with free radicals and are themselves converted into free radicals.

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20
Q

What are ROS and how are they produced

A

Oxygen derived free radical.
They are produced normally in cells during energy generation.
However ROS scavengers remove them.
Also produced by activated leukocytes during active inflammation (particularly neutrophils and macrophages).

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21
Q

List 6 ways free radicals are generated

A
  • Reduction-oxidation reaction during normal metabolism
  • Absorption of radiation e.g X rays
  • Activated leukocytes produce ROS
  • Metabolism of exogenous chemicals or drugs (paracetamol and carbon tetrachloride)
  • Transition metals
  • Nitric oxide
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22
Q

How do we remove free radicals

A
  1. antioxidants
    - Lipid soluble Vit E, A, vit C and glutathione in the cytosol
  2. Binding iron and copper
    - transferrin
    - ferritin
    - Lactoferrin
    - Ceruloplasmin
  3. enzymes mopping them up,
    - catalase
    - Superoxide dismutases
    - Glutathione peroxidase
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23
Q

List 5 ROS examples

A
  • NO (Nitric oxide)
  • H2O2 (Hydrogen peroxide)
  • O2 (Superoxide anion)
  • ONOO (Hydroxyl radical)
  • OH (Hypochlorite)
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24
Q

List 3 pathologic effects of free radicals

(What type of death does ROS cause)

A
  • Lipid per-oxidation in membranes (i.e punches holes in membranes)
  • Oxidative modification of proteins (oxidation of protein backbone, disrupts proteins, unfolds proteins, damages enzymes)
  • Lesions in DNA (Causes single and double stranded breaks in DNA)

Necrosis and apoptosis

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25
Q

List the 5 types of necrosis

A

Coagulative
Liquefactive
Fat
Caseous
Fibrinoid

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26
Q

What is coagulative necrosis

A
  • Form of necrosis in which the architecture of dead tissue is preserved for a span of a few days.
  • Affected tissue has a firm structure.
  • Injury denatures proteins and enzymes and organelles
  • Given enzymes are blocked dead cells cant be digested. Infiltrating leucocytes eventually degrade dead cells.
  • Cell swelling
  • Lots of eosinophils
  • Localised area of coagulative necrosis = INFARCT
  • Commonly seen in myocardium, kidney, liver & other organs (NOT seen in CNS)
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27
Q

What is liquefactive necrosis

A
  • Characterised by digestion of dead cells = viscous liquid
  • Occurs when autolysis & heterolysis prevail over protein denaturation
  • Focal bacterial or occasionally fungal infections
  • Necrotic area is soft and filled with fluid > creamy yellow because of presence of dead white cells
  • CNS cells always die by liquefactive necrosis
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28
Q

What is fat necrosis

A
  1. Necrosis of adipose tissue, induced by action of lipases (from pancreatic duct, small intestine or macrophages)
  2. These catalyse FFA release from triglycerides
  3. FFA then binds with Ca > Ca soap
  4. These generate chalky white areas > fat saponification
  5. Think pancreatitis, trauma
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29
Q

What is caseous necrosis

A
  • Characteristic of TB
  • Appears grossly as soft, friable, ‘cheesy’ material
  • Microscopically as amorphous eosinophilic material with cell debris
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30
Q

What is fibrinoid necrosis and when is it seen

A

Special form of vascular damage, seen in immune reactions involving blood vessels.
Complexes of antigens and antibodies are deposited in walls of arteries.

  • Rheumatic fever
  • Malignant hypertension
  • The arthus phenomenon
  • x-ray damage of the skin
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31
Q

What happens to necrotic cells that are not promptly destroyed or reabsorbed

A
  • They become a foci for calcium and other minerals to deposit and thus tend to become calcified.
  • Dystrophic calcfication
  • Happens in all tissue types of necrosis
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32
Q

Is serum calcium normal or abnormal in dystrophic calcificaiton

A

Normal

33
Q

What is the histological morphology of dystrophic calcification and give examples

A
  • Basophilic amorphous granular
  • Asbestos bodies
  • atheroma, e.g. calcium in atherosclerosis, Monckeberg’s sclerosis
  • damaged heart valves, e.g. aortic valve calcification
  • TB, e.g. Ghon lesions
  • Cancer
    a. psammoma bodies in papillary thyoid cancer
    b. psammoma bodies in papillary ovarian cancer
    c. calcified comedo breast cancer
34
Q

What histological sign is diagnostic of necrosis

A

nuclear pyknosis

35
Q

How do chemicals directly injure cells

A

By binding to some critical component of a molecular pathway.

For example
- Mercury binds to cell membrane proteins. This increases membrane permeability and inhibits ATPase dependent transport.
- Mainly occurs in GI tract and kidneys

36
Q

How do chemicals indirectly injure cells

A

By converting them to toxic metabolites, normally by CP450 oxidases in the smooth ER of the liver and other organs

37
Q

How does Carbon tetrachloride indirectly injure cells

A

CCL4 (common dry cleaning chemical) is converted to CCL3 (highly reactive free radical) in sER of the liver.
- This initiates lipid peroxidation and autocatalytic reactions.
Results in
- Cell swelling and breakdown of ER, dissociation of ribosomes
- Reduced hepatic protein synthesis
- Reduced lipid export from liver cells because impaired production of apoprotein
- lipid accumulation and fatty change in liver
- progressive cellular swelling, plasma membrane damage
- Cell death

38
Q

How does acetaminophen indirectly injure cells

A

Acetaminophen (paracetamol) is metabolised in the liver and excreted in the urine (as sulfate of glucuronate), with a small amount being converted to a toxic metabolite (NAPQI) (through the activity of CYP).
NAPQI is normally mopped up by glutathione but when large doses of paracetamol are ingested hepatocellular injury occurs.
- Glutathione is depleted, ROS injury occurs.
- NAPQI binds to hepatic proteins which damages membranes and mitochondria.

39
Q

Is it good to still re-perfuse early and why

A

Despite reperfusion damage, the eventual volume of necrosis is significantly reduced by early re-perfusion > this is the rationale for streptokinase/tP A use early in the evolution of myocardial infarction

40
Q

What is ischaemia-reperfusion injury

A
  • Restoration of blood flow to ischaemic tissues can promote recovery of cells it they are reversibly injured, but can also paradoxically exacerbate cell injury and cause death.
  • Therefore, re-perfused tissues may sustain loss of viable cells in addition to those that are irreversibly damaged.
41
Q

How does ischaemia-reperfusion injury occur (4 mechanisms)

A
  1. Oxidative stress
    - Increased generation of ROS and and nitrogen species.
    - Created due to incomplete reduction of oxygen in leukocytes, endothelial cells, parenchymal cells.
    - Damaged cells are even more sensitive to free radical damage (antioxidant mechanisms have been compromised).
  2. Intracellular calcium overload
    - Blood brings in calcium with it, calcium overload makes membrane even more permeable.
  3. Inflammation
    - Dead cells release danger signals, immune cells release cytokines which recruits more neutrophils and further inflammation occurs. .
  4. Activation of the complement system
    - igM antibodies have propensity to deposit in ischaemic tissues.
    - When blood is re-perfused these antibodies bind to complement proteins.
42
Q

Examples of diseases caused by mis-folding proteins

A
  • CF (CFTR)
  • Familial hypercholesterolemia (LDL receptor)
  • Tay-Sachs disease (Hexosaminidase B subunit)
  • Creutzfeldt-Jacob disease (Prions)
  • Alzheimer disease (AB peptide)
43
Q

Rationale for reperfusion in MI

A

Despite reperfusion damage, the eventual volume of necrosis is significantly reduced by early reperfusion ! this is the rationale for streptokinase/tP A use early in the evolution of myocardial infarction

44
Q

What is apoptosis, what is it designed for and is it pathological or physiological

A
  • Type of cell death, when cells destined to die activate intrinsic enzymes to degrade DNA.
  • Can occur as part of normal physiological processes and as part of pathophysiologic mechanisms.
  • Serves to eliminate cells no longer needed (that has obtained damage) and to control cell numbers
45
Q

List the physiological scenarios in which apoptosis occurs (5)

A
  1. Removal of supernumerary cells (i.e excess cells during development)
  2. Involution of hormone dependent tissues on hormone withdrawal
    - e.g endometrial breakdown during menses, regression of lactating breast after weaning, ovarian follicular atresia in menopause
  3. Cell turnover in proliferating cell populations
    - Immature lymphocytes in bone marrow, thymus
  4. Elimination of potentially harmful self-reactive lymphocytes
  5. Death of cells that have served their purpose e.g neutrophils in an inflammatory response and lymphocytes in an immune response
46
Q

In what pathological circumstances does apoptosis occur

A
  • DNA damage (by things like radiation, anti-cancer drugs)
  • Accumulation of misfolded protein
  • Induced during certain infections (Adenovirus, HIV, GVHD, cytotoxic T lymphocytes)
  • Exocrine duct obstruction (pancreas, parotid, kidney)
47
Q

What enzymes are activated in apoptosis

A

Caspases

48
Q

What are the 2 major pathways that initiate apoptosis

A
  1. Mitochondrial (intrinsic)
  2. Death receptor (extrinsic)
49
Q

Outline how apoptosis occurs via the intrinsic pathway

A
  • Triggered by DNA damage, protein mis-folding, growth factor withdrawal
  • Results from increased permeability of the mitochondrial outer membrane which releases death inducing molecules. e.g Cytochrome C when released into cytoplasm initiates the suicide program of apoptosis.
  • Normally proteins like BCL2 (anti-apoptotic) keep the membrane impermeable and prevent cytochrome C from leaking.
  • Death inducing molecules include (i.e pro-apoptotic) BAX/ BAK (BH3) are upregulated by the stimuli above or when growth factors are removed (Like hromones). They make the membrane more permeable, allowing cytochrome C to leak. They may also bind to BLC2 and block its function. BCL2 is also down regulated because it requires the presence of the survival/ growth signals.
  • Once Cytochrome C is released it binds to APAF-1 forming a complex called Apoptosome. This complex binds to capase 9 and initiates the caspase pathway.
50
Q

What is the execution phase of apoptosis

A

The intrinsic and extrinsic pathways converge on the caspase pathway.
- Intrinsic activates 9 extrinsic activates 8 and 10.
- Both activate the execution pathway (e.g 3 and 6)

both activate DNAse allowing DNA degradation to commence, promoting fragmentation of nuclei
(e.g endonuclease which is calcium depdendent)

51
Q

How is the extrinsic pathway initiated

A

Initiated by engagement of plasma membrane death receptors

Mechanism of killing by cytotoxic T lymphocytes.

The death receptors contain a cytoplasmic death domain which is essential for delivering the apoptosis signal.

TNF1
FAS CD95
- Death receptor expressed on many cell types)
- FasL - ligand expressed on T lymphocytes which respond to self antigens and on some cytotoxic T cells that kill virus and tumour cells.

FasL binds to FAS - creates death domain binding site.

52
Q

How are dead cells removed in apoptosis.

A

Formation of apoptotic bodies ie bite sized fragments for phagocytes.
- Express phospholipids on their membranes
- Coat themselves with Clq
“Eat me signals”

53
Q

What is adaptation

A

Reversible changes in size, number, phenotype, metabolic activity or function of cells in response to changes in their environment
- Hypertrophy
- Hyperplasia
- Metaplasia
- Atrophy

54
Q

What is metaplasia

A

Change in phenotype of differentiated cells, often in response to chronic irritation, makes cells better able to withstand stress. May result in reduced functions or increased propensity for malignant transformation
REVERSIBLE once stimulus goes away

55
Q

What is the most common epithelial metaplasia and give examples of where this occurs

A

Columnar to squamous
Vitamin A deficiency - squamous metaplasia in the resp tract and in the cornea
Stones in excretory ducts of salivary glands, pancreas, bile ducts

56
Q

Give two other examples of metaplasia

A

Squamous to columnar - Barretts oesophagus
Connective tissue metaplasia - Formation of bone, adipose tissue or cartilage in tissues that do not contain these elements e.g bone in muscle (myositis ossificans can occur after intramuscular haemorrage) (this type of metaplasia is not associated with increased cancer risk.

57
Q

What is hyperplasia

A
  • Increased cell numbers in response to hormones and other growth factors.
  • Occurs in tissues whose cells are able to divide or contain abundant stem cells.
  • Characteristic response to viral infections (e.g warts with papillomaviruses)
  • Although hyperplasia is distinct from cancer - cancerous proliferations may arise from it (provides an ideal substrate)
58
Q

Is hyperplasia pathological or physiological

A

Can be either
Physiologic - In response to increased need (e.d. breast acini during lactation.
Pathologic- In response to inappropriate secretion of hormone (e.g endometrial hyperplasia in response to excessive estrogen stimulation.

59
Q

What is hypertrophy

A
  • Increase in the size of cells ie no new cells just larger cells
  • Cells capable of division may undergo hypertrophy and hyperplasia, non-dividing cells undergo hypertrophy only (e.g myocardial cells)
60
Q

Is hypertrophy pathological or physiological

A

Can be either
Pathological: Striated muscles in heart and skeletal muscle. They hypertrophy in response to
Physiological: Uterus in response to estrogen in pregnancy

61
Q

Describe the mechanism of hypertrophy

A
  • Mechanical sensors detect increased load
  • Activate a complex of downstream signalling pathways (PI3K/ AKT pathway or GPCR) which stimulate growth factors (IGF-1, endothelin 1, angiotensin II
62
Q

What is atrophy

A

Decreased cell and organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis of cellular building blocks and increased breakdown o cellular organelles by increased autophagy.

63
Q

Is atrophy pathological or physiological

A

Can be both
- Physiological - e.g thyroglossal duct, decrease in size of uterus
- Pathological - Disuse atrophy and denervation atrophy

64
Q

What are the causes of fatty liver (7)

A
  1. alcohol abuse
  2. protein malnutrition
  3. Hep C (but not B)
  4. DM
  5. obesity
  6. hepatotoxins and drugs, e.g paracetamol
  7. acute fatty liver of pregnancy and Reye’s syndrome are rare but sometimes fatal > ?defect in mitochrondrial oxidation
65
Q

How does steatosis occur (6)

A
  1. excessive entry of FFA into liver (e.g. starvation, corticosteroid therapy)
  2. enhanced FA synthesis
  3. decreased FA oxidation
  4. increased esterification of FAs to TAG as a result of an increase in a-glycerophosphate (alcohol)
  5. decreased apoprotein synthesis (carbon tetrachloride poisoning)
  6. impaired lipoprotein secretion from the liver (alcohol, orotic acid administration)
66
Q

Does steatotis commonly cause derranged LFTs

A

NO

67
Q

Is steatosis associated with hepatitis

A

though common with active hep C, is not part of hep B infection

68
Q

Is steatosis reversible

A

yes

69
Q

What are the 4 causes of metasatic calcification

A
  • increased secretion of PTH, e.g. hyperparathyroidism, from parathyroid tumours, ectopic secretions
  • destruction of bone tissue, e.g. multiple myeloma, diffuse skeletal metastasis (e.g. breast cancer)
  • vitamin D-related causes including vit D intoxication & systemic sarcoidosis
  • renal failure - causes secondary hyperparathyroidism
70
Q

Where does metastatic calcification occur

A

can occur anywhere, but mainly affects interstitial tissues of gastric mucosa, kidneys, lungs, systemic arteries, & pulmonary veins

71
Q

Give examples of metastatic calcification (5)

A
  • nephrocalcinosis
  • renal calcification complicating disseminated breast cancer
  • alveolar wall calcification complicating acute leukemia
  • calcium encrustation of internal elastic lamina of arteries
  • calcification of multiple myeloma
72
Q

What is a hamartoma associated with

A

Hamartomata is a/w
* Cystic hygroma
* Small intestinal polyp (Peut-Jehger type)
* Intradermal naevi

73
Q

What is a harmatoma

A
  1. this is a disorganized overgrowth of well differentiated mature cells at an appropriate site
  2. a lung hamartoma is relatively common, benign, nodular neoplasms that may contain
    * cartilage
    * respiratory
    * mixtures of tissues, e.g. fat, blood vessels, fibrous tissue
74
Q

What are two phenomena that characterise irreversibility with respect to cell injury

A
  • Lack of oxidative phosphorylation and ATP generation (even after the resolution of the original injury i.e this is the inability to reverse mitochondrial dysfunction)
  • Profound disturbances in membrane function
75
Q

How does mitochondrial damage injure the cell
- what type of death does it cause
- 3 main consequences of damage to mitochondria

A
  1. Mitochondrial damage
    - Can occur in many ways (due to ROS, Ca, oxygen deprivation)

3 main consequences

  1. ATP depletion (associated with hypoxia and chemical injury). Mitochondrial damage creates mitochondrial permeability transition pore. Mitochondria loses its membrane potential. Oxidative phosphorylation fails. ATP depletes = NECROSIS.
  2. NA/K ATPase pump fails
    - Sodium enters, cell swells
  3. Alteration of energy metabolism
    - Glycogen stores are rapidly depleted
    - Accumulation of lactic acid = decreased pH
    - Reduction in protein synthesis = detachment of ribosomes.
76
Q

How does membrane damage injure the cell
What type of death does it cause.

4 Causes of membrane damage

3 consequences of membrane damage

A

Consistent feature of most forms of cell injury (EXCEPT APOPTOSIS).

Can occur due to ATP depletion or calcium activating phospholipases.

  1. ROS
    - Lipid peroxidation
  2. Decreased phospholipid synthesis
    - Can be due to hypoxia or defective mitochondria
  3. Increased phospholipid breakdown
    - Increased Ca
    - Leads to accumulation of lipid breakdown products which can alter permeability of membrane
  4. Cytoskeletal abnormalities
    - Calcium activates proteases which breaks down the cytoskeleton. Rendering it susceptible to stretching or rupture.

Consequences

  1. Mitochondrial membrane damage
    - Increased permeability, apoptosis
  2. Plasma membrane damage
    - Loss of osmotic balance
  3. Lysosomal membranes
    - Leakage of enzymes into cystoplasm
    - Push cells into necrosis
77
Q

How does DNA damage occur and how does it cause cell death

A

Can be caused by drugs (including chemo), radiation, ROS or can be spontaneous

DNA damage activates p53
- p53 arrests cells in the G1 phase and activates DNA repair. If DNA can’t be repaired p53 induces apoptosis via the mitochondrial pathway.

78
Q

How does disturbance of calcium homeostasis cause cell injury

A

Cytosolic calcium normally kept at very low concentration compared to extracellular.

Cytosolic calcium is also hidden away in mitochondria/ ER.

Ischaemia and toxins increase intracellular Ca causing injury.

Damages mitochondria (messes with ATP)

Activates lots of enzymes like phospholipases, proteases and endonucleases and ATPases.

(break down cell membrane, cytoskeletal structure, DNA and ATP depletion)

79
Q

How does the accumulation of misfolded proteins cause cell damage and what type of cell death does it cause.

A

Accumulation of misfolded proteins in the ER can trigger apoptosis
= ER stress.

Can happen due to viral infections, deleterious mutations

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