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BPS > Cell Injury, Cell Death And Adaptions > Flashcards

Cell Injury, Cell Death And Adaptions Flashcards

1
Q

Name the seven types of causes of cell injury

A
  • Oxygen deprivation
  • Physical agents
  • Chemical agents and drugs
  • Infectious agents
  • Immunologic reactions
  • Genetic abnormalities
  • Nutritional imbalances
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2
Q

Why does the cytoplasm of injured cells appear red (eosinophilic) when stained with hematoxylin and eosin (H&E)?

A

Due to the loss of RNA, which normally binds the blue hematoxylin dye

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3
Q

What are the two features consistently seen in reversibly injured cells?

A
  • Generalised swelling of the cell and organelles. (Usually caused by failure of the ATP dependent Na/K pump due to depletion of ATP)
  • Fatty change in organs that are actively involved in lipid metabolism. Rapid accumulation of triglyceride filled lipid vacuoles.
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4
Q

List 5 ultra-structural changes of reversible cell injury that are visible by electron microscopy

A
  • plasma membrane alterations e.g. blebbing, blunting and loss of microvili
  • mitochondrial changes, including swelling and the appearance of small amorphous densities
  • accumulation of “myelin figures” in the cytosol composed of phospholipids derived from damaged cellular membranes
  • dilation of the ER, with detachment of polysomes
  • nuclear alterations, with disaggregation of granular and fibrillar elements
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5
Q

Characterise Necrosis

A

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

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6
Q

The three patterns of nuclear change in necrosis are karyolysis, pyknosis and karyorrhexis. What to these entail?

A

Karyolysis - basophillia of the chromatin fades
Pyknosis - nuclear shrinkage and increased basophillia (as the chromatin condenses). Seen also in apoptosis
Karyorrhexis - when the pyknotic nucleus undergoes fragmentation and in 1-2 days the nucleus completely disappears

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7
Q

What two phenomena consistently characterise irreversibility of cell injury?

A
  • the inability to reverse mitochondrial dysfunction
  • profound disturbances in membrane function
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8
Q

List and briefly describe the 6 grossly observable patterns of tissue necrosis

A
  • Coagulative Necrosis - the tissue has a firm texture and architecture preserved for at least a few days e.g. infarcts in all areas bar the brain
  • Liquefactive Necrosis - characterised by digestion of dead cells leading to a viscous liquid, leukocytes lead to the frequent creamy yellow colour. Frequently associated with bacterial infections, also hypoxic CNS cell death
  • Gangrenous Necrosis - usually a limb that has lost blood supply and undergone necrosis of multiple tissue planes. (Often coagulative, liquefactive when infected)
  • Caseous Necrosis - structureless collection of fragmented/lysed cells and amorphous granular debris enclosed in an inflammatory border. Commonly associated with TB infection
  • Fat Necrosis- focal areas of fat destruction. Generated fatty acids combine with calcium making grossly visible chalky-white areas (fat saponification). Cause typically acute pancreatitis.
  • Fibrinoid Necrosis- deposits of antigen/antibody complexes in the walls of arteries combined with leaked plasma proteins. H&E stains bright pink.
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9
Q

List 5 situations where physiologic apoptosis is important

A
  • Removal of supernumerary cells
  • Involution of hormone-dependent tissues on hormone withdrawal
  • Cell turnover in proliferating cell populations
  • Elimination of potentially harmful self-reactive lymphocytes
  • Death of host cells that have served their useful purpose
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10
Q

What are 4 pathologic states where cell death can be via apoptosis?

A
  • Unrepairable DNA damage
  • Accumulation of misfolded proteins
  • Infections (particularly viral)
  • Pathologic atrophy in parenchymal organs after duct obstruction
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11
Q

What are the four morphological features characteristic of apoptosis?

A
  • cell shrinkage
  • chromatin condensation (usually peripherally)
  • formation of cytoplasmic blebs and apoptotic bodies
  • phagocytosis of apoptotic cells/cell bodies (usually by macrophages)
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12
Q

What are some of the anti-apoptotic, pro-apoptotic and regulated apoptosis initiators (BH-3 only) BCL2 proteins?

A
  • anti-apoptotic - BCL2, BCL-X(I), MCL1
  • pro-apoptotic- BAX and BAK
  • regulated apoptosis initiators - BAD, BIM, BID, Puma, Noxa
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13
Q

Which BCL2 homology (BH) domains do anti-apoptotic, pro-apoptotic and regulated apoptosis initiators possess?

A
  • anti-apoptotic- BH1-4
  • pro-apoptotic BH1-3
  • regulated apoptosis inhibitors- BH3
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14
Q

What forms the apoptosome complex which binds to caspase 9, activating it through autocatalytic cleavage?

A

Apoptosis-activating factor-1 (APAF-1) and cytochrome c

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15
Q

IAPs can be neutralised by binding by mitochondrial proteins like Smac and DIABLO. What is the normal function of IAPs?

A

To block the inappropriate activation of caspases

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16
Q

Outline the extrinsic pathway of apoptosis using the example of the Fas (CD95) protein (a member of the TNF receptor family)

A

A T cell recognises a self antigen, expresses FasL (ligand). FasL binds to Fas, leading to three or more Fas molecules coming together allowing the cytoplasmic death domains to form a binding site for FADD (adaptor protein, Fas-associated death domain). FADD binds inactive caspase 8 (or 10), bringing together multiple caspases leading to autocatalytic cleavage and active caspase 8 and/or 10.

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17
Q

What is the name of a protein that can inhibit the extrinsic apoptosis pathway and how?

A

FLIP - by binging to pro-caspase 8, blocking FADD binding

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18
Q

What are the steps for autophagy?

A
  • Initiation -nucleation and formation of an isolation membrane/phagophore
  • Elongation (as it surrounds its cytosolic ‘cargo’)
  • Maturation of the autophagosome (note has a double lipid bilayer)
  • Fusion with a lysosome and degradation (including the inner lipid bilayer)
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19
Q

If autophagy is inadequate to cope with a stressor (e.g. nutrient deprivation or depletion of growth factors) what happens?

A

Cell death (pathway unknown but distinct from necrosis and apoptosis)

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20
Q

Name a marker for identifying cells in which autophagy is occurring

A

PE-lipidated LC3 (involved in elongation and closure of the initiation membrane)

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21
Q

How is autophagy affected in Alzheimers disease and Huntington disease?

A
  • Alzheimers - impaired autophagosome maturation
  • Huntington - mutant huntingtin impairs autophagy
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22
Q

What are the four cellular principal targets of injurious stimuli?

A
  • mitochondria
  • cell membranes
  • machinery of protein synthesis and secretion
  • DNA
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23
Q

What are the three major consequences of mitochondrial damage?

A
  • ATP depletion
  • Formation of ROS through incomplete oxidative phosphorylation
  • Leakage of proteins
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24
Q

What are three major causes of ATP depletion?

A
  • mitochondrial damage
  • reduced supply of oxygen and nutrients
  • the actions of some toxins (e.g. cyanide)
25
Q

What effects can a depletion of ATP to 5-10% of normal levels have on the cell?

A
  • Reduced activity of Na,K-ATPase
  • Glycogenolysis and glycolysis (rapidly depleted glycogen stores, and if anaerobic, build up of lactic acid and inorganic phosphates reducing pH, reducing enzyme function)
  • Structural disruption of protein synthetic apparatus (manifests as detachment of ribosomes and dissociation of polysomes)
  • Irreversible damage to mitochondrial and lysosomal membranes leading to necrosis
26
Q

What are three important membranes to consider in cellular injury?

A
  • Plasma membrane
  • Mitochondrial membranes
  • Lysosomal membranes
27
Q

What are some biochemical mechanisms that may contribute to membrane damage?

A
  • ROS (by lipid peroxidation)
  • Decreased phospholipid synthesis
  • Increased phospholipid breakdown with accumulation of lipid breakdown products that can interact with the membrane
  • Cytoskeletal abnormalities
28
Q

What is the role of p53 in the cell cycle?

A

To arrest the cell in the G1 phase of the cycle and activate repair mechanism if damaged DNA is present

29
Q

Give some examples that can damage the mitochondria, membranes and DNA respectively

A
  • increased cytosolic calcium, ROS, oxygen depravation
  • calcium mediated activation of phospholipases, bacterial toxins, lytic complement components
  • radiation, chemotherapeutic drugs, ROS
30
Q

What are three effects of ROS and other free radicals relevant to cell injury?

A
  • Lipid peroxidation in membranes (note peroxides are also unstable)
  • Oxidative modification of proteins
  • Lesions in DNA
31
Q

Name three enzymes that break down ROS with their target ROS and products

A
  • Catalase H2O2 to O2 + 2H2O
  • Superoxide dismutases (SODs) O2.-(one electron) to H2O2
  • Glutathione peroxidase H2O2 or .OH to 2H2O (note GSH oxidises to GSSG and that ratio is an important indicator of a cells ability to detoxify ROS).
32
Q

What are 5 ways through which free radicals can be generated?

A
  • Normal reduction-oxidation reactions
  • Absorption of radiant energy
  • By activated leukocytes during inflammation
  • Enzymatic metabolism of exogenous chemicals or drugs (generally not ROS)
  • Transition metals donating or accepting free electrons during intracellular reactions.
33
Q

What can cause an excessive increase in cytosolic calcium?

A

Ischemia and certain toxins

34
Q

Give three examples that could cause the unfolded protein response

A
  • Increased demand for insulin in insulin resistant states
  • Viral infections (large quantities of viral proteins overwhelm the quality control system)
  • Deleterious genetic mutations
35
Q

What are three effects of hypoxia-inducible factor-1 (HIF-1)

A
  • Promotes new blood vessel formation
  • Stimulates cell survival pathways
  • Enhances glycolysis
36
Q

How is ischemia different to hypoxia?

A

Ischemia involves reduced blood flow and so compromises the delivery of substrates for glycolysis as well as the wash out of metabolites, rather than hypoxia alone where blood flow is maintained.

37
Q

What are four proposed mechanisms to explain ischemia-reperfusion injury?

A
  • Oxidative stress
  • Intracellular calcium overload
  • Inflammation
  • Activation of the complement system (some IgM antibodies deposit in ischemic tissue)
38
Q

What are the two general mechanisms by which chemicals induce cell injury?

A
  • Direct toxicity
  • Conversion to toxic metabolites
39
Q

When the mechanical sensors of myocytes detect an increased load, which receptor pathway is thought to be more important in physiologic and which in pathologic hypertrophy?

A
  • Physiological - Phosphoinositide 3-kinase (PI3K)/AKT
  • Pathological - G-protein coupled receptor pathways
40
Q

In hypertrophy of the myocyte what are three of the transcription factors, activated by growth factors, that increase the expression of genes that encode muscle proteins?

A
  • GATA4
  • NFAT (nuclear factor of activated T cells)
  • MEF2 (myocyte enhancer factor 2)
41
Q

Cardiac hypertrophy is associated with a switch in gene expression of what to what?

A

From genes that encode adult type contractile proteins to genes that encode fetal isoforms of the same proteins. E.g a isoform of myosin heavy chain is replaced by the B isoform which is slower and more energetically economical in contraction

42
Q

Hypertrophic myocytes also have altered proteins from genes that participate in the cellular response to stress. Give an example of this.

A

Increased atrial natriuretic factor (a peptide hormone) gene expression. This decreases blood volume and pressure by causing salt secretion by the kidney.

43
Q

What are six common causes of atrophy?

A
  • Decreased workload
  • Loss of innervation
  • Diminished blood supply
  • Inadequate nutrition (through use of skeletal proteins as a source of energy)
  • Loss of endocrine stimulation
  • Pressure
44
Q

Atrophy results from decreased protein synthesis and increased protein degradation in cells. What are two pathways by which protein degradation occurs?

A
  • Mainly by the ubiquitin-proteasome pathway
  • Increased autophagy
45
Q

Trophic signals (e.g. those produced by growth receptors) are reduced in atrophy, what do these usually do?

A

Enhance uptake of nutrients and increase mRNA translation

46
Q

Metaplastic change is stimulated by cytokines, growth factors and extracellular matrix components in the cell’s environment. What two processes leading to metaplasia could be stimulated by these?

A
  • Reprogramming of local tissue stem cells
  • Colonisation by adjacent differentiated cell populations
47
Q

Name four pathological processes where accumulations of cholesterol and cholesterol esters are seen histologically in intracellular vacuoles

A
  • Atherosclerosis
  • Xanthomas
  • Cholesterolosis (of the gallbladder)
  • Niemann-Pick disease, type C
48
Q

Steatosis can occur in the liver, heart, muscle and kidney. What are some of the causes?

A
  • Toxins
  • Protein malnutrition
  • Diabetes mellitus
  • Obesity
  • Anoxia
49
Q

When do reasbsorption droplets in proximal renal tubules appear?

A

In renal diseases associated with proteinuria. The normally small amounts of protein filtered through the glomerulus are reabsorbed by pinocytosis in the proximal tubule. High amounts of filtered protein saturate the cells ability to clear this.

50
Q

What is hyaline change?

A

Usually refers to an alteration within cells or the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained with H&E. Intracellular causes can include reabsorption droplets, Russel bodies and alcoholic hyaline.

51
Q

How can you check for the presence of glycogen in cells?

A

Needs to be fixed in absolute alcohol (as will dissolve in water). Stain with Best carmine or the PAS reaction leads to a rose to violet colour, but this can also be protein bound carbohydrates so need diastase digestion of a parallel section that demonstrates the loss of staining due to glycogen hydrolysis

52
Q

In diabetes mellitus, where can glycogen accumulation be found?

A
  • Renal tubular epithelial cells
  • Liver cells
  • B cells of the islets of Langerhans
  • Heart muscle cells
53
Q

What are two forms of exogenous pigmentation of tissue through macrophage phagocytosis?

A
  • Inhaled carbon (coal dust)
  • Tattooing
54
Q

Name, and briefly describe three endogenous pigments.

A
  • Lipofuscin - Yellow brown, finely granular. Composed of polymers of lipids and phospholipids in complex with protein. Not injurious to the cell. Telltale sign of free radial injury and lipid peroxidation
  • Melanin - Brown-black. Formed when tyrosinease catalyses the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes.
  • Hemosiderin - Golden yellow to brown, granular, or crystalline. One of the major storage forms of iron (when excess iron ferritin forms hemosiderin granules). Local excess usually hemorrhages in tissues. Systemic overload examples that can lead to hemosiderosis are hemochromatosis (increased iron absorption), haemolytic anemias and repeated blood transfusions.
55
Q

How are dystrophic and metastatic calcification different?

A

Dystrophic calcification occurs in areas of necrosis and can occur with normal levels of serum calcium.
Metastatic calcification occurs with hypercalcemia and deposits in normal tissues

56
Q

What are the four principal causes of hypercalcemia?

A
  • increased secretion of PTH/PTH related protein with subsequent bone resorption
  • resorption of bone tissue secondary to primary tumours of bone marrow
  • vitamin-D related disorders (e.g. sarcoidosis)
  • renal failure which leads to secondary hyperparathyroidism through retention of phosphate
57
Q

What is cellular aging the result of?

A

Accumulating cellular damage, replicative senescence, reduced ability to repair damaged DNA and defective protein homeostasis

58
Q

Telomeres are short repeated sequences of DNA present at the ends of linear chromosomes. What is their significance?

A

Important for ensuring the complete replication of chromosome ends and for protecting them from fusion and degradation. Become shorter with each division. Telomerase can maintain telomere length, it is present in germ cells and in low levels in stem cells.

59
Q

Caloric restriction increases lifespan in all eukaryotic species in which it has been tested, what are the two major neurohormonal circuits that regulate metabolism that may help explain this?

A
  • Insulin and insulin-like growth factor 1 (IGF-1), as they promote an anabolic state and cell growth and replication. Particular targets of interest in IGF-1 signalling are AKT and it’s target, mTOR (e.g. rapamycin increases life span of middle aged mice)
  • Sirtuins (NAD-dependent protein deacetylases family), thought to promote genes whose products increase longevity such as proteins that inhibit metabolic activity, reduce apoptosis, stimulate protein folding and counteract the harmful effects of free radicals.

BPS (13 decks)

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