Cell injury and death Flashcards

Question

List the 5 types of necrosis

Answer 1

Coagulative Liquefactive Fat Caseous Fibrinoid

Answer 2

- 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)

Answer 3

- 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

Answer 4

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

Answer 5

- Characteristic of TB - Appears grossly as soft, friable, ‘cheesy’ material - Microscopically as amorphous eosinophilic material with cell debris

Answer 6

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

Answer 7

- 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

Answer 8

- 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

Answer 9

nuclear pyknosis

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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.

Answer 14

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

Answer 15

- 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.

Answer 16

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.

Answer 17

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

Answer 18

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

Answer 19

- 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

Answer 20

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

Answer 21

- 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)

Answer 22

1. Mitochondrial (intrinsic) 2. Death receptor (extrinsic)

Answer 23

- 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.

Answer 24

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)

Answer 25

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.

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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.

Answer 31

- 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)

Answer 32

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.

Answer 33

- 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)

Answer 34

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

Answer 35

- 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

Answer 36

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.

Answer 37

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

Answer 38

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

Answer 39

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)

Answer 40

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

Answer 41

- 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

Answer 42

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

Answer 43

* 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

Answer 44

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

Answer 45

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

Answer 46

- 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

Answer 47

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.

Answer 48

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

Answer 49

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.

Answer 50

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)

Answer 51

Accumulation of misfolded proteins in the ER can trigger apoptosis = ER stress. Can happen due to viral infections, deleterious mutations