CELL DEATH ALL

Explain what homeostasis is

ongoing maintenance of physical and chemical conditions in a cell

What is hyperplasia

What is mannosidosis

What are the four most frequently affected cellular components by injury?

• dna

• ribosomes

• phospholipid bilayer

• mitochondria

name 7 things that can cause cell injury

• infectious agents

• genetic derangements

• immunological reactions

• oxygen deficiency

• toxins, drugs, chemicals

• physical agents (force)

• nutritional imbalances

What is hypoxia, what causes this

deficiency of oxygen

reduced blood flow, severe blood loss, inadequate oxygenation of blood due to cardiorespiritory failure

How does hypoxia cause cell injury ?

low o2 → less atp made → Na/K channels close → Na accumulates in cell → messed up osmolarity → possible cell lysis due to osmosis of water into cell

Name two types of genetic derangements and mechanisms of action

Chromosomal abnormalities

Base pair substitution

• alter proteins

  • enzymes, structural proteins, receptors

What is oxidative stress?

accumulation of free radicals

• reactive oxygen species, unstable and bind to any molecule

• important targets are lipids, proteins, dna.

important in the action of drugs, radiation, again and normal metabolism.

What are the consequences of loss of calcium homeostasis, what causes this?

injurious agents cause increased Ca+ into cells

increased cytosolic Ca+ activates enzymes

• ATPase = decreased ATP

• phospholipase = decreased phospholipids

• endonuclease = nuclear chromatin damage

• protease = disruption of membrane and cytoskeletal proteins

What are cellular adaptation, what can cause these?

reversible changes in size, number, phenotype metabolic activity or functions of cells.

can have physiological or pathological causes

• eg stress, injury

What is atrophy, what can cause this

reduction in size / number of cells, occurring after organ development

disuse, denervation, reduced perfusion, poor nutrition, bad endocrine stimulation, senility, pressure.

What are the mechanism of atrophy

reduced protein synthesis, increased protein degradation, reduction in cellular organelles and cytoskeletal proteins, apoptosis.

What is involution

reduction in size and number of cells, after organ development. physiologic atrophy

what is hypoplasia

reduction in size and number of cells, during organ development

what is aplasia

absence of an organ during organ development, with primordium present.

what is agenesis

absence of an organ during organ development due to lack of primordium

what is hypertrophy

increase in size of cells

• no cell division

• no new cells

• often accompanied by hyperplasia

• when limit is reached, degeneration occurs.

what causes hypertrophy, what are the mechanisms of this?

increased functional demand

• skeletal muscle

• endocrine cells

mechanisms

• increased cellular organelles

• increased synthesis of growth factor

What is hyperplasia, what caused this, what is the mechanism?

increase in no of cells, only in cells that can divide. increased mitotic activity.

• cells proliferate in response to hormones / growth factors

• can be caues by inflammation, physical trauma

give examples of hormonal hyperplasia and compensatory hypoplasia

hormonal -

• eg proliferation or mammary and uterine epithelium during pregnancy

compensatory -

• with partial loss of parenchyma

• in symmetrical organs with functional loss of one organ.

List three triggers for pathological hyperplasia

1. excessive hormone production or effect of growth factors, eg cystic endometrial hyperplasia

2. attempt of regeneration, eg nodular hyperplasia in spleen, liver, pancreas

3. with viral infections eg papilloma

What is metaplasia?

one differentiated cell type replaced by another.

What are potential causes of metaplasia?

reprogramming of local tissue stem cells

colonisation from other cell populations

usually a response to chronic irritation

Name three common intracellular accumulations

1) normal cellular components

eg water, lipids, proteins, carbs

2) abnormal substances eg:

a) exogenous minerals, products of infectious agents

b) endogenous, due to abnormal synthesis / metabolism

3) pigments

List three ways intracellular accumulations occur.

• normal / increased production with inadequate removal of endogenous substance

• genetic defects causing abnormal substances or storage

• abnormal exogenous substance eg carbon/ sillica

How do accumulations of lipids occur?

steatosis / lipidosis (fatty change)

• accumulation of triglycerides withing parenchymal cells of liver

  • caused by toxins, protein malnutrition, diabetes, obesity, anorexia.

What gross discolouration does lipid accumulation cause?

diffuse yellow

What does a protein accumulation look like, and what causes this?

round, eosinophilic droplets / vacuoles

caused by :

• excesses of protein presented to cell or excessive synthesis

• defects in protein folding

Explain in detail how protein accumulations occur in cells.

a) reabsorption of droplets in proximal renal tubules

• proteinuria → tubular epithelium : pinocytosis → phagolysosomes → hyaline droplets

b) synthesis of excessive amount of normal secretory protein

• Immunoglobulins → distension of ER → increased Russel bodies in plasma cells

Name some causes of defects in protein folding and what this causes intracellularly

• genetic mutations

• aging

• environmental factors

• TSEs

• amyloidosis

causes defective intracellular transport and secretion of critical proteins, toxicity of aggregated abnormally folded proteins.

What causes intracellular glycogen accumulation

• diabetes mellitus

• glucocorticoid hepatopathy

• glycogen storage diseases

What are some normal and abnormal pigment accumulations

normal

• melanin

abnormal

• exogenous - carbon, coal (anthracosis), tattoo ink

• endogenous - lipofuscin

Describe two endogenous pigments that can accumulate

Lipofuscin

• insoluble, polymers of lipids/phospholipids, not injurious, yellow-brown.

Melanin

• brown-black, found in melanocytes, non-haemoglobin derived

Haemosiderin

• Heamoglobin derrived, gold-yellow-brown

• storage form of iron

When is haemosiderin present, and what are the different forms it can take?

from haemorrhage - degradation of haemoglobin.

Heme - red-blue → heamosidering (yellow, brown, gold)

Biliverdin (green)

Bilirubin (green / blue)

Where is bilirubin found, what does an excess cause?

bile, excess causes jaundice.

What are the three causes of jaundice (icterus)

pre-hepatic

• excessive haemolysis

Hepatic

• severe hepatic damage

Post-hepatic

• bile obstruction

What is amyloid

pathological proteinaceous substance deposited between cells (i.e. extracellular)

Describe briefly the tissues amyloidosis effects and its components

affects various tissues and organs

uniform morphology but chemically variable

95% fibril proteins

5% P component and other glycoproteins

What are the four chemicals in amyloid?

give a brief description

AA (amyloid associated)

• synthesised in liver, no Ig, derived from serum amyloid A (SAA)

AL (amyloid light chain

• - derived from plasma cells, contains Ig light chains, associated with b cell proliferation

b-amyloid protein

• deposited in spongiform encephalopathies

islet amyloid polypeptide

• deposited in pancreatic islets

What is systemic amyloidosis

deposition in several organs

What is an example of localised amyloidosis

deposition in cutaneous plasmacytomas

What is primary amyloidosis

deposition with an immunologic disorder

eg multiple myeloma

What is hereditary / familial amyloidosis

genetic deposition of amyloid

What is an example of endocrine amyloidosis

deposition in the islet cells

What is the stain for amyloid?

Congo red

What does amyloidosis look like grossly?

yellow organ discolouration

What is pathologic calcification, name two types.

abnormal deposition of calcium salts

• dystrophic calcification

• metastatic calcification

Describe the pathogenesis of dystrophic calcification

1. initiation can occur via :

• intracellular : Ca accumulates in mitochondria of dying cells

• extracellular : phospholipids in membrane bound vesicles in dying cells

2. propagation :

• membrane facilitated calcification

  • Ca binds to phospholipids in membrane

  • forms groups

  • leads to Ca deposition near membrane

  • microcrystal formation leads to membrane perforation.

Describe the pathogenesis of metastatic calcification

Occurs in normal tissues with hypercalcaemia

hypercalcaemia can occur due to :

• increased PTH secretion

• destruction of bone tissue

• vitamin D intoxication

• renal failure (due to secondary hypothyroidism)

Affects interstitial tissues in lungs, arteries, veins, kidneys, gastric mucosa

What stain do you use to visualise calcification on a microscope slide?

Von kossa - black.

What two things can occur due to irreversible cell injury?

necrosis

apoptosis

What is necrosis?

Irreversible cell death leading to denaturation of proteins, leakage of cellular contents.

Why is necrosis irreversible?

inability to reverse mitochondrial dysfunction

disturbances in membrane function

What are the four mechanisms of necrosis

damaged cell membrane

protein denaturation

local inflammation (DAMP)

enzymatic digestion of necrotic cells.

What is meant by the terms autolysis and heterolysis?

autolysis : destruction of a cell through the action of its own enzymes

heterolysis : spontaneous death and disintegration of a cell from factors other than itself

Describe the cellular morphology of necrosis

increased cellular eosinophilia

nuclear shrinkage + increased basophilia (pyknosis)

fragmentation of nucleus (karyorrhexis)

loss of nuclear basophilia (karyolysis)

What is the gross morphology of necrosis

pale tan discolouration

Name 7 types of necrosis.

coagulative

lytic

caseous

liquefactive

steatonecrosis (adipose tissue)

gangrenous

fibrinoid

describe coagulative necrosis

protein denaturation

retention of cellular borders

ischemia

describe lytic necrosis

enzymatic digestion

loss of cell borders

neutrophil rich inflammation (bacterial)

Describe caseous necrosis

subtype of lytic necrosis

mycobacterial granulomas

describe liquefactive necrosis

subtype of lytic necrosis

end stage = fluid filled lesion.

final stages of necrosis in brain

describe steatonecrosis

necrosis of adipose tissues, between lytic and coagulative.

Describe gangrenous necrosis

subtype of lytic

occurs in distal limbs or dependant portions of organs

dry = vascular damage

wet = bacterial proliferation

describe fibrinoid necrosis

specific form of lytic necrosis, occurs during vascular damage

intramural () accumulation of fibrin, other proteins and immunocomplexes in vessels ( associated with vasculitis)

What is apoptosis?

regulated cell death.

What enzyme mediates apoptosis

describe what happens when this is activated

Caspases

protein containing cystine in their active site, cleave proteins after aspartic residues

Endonuclease activation = DNA fragmentation

Breakdown of cytoskeleton

cytoplasmic buds form → apoptotic body → eaten by phagocyte.

List 5 causes of apoptosis

DNA damage (intrinsic)

accumulation of misfolded proteins (intrinsic)

pathogenic infection (via cytotoxic t cells)

tumour necrosis ligand factor TNF1 receptor - death domain. (extrinsic)

normal homeostasis

What are the intrinsic mechanisms of apoptosis (describe in detail)

intrinsic = mitochondrial pathway.

1. withdrawal from growth factors, hormones.

• causes pro-apoptotic molecules eg cytochrome C to activate executioner caspases.

1. injury due to radiation, toxins, free radicals

• causes DNA damage → P53 → mitochondria → cytochrome c → executioner caspases

Describe in detail the extrinsic mechanism of apoptosis

Via cytotoxic T lymphocytes

bind to surface and activate granzyme B → executioner caspases.

Describe morphology of apoptosis at a cellular level

Cell shrinkage and eosinophilia

chromatin condensation

formation of apoptotic bodies

phagocytosis of apoptotic bodies

What is the role of apoptosis inn homeostasis

programmed cell death during embryogenesis

cell depletion in proliferating tissues (turnover)

cell death in tumours

lymphocyte selection during immune system maturation