cells to systems 3 Flashcards
(108 cards)
1
Q
what are the two types of cell injury and what cell type undergoes both
A
1) sublethal and reversible (= cell degeneration)
2) irreversible and lethal (= cell death via oncotic necrosis or apoptosis)
- Liver cells generally undergo both frequently
2
Q
what is hydropic degeneration how common, and what occurs, in health how is it normally controlled
A
acute cell swelling
most common expression of cell injury
affected cell can no longer maintain homeostasis and regulate entry and exit of water or ions so their cytoplasm swells with water
intra cellular water and ion concentration largely a function of Na+/K+ ATPase
3
Q
what are the 2 main causes of hydropic degeneration what occurs and an example
A
1) physical damage to plasma membrane and/or organelle membranes
the damaged membranes are leaky, allowing entry of water and Na+ and Ca++ ions, and loss of intracellular K+ and Mg++ ions
- Causes cytoplasm swelling and sometimes swelling of the goli body and endoplasmic reticulum
eg - bacterial toxins
2) failure of cell energy production
- hypoxia decrease O2 so decrease aerobic respiration decrease ATP failure of Na+/K+ ATPase movement of Na+ into cell and consequent movement of water in
4
Q
ultrastructural appearance of hydropic degeneration
A
- dilated cisternae of smooth and rough endoplasmic reticulum, the Golgi apparatus and the outer nuclear membrane
- swollen mitochondria
- detachment of ribosomes from rough endoplasmic reticulum
- +/- swollen, distorted or lost cilia and microvilli
5
Q
microscopic appearance and gross appearance of hydropic degeneration
A
- affected cells appear swollen, with pale, cloudy or wispy to finely vacuolated cytoplasm
- the mildest form is often referred to as cloudy swelling
- extreme his referred to as ballooning degeneration, with marked cell enlargement and voluminous clear cytoplasm due to water accumulation and degradation of cytoplasmic proteins (e.g. virus-infected epithelial cells)
gross - heavy, pale, swollen. soft, friable
6
Q
fate of affected cell that under hydropic degeneration
A
dysfunctional
- however, the injury is still potentially reversible
- if the membrane damage can be repaired or the oxygen supply restored before the “point of
no return” is reached, affected cells can return to normal appearance and function
7
Q
what is fatty change, what is it also called, what cells occur the most and what form of fat most involved
A
intracellular accumulation of excess lipid
- also called lipidosis, steatosis or fatty degeneration
(especially hepatocytes but also renal tubular epithelial cells and myocardial fibres)
- the lipid that accumulates is predominantly in the form of triglycerides (triacylglycerols)
8
Q
hepatic lipidosis what occurs
A
most incoming fatty acids are esterified by the hepatocytes to form triglycerides, are then packaged by the hepatocytes with apoproteins to form VLDL exported into the circulation as a readily available energy source for other tissues
the packaging involved lots of energy so injured cells may not pack but may continue creating
9
Q
causes of hepatic lipidosis and example
A
1) entry of excess fatty acids into the liver, exceeding its capacity for rapid processing
- e.g. high lipid diets (including milk in suckling animals)
2) inadequate supply of proteins or cofactors to permit synthesis of apoproteins
- e.g. chronic protein malnutrition
3) sublethal hypoxia
- diminished hepatocyte ATP (energy) stores available for synthesis of apoproteins and packaging of VLDL for export
4) sublethal toxic injury
eg - damage to rough endoplasmic reticulum of hepatocytes, decreased apoprotein
10
Q
microscopic appearance and gross of fatty change
A
distended by a single large clear cytoplasmic vacuole that displaces the nucleus
gross - organs may be enlarged, slightly pale, soft, friable
11
Q
fate of affected cells that have undergone to fatty change
A
may or may not be dysfunctional
- if the cause can be removed and the cell injury repaired, affected cells can return to normal appearance and function
however, severe and prolonged fatty change can lead to cell death and/or to tissue fibrosis (scarring) and architectural remodelling that can be irreversible
12
Q
intracellular accumulation of glycogen where does storage normally occur, does it occur in health
A
stored in the cytoplasm of skeletal myocytes and hepatocytes
does occur in health so cell function not neccessarily compromised
13
Q
List 3 examples of pathological accumulation of glycogen
A
1) steroid hepatopathy in dogs
2) glycogen storage in diabetes mellitus
3) glycogen storage disorders
14
Q
steroid hepatopathy in dogs, common in dogs with what, how to confirm it is glycogen, is it responsible for dysfunction and is it reversible
A
- accumulation of excess glycogen in hepatocytes is common in dogs with hyperadrenocorticism and referred to as steroid hepatopathy
- due to a functional ACTH-producing pituitary tumour (most common) (caused by excessive use of corticosteroids - excess storage of glycogen in hepatocytes
- confirmed as being glycogen by performing histochemical stains (glycogen stains positively with periodic acid Schiff (PAS) stain and the positive staining is lost after addition of diastase)
not responsible for dysfunction of hepatocytes and is a reversible change
15
Q
intracellular accumulation of proteins what sometimes called and 4 examples of how this occurs
A
hyaline droplets
1) absorbed colostrum proteins - neonatal - normal
2) resorbed protein droplets - within renal proximal tubular epithelial cells with damage leakage into urine
3) excess immunoglobulins (russell bodies) accumulate within aged plasma cells
4) cells may accumulate misfolded proteins
16
Q
lysosomal storage disorders what occurs and the two types
A
- lysosomal storage disorders (LSD) are conditions in which substrates derived from normal cell catabolism accumulate within lysosomes rather than being degraded by lysosomal enzymes
1) inherited lysosomal storage disorders
2) acquired lysosomal storage disorders
17
Q
inherited lysosomal storage disorders what pattern of inheritance, what occurs and clinical signs, what are the most vulnerable fibres
A
inherited in an autosomal recessive pattern, reduced lysosomal enzyme activity so reduced deregulation activity, substrate accumulation begins in utero and progressively gets worse, clinical signs depend on degree of compromise of enzymatic activity generally get signs after a few months of life
neurons and myocardial fibres
18
Q
what is an example of an inherited LSD in animals
A
glycoproteinoses - defective catabolism of the carbohydrate component of N-linked glycoproteins - e.g. α-mannosidosis in Angus, Murray Grey and Galloway cattle and cats
19
Q
acquired lysosomal storage disorders how acquired, clinical disease what like and how to tell difference between inherited
A
lyososomal enzymes may also be inhibited by exogenous toxins
alpha mannosidosis
clinical disease comparable to the inherited and inherited effects young animals
20
Q
list 3 disorders of degeneration of extracellular tissues
A
1) amyloidosis
2) fibrinoid change
3) collagenolysis
21
Q
what is amyloid, what is amyloidosis, what makes them permanent
A
amyloid = an insoluble, extracellular, fibrillar glycoprotein deposit
amyloidosis = disease resulting from localised or generalised (systemic) tissue deposition of amyloid
- the β-pleated conformation renders the deposits resistant to enzymatic degradation (e.g. by proteolytic enzymes of macrophages)
22
Q
what are the 4 main types of amyloid what each derived from
A
1) AL Amyloid - humans most common type of amyloid derived from antibodies (light chains) - may develop domestic animals
2) AA amyloid - most common in domestic animals - insoluble fragment from serum amyloid A (SAA)
3) IAPP Amyloid - many cats with type 2 diabetes mellitus, develop deposits of amyloid in the pancreatic islets of Langerhans (islet amyloidosis)
4) Amyloid derived from misfolded prion proteins - transmissible spongiform encephalopathies (TSE), amyloid deposits composed of misfolded proteins may develop in the brain
eg - scrapie in sheep
23
Q
describe AA Amyloid and how identified and causes
A
fragment from serum amyloid A (SAA) normally produced by liver in small concentrations. most with increase SAA blood concentrations don’t develop amyloidosis
- identified by its loss of affinity for Congo red stain
cause - underlying disease or inherited or familial
24
Q
how do transmissible spongiform encephalopathies work in terms of protein
A
- in these disorders, the amyloid is thought to be due to aberrant post-translational misfolding (β-pleating) of a normal α-helical host cell membrane sialoglycoprotein (PrPc), caused by exposure to a prion (a proteinaceous infectious particle) (PrPSc)
it is currently thought that PrPSc acts as a template on which PrPc is refolded, thereby progressively converting the host PrPc into a likeness of itself
25
microscopic appearance of amyloidosis in terms of staining and gross appearance
H&E stain eosinophilic
congo red stain - positive orange-red
it appears green and birefringent when stained with Congo red and viewed with polarised light (“apple-green fluorescence”)
gross - only apparent if severe will get enlarged, firm, pale tissues
26
effects of amyloid deposition
mild - moderate deposition
severe hepatic amyloidosis
renal amyloidosis
- may be asymptomatic
- however, can physical compression of adjacent cells and compromised vascular perfusion (Act as concrete and prevent capillary access, atrophy or cell degeneration (with decreased cell function) or cell death
- severe risk of spontaneous liver rupture, potentially fatal
- renal amyloidosis often succumb to renal failure and those with renal glomerular amyloidosis may suffer from hypoproteinaemia due to loss of circulating proteins through the damaged glomeruli into urine
27
fibrinoid change what is it, what occurs and when visible
• fibrinoid change = an extracellular degenerative phenomenon observed in damaged blood vessels, especially small arteries and arterioles
- accumulation of plasma proteins (including polymerised fibrin derived from circulating fibrinogen),
- +/- complement and/or immunoglobulins (antibodies) in the tunica intima
-only visible microscopically but may be accompanied by vascular thrombosis and/or haemorrhage and oedema that may be visible grossly
the extravasated plasma proteins (especially fibrin) appear deeply eosinophilic in H&E- stained sections
28
List 5 causes of fibrinoid change
1) e.g. renal failure - due to endothelial injury by circulating toxins
2) e.g. systemic hypertension - high systemic blood pressure - problem in older patients
3) e.g. vasculitis
4) e.g. selenium/vitamin E deficiency in pigs - due to endothelial injury by reactive oxygen species
e. g. oedema disease in pigs - due to endothelial injury by circulating E. coli toxins
29
collagenolysis what is it, how look under stain, what may be preceded by
collagenolysis = lysis (dissolution) of collagen fibrils
- a microscopic lesion caused by proteolytic enzymes released by such cells as eosinophils and neutrophils
- the affected collagen fibrils appear amorphous and lightly eosinophilic in H&E-stained sections
- may be preceded by a so-called collagen degeneration stage in which targeted collagen fibres are surrounded by brightly eosinophlilic, granular to amorphous material representing massed eosinophils and their released granules (“flame figures”)
30
give 3 examples of causes of collagenolysis
1) e.g. insect bite hypersensitivity reactions
2) e.g. mast cell tumours
3) e.g. eosinophilic collagenolytic granulomas in cats and horses
31
necrosis what is it
the term used traditionally to describe the death of cells in a living organism and the gross and microscopic morphological changes that are indicative of this event
32
what are the two major types of necrosis what is most common and how to distinguish
1) oncosis (or oncotic necrosis) = ante mortem cell death via swelling (onco = swelling) - most common
2) apoptosis (or apoptotic necrosis) = ante mortem cell death via shrinkage (apo = off, ptosis = falling or dropping)
often impossible to distinguish need electron microscopy or agar gel electrophoresis
33
apoptosis what can it be caused by, how fast, does it induce inflammatory response, what cells does it involve and is it grossly visible
- can be a normal (physiological) process or an abnormal (pathological) process
- occurs rapidly
- does not induce an inflammatory response
- involves individual cells or small clusters of cells that are being selectively eliminated
- therefore, apoptosis is never grossly visible
34
Give 2 examples of physiological apoptosis
1) during embryogenesis, foetal development and post-natal growth
- allows scheduled destruction of certain cell populations
2) elimination of cells that are potentially damaging to the body
- e.g. self-reactive lymphocytes
35
give some examples of pathological apoptosis
- radiation injury
- • cell damage caused by reactive oxygen species
- • some viral infections
- • tissue injury induced by cell-mediated immune responses
- • malignant neoplasia
- • tissue reactions to certain administered drugs - e.g. corticosteroids, cytotoxic
- chemotherapeutic agents
36
ultrastructural (electron microscope) apoptosis characterised by
condensation of nuclear chromatin under the nuclear membrane
| • blebbing, budding or fragmentation of the nucleus (karyorrhexis)
37
pathogenesis of apoptosis
1) involves an intracellular proteolytic cascade ( execution phase of apoptosis) mediated by the cell’s own caspase enzymes
2) activate endonucleases to cleave nuclear proteins involved in DNA so cell death
3) flipping of interior outside promote recognition by neighboring cells as abnormal so rapid phagocytosis
no release of pro-inflammatory components so no significant inflammatory response
38
oncotic necrosis what caused by, does it get an inflammatory response and can you see with naked eye
- caused by severe cell membrane injury or sustained cell hypoxia/anoxia
- release of products of cell membrane phospholipid degradation , chemoattraction of leukocytes - inflammatory response from adjacent viable tissue - therefore sometimes able to see with naked eye
39
what plays a pivotal role in final demise of many lethally injured cells and how does it occur
```
ionised calcium (Ca++) plays a pivotal role in the final demise of many lethally injured cells
○ direct injury to cell membranes or failure of membrane ion pumps - influx of Ca++ into cells
○ damaged mitochondria and endoplasmic reticulum may also release sequestered Ca++ into the cell cytoplasm
○ free cytosolic Ca++ acts as an intracellular messenger and enzyme activator (Figure 3)
- Attack cell - membrane and nuclear damage from these enzymes leading to described above
```
40
what does free cytosolic Ca2+ cause the activation of (oncotic necrosis) and what do they do
1) membrane-bound phospholipases - enzymatic destruction of membrane phospholipids of mitochondria and other organelles
2) ATPases - accelerated depletion of remaining cell ATP stores
3) proteases - enzymatic destruction of membranes and cytoskeletal proteins
4) endonucleases - degradation of nuclear chromatin
41
what occurs after cell death by oncotic necrosis
the cells are degraded by hydrolytic lysosomal enzymes, with denaturation of cell proteins and lysis of cell components
42
where are lysosomal enzymes used to degrade cells after oncotic necrosis derived from
1) the dead cells themselves (= autolysis = self-digestion), AND
2) leukocytes recruited into sites of oncotic necrosis (= heterolysis = digestion by others)
43
list some ultrastructural (electron microscopic) features of oncotic necrosis
1) obvious fragmentation of plasma membrane and organelle
2) poor definition of cytoplasmic organelles
3) severe swelling of mitochondria and lysosomes
4) moderate-severe clumping of nuclear chromatin
44
light microscopic features of oncotic necrosis how long does it take to see after onset, list a few main changes seen
4-12 hours after onset before light microscopic evidence of oncotic necrosis appears - longer patient stays alive after necrotic event more likely to see necrotic features
- progressively severe cell swelling
- appearance of nucleus most important - their are 3 changes they undergo
1. pyknosis
2. karyorrhexis
3) karyolysis
45
give the 3 changes oncotic necrosis cells undergo in terms of their nucleus
1) pyknosis = a shrunken, darkly staining (basophilic, hyperchromatic) nucleus (also seen in apoptosis)
2) karyorrhexis = rupture of the nuclear envelope with extrusion of dark nuclear fragments also seen in apoptosis)
3) karyolysis = fading of the nucleus (due to the actions of activated RNAases and DNAases) eventual disappearance
46
gross features of oncotic necrosis how long after onset may be visible and some changes
it may take 12 to 24 hours after onset for gross lesions of oncotic necrosis to become visible
foci of oncotic necrosis displays: - softness, friability, sharply defined, fat can become hard may get red band with white band within
47
consequences of oncotic necrosis in small areas involving labile tissue, large areas and small areas of permanent cells
1) healing involves regenerative cell hyperplasia (mitotic division) with some fibrosis
2) significant scar tissue and some areas may be walled off
3) tissue regeneration is impossible so repair involved fibrosis
48
List 5 types of oncotic necrosis
1) coagulative necrosis
2) gangrenous necrosis
3) liquefactive necrosis
4) caseous necrosis
5) fat necrosis
49
coagulative necrosis what is it, how do cells appear and what can it be induced by
typical of lethal hypoxic injury in all body tissues except the central nervous system
- the necrotic cells appear shrunken and hypereosinophilic, with the nuclei pyknotic, karyolytic or karyorrhectic
- the basic outline of the dead cells persists for at least several days
- affected cells ultimately lyse (fragment)
be induced by certain exotoxins of anaerobic bacteria (e.g. Clostridium species, Fusobacterium necrophorum)
50
what are the two types of gangrenous necrosis how occur and examples of when occur
1) dry gangrene
= coagulative necrosis induced by ischaemia (i.e. infarction)
- the affected tissue eventually mummifies due to dehydration shrivelled - eventual sloughing
- e.g. frostbite
2) wet gangrene or gas gangrene
= necrosis of tissue (usually of coagulative type) that is then colonised by bacteria - liquefaction
- the bacteria are saprophytes derived from the soil, air, skin or gastrointestinal tract)
- affected tissue becomes moist, soft, red-brown to black and is malodorous due to gas production by the bacteria
- e.g. gangrenous pneumonia following inhalation of rumen contents into the lungs
51
liquefactive necrosis what occurs, what see microscopically, what causes and where normally occurs
- there is rapid enzymatic degradation of the dead cells (involving both autolysis and heterolysis) obliteration of the original tissue architecture and formation of liquid
- microscopically, see amorphous eosinophilic debris containing pyknotic or karyorrhectic nuclear remnants
- typical of abscesses caused by pyogenic (pus-forming) bacteria (e.g. staphylococci, streptococci, Arcanobacterium
- typical in CNS, intestines and pancreas
52
caseous necrosis what occurs, what can it undergo and what generally causes it
- the dead tissue is converted into a grossly dry, granular, cream-white to yellow, friable coagulum (caseous = cheesy)
- undergo dystrophic mineralisation with the mineralised debris persisting indefinitely
causes
1) infection by bacteria with complex cells walls and poorly degradable lipid components (e.g. tuberculosis caused by Mycobacterium tuberculosis
2) fungal infections with rapidly growing tumours
3) chronic abscesses caused by pyogenic bacteria
53
fat necrosis what do they look grossly and microscopically and why get large inflammatory response
firm, surrounded by red border (inflammation)
eosinophilic with wispy or micro - bubbly cytoplasm and pyknotic, karyorrhectic or karyolytic nuclei
- release of free fat is irritant so chronic foreign body - large macrophages and giant cells
54
list 5 things that can induce fat necrosis and examples
1) lipolytic enzymes
- e.g. local release of activated lipases from the necrotic exocrine pancreas
2) trauma
- e.g. crushing of fat pads in the pelvic canal of heifers during a difficult calving
3) reactive oxygen species (free radicals)
- e.g. in deficiency of vitamin E and/or selenium (anti-oxidants)
4) hypoxia
- e.g. within large fat stores in obese sheep
5) unknown causes
- e.g. massive necrosis of peritoneal fat stores in cattle
55
dystrophic mineralisation what is it, when occurs, occurs despite of what, in contrast to what, is it common
- is the deposition of calcium salts in tissues that have undergone oncotic necrosis
- occurs despite normal serum calcium and phosphate concentrations and in the absence of derangements in calcium and phosphate metabolism (in contrast to metastatic mineralisation)
- a common phenomenon
56
how is dystrophic mineralisation detected grossly and microscopically and how does it begin
○ grossly, large mineral deposits may be detectable as gritty to hard, chalky-white foci
○ mineral deposits appear histologically in H&E-stained sections as dark blue-purple (basophilic), granular, amorphous deposits
intracellular starts with accumulation of calcium within mitochondria of dying cells
57
list the 3 ways cells communicate
1) gap junctions
2) cell-to-cell direct signalling - contact dependent signalling
3) cell-to cell signalling via secreted molcules
58
gap junctions where found, structure and what moves across, what is permeability controlled by
Cells that are in direct contact (adjacent) to each other can have gap junctions (arrays of small channels) that link the interior of adjacent cells.
Structure - aqueous pores made from six connexin molecules.
Gap junctions are dynamic structures because connexons are able to open and close.
- They permit the movement of small molecules such as cAMP, glucose -6- phosphate and Ca2+ between cells.
- The permeability of the gap junctions are regulated by changes in cytosolic concentrations of Ca2+, cAMP and pH.
59
give an example of a gap junction
electrical coupling such as the spread of a electrical activity in the heart from one cardiac cell
60
cell-to-cell direct signalling what occurs and example
- Direct contact through cell surface molecules on the surface of both cells (or via contact with extracellular matrix components.
example is via antigen presentation by dentritic cells to T lymphocytes that inturn initiates an immune response - the lymphoctyes know which part of the body to go to due to upregulation of certain receptors at site of infection
61
Cell-to-cell signalling via secreted molecules example of secreted molecules
neurotransmitter or hormones
| eg - adrenaline binds to an adrenergic receptor
62
what are the 4 classifications of signalling molecules
1) paracrine
2) autocrine
3) endocrine
4) synaptic
63
paracrine signalling what occurs and why important
- Affects neighbouring different cell types - don't create large amounts of molecules
- Important in localized signalling such as inflammation and angiogenesis.
- signal either rapidly taken up by cells or broken down by extracellular enzymes
64
autocrine signalling what occurs and when important
- Affects self or neighbouring cells of the same type
- important in regulating clonal expansion of cells.
○ IL-2 cytokine important in lymphocyte proliferation following activation works in this way. - T cell doesn't divide until receive this signal
65
List 7 signal types and give examples for each
1) hormones - steroids
2) neurotransmitters - acetlycholine
3) external environmental factors - light
4) mechanical - stretch
5) immunological - antigens
6) metabolic - Ca2+
7) dissolved gas - NO
66
what are the two types of neurotransmitters and give an example for each
a) the ‘classical’, small molecule neurotransmitters
Eg acetylcholine, amino acids
b) The relatively larger neuropeptide neurotransmitters
corticotrophin releasing hormone
67
define a hormone and what are the two types with examples
may be any substance which brings about changes in cell function, either locally or distant.
1) Tropic hormone - A hormone that as its primary function regulates the hormone secretion of other endocrine glands.
- E.g Thyroid stimulating hormone produced by the anterior pituitary to cause the release of another hormone thyroxine
2) Non-tropic hormone- Exerts its effects on non-endocrine target tissues,
- e.g. insulin acts on the liver and muscle and adipose tissue.
68
list the 4 main types of hormones
1) Peptides and proteins
2) Steroids
3) Amines (Tyrosine derivatives)
4) Eicosanoids
69
peptide hormone what is the half-life give an example and its main tissue targets
circulating peptide half-life only a few minutes
Main targets
• Liver, adipose tissue and muscle
70
List 5 functions of insulin
1) In liver, insulin promotes storage of glucose as glycogen, as well as conversion of glucose to triglycerides
2) In muscle, insulin promotes the uptake of glucose via activation of Glut -4 transport channels and promotes glucose conversion into glycogen - increases the amount of Glut-4 transporters on the cell surface
3) In adipocytes, insulin promotes uptake of glucose and its conversion to triglycerides for storage
4) Anabolic hormone secreted in times of excess nutrient availability
- Allows the body to use carbohydrates as energy sources and store nutrients
5) stimulates uptake of amino acids for incorporation into protein
71
what is a half-life and what increases it for hormones
how long hormone available in blood before binds to receptors
increase by binding to proteins in the blood - make more stable
72
give an example of a steroid hormone its functions and how it achieves them
Cortisol (a glucocorticoid)
1) stimulates gluconeogenesis, particularly in the liver.
- results in the synthesis of glucose from non-hexose substrates such as amino acids and lipids
2) Metabolic Actions Corticosteriods
1. Defence against hypoglycaemia.
- Increase plasma glucose - increase glucose production
- Liver Increased glucose output
- Promotes gluconeogenesis, glycogenolysis & lipolysis
2. Prior action of cortisol
- Build- up of glycogen stores
3) Anti-inflammatory actions
- Inhibits arachidonic acid production by inhibiting enzyme that creates from phospholipid so prostaglandins and leukotrines
73
amine hormones where all derived from and what are the two main types with examples within
- All amine hormones are nitrogen containing derivatives of the amino acid tyrosine.
1) thyroid hormones (eg. Thyroxine (T4) & triiodothyronine (T3)
2) the hormones produced by the adrenal medulla (catecholamines; eg adrenaline and noradrenaline).
74
functions of T4 and T3, secretion and regulation of secretion
regulate metabolic rate an essential for nerve development and brain function and growth
1) Thyrotropin releasing hormone (TRH)
2) Stimulates thyrotropes to release TSH - in anterior pituitary
3) Stimulates follicular thyroid cells to produce and secrete T3 & T4 in thyroid gland
Feedback - thyroid hormone feeding back to anterior pituitary - by downregulating the TRH receptors on the anterior pituitary
75
differences between catecholamines and thryoid hormones
catecholamines then throid
1. Hydrophilic and are transported in blood 50% bound to proteins
Lipophilic - mostly bound to plasma proteins
2. Stored in chromaffin granules, Released following exocytosis of granules
stored in colloid, release when phagocytosed
3. Bind to alpha and beta receptors on target cell surfaces.
bind receptors inside cell
4. Activate a second messenger system.
activate specific genes to produce new proteins
76
adrenalin where created, how long half-life, how travel through blood, function
- Chromaffin cells in medulla in adrenal gland
- Very short half-life
- Can be free hormone or bound to plasma proteins
- Uses second messenger system - through its action on alpha-adrenergic receptors, adrenaline causes smooth muscle contraction.
○ its action on beta-adrenergic receptorsd increase cardiac output by increasing heart rate and force of contraction to increase blood pressure.
○ It’s metabolic actions include increasing hepatic glucose output and lipogenesis.
77
what are the 4 major functions of thyroid hormones
1. Metabolic rate - sodium potassium pumps
2. Oxygen utilization
3. Nutrients mobilization and utilization
4) Thermogenesis
78
prostaglandin how long half-life what type of signalling used, act on what cells and functions
- are potent but have a short half-life before being inactivated and excreted.
○ exert only a paracrine or autocrine function
- act on a variety of cells such as vascular smooth muscle cells causing constriction or dilation, on platelets causing aggregation or disaggregation and on spinal neurons causing pain.
- Prostaglandins also have a wide variety of actions in inflammation.
79
factors controlling insulin secretion and which most important
```
1) -β cells monitor levels of circulating metabolites
• Glucose - most important
• Leucine & alanine
2) Neuronal & hormonal
• Parasympathetic stimulation
• CCK (cholecystokinin)
3) Inhibitors
• Somatostatin
• Sympathetic stimulation via α adrenergic receptors
```
80
secretion of cortisol, regulation and stimulus
1) Hypothalamus produce corticosteroid releasing hormone
2) Anterior pituitary cells called corticotrophs produce ACTH
3) Goes to adrenal cortex where cortisol is released
- regulation on pituitary and hypothalamus by cortisol
- regulation on hypothalamus by ACTH
Stimulus for cortisol release include
- Stress from low blood glucose
- Physical stress - breaks bone, under anaesthetic
81
how is hypothalamus connected to the pituitary gland and what does it produce and transport down to posterior pituitary gland
- Connected to the pituitary via the infundibulum (pituitary stalk) which contains vascular and neural connections
ADH (Anti-diuretic Hormone) and oxytocin
82
anterior pituitary gland list hormones produced and what type they are
- Glycoproteins
1. Thyroid Stimulating Hormone (TSH)
2. Follicle Stimulating Hormone (FSH)
3. Luteinizing Hormone (LH)
- Single Chain Polypeptides
4. Growth Hormone (GH)
5. Adrenocorticotrophic Hormone (ACTH)
6. Prolactin (PRL)
83
target and functions of prolactin
target is mammary gland
1) Prolactin induces mammary growth (lobuloalveolar growth).
- Alveoli are the clusters of cells in the mammary gland that actually secrete milk.
2) Prolactin stimulates lactogenesis or milk production after giving birth.
- Induces transcription of milk proteins
- Casein, lactalbumin, β-lactoglobulin
84
2 parts of the posterior pituitary and what does it secrete
1. supraoptic nucleus
2. paraventricular nucleus
○ Oxytocin (OCT)
- Anti-diuretic hormone (ADH )
85
anti-diuretic hormone ADH where produced, released target and function
- Produced in hypothalamus
○ supraoptic and paraventricular nuclei
- Released by posterior pituitary
○ Osmoreceptors: ECF osmolality
○ Baroreceptors: Blood pressure/volume
1) Acts on renal collecting ducts to increase water reabsorption from urine
- Binds on V2 receptors of principal cells (cAMP pathway)
- Increases the amount of aquaporin's by increasing their production
2) Increases vascular resistance
- Binds V1 receptors smooth muscle cells (PIP2 pathway)
86
oxytocin where produced and where released, what target and functions
- Produced in supraoptic and paraventricular nuclei
• Released by posterior pituitary
- receptors are on smooth muscle cells
○ mammary gland and uterus
1) Promotes milk ejection (milk let down) during lactation
- Milk initially secreted into alveoli (sacs) within mammary gland
- OCT stimulates contraction of myoepithelial cells (smooth muscle cells) which surround alveoli
2) Uterine contraction during parturition
- Important in cervical dilation & uterine contractions
- After birth maintains hemostasis & evacuation of placenta
87
how is the release of pituitary anterior hormones is regulated
- controlled by hypothalamic inhibiting & releasing hormones that are released into the hypothalamo-hypopyseal portal system then drains into secondary capillary plexus within anterior pituitary
88
list stimulators of GH and inhibitors
```
Stimulators
- Hypoglycemia - drop in blood glucose
- stress
- dietary protein
- low fatty acids
- Exercise
- Ghrelin (stomach hormone).
• Inhibitors of GH secretion include
- high carbohydrate
- negative feed back
○ IGF-I & GH
```
89
concentration as seen by target cells is determined by what 3 factors
1) Rate of production
2) Rate of delivery
3) Rate of degradation and elimination
90
list hte factors that determine the level and duration of hormonal effects
1) how much free biologically active in plasma
2) how much bound to plasma proteins
3) if need to be metabolised in tissues
4) if excreted in urine
91
positive regulation of oxytocin secretion
1) Suckling
- Neurogenic reflex to hypothalamus increase amount of oxytocin
- once no more suckling than oxytocin ceases
2) Pregnancy and Parturition
- Oxytocin receptors in uterus increase late trimester & during labour
- Estrogen induced
Uterus stretching ---> more oxytocin released
92
endocrine rhythms what are they and how occur what other rhythms
Hormone levels may fluctuate in response to external stimuli (food, light, activity)
• Circadian and longer rhythms also exist
93
reduced hormonal activity what are the 3 causes and example
1) Hormone deficiency or hyposecretion diseases
eg - autoimmune disease - diabetes type 1 destroy beta cells decrease insulin
2) increased removal or hormone from the lood
3) transduction failure - target cells fail to respond
eg - hypothyroidism tumour in thryoid
94
increased hormone activity what are the 3 causes and examples
1) Hormone excess or hypersecretion diseases
eg - tumours or immunological causes - hormone producing without regulation - lost inhibitory control - also amplification of amount of cells producing hormone
2) Reduced plasma protein binding
- Can't deliver to high concentration to target
- eg liver disease
3) Reduced inactivation; failure of negative feedback.
- Dogs Cushings disease - too much cortisol being produced
95
List the 3 main types of signal transduction pathways
1) ligand gated ion channel receptor
2) G-protein coupled receptor
3) enzyme linked receptor
96
ligand gated ion channel what type of receptor, how works and example
- Ionotropic receptor
- Open or close in response to ligand thus transduce chemical signal into electrical
Eg - Ach diffuses across synaptic cleft of neuromuscular junction to receptor that opens Na+ channels which alters ion permeability of the cell. Results in change in membrane potential triggers a nerve impulse
97
G-proteins how many transmembrane domains, subunits and what are the 3 major functions
7 transmembrane alpha helices
alpha, beta and gama subunits - alpha has GDP and GTP binding sites
1. bind potassium or calcium ion channels in neurotransmission.
2. activate kinases (enzymes that phosphorylate).
3. cause either the release or formation of major second messengers such as cyclic AMP (cAMP) and calcium ions.
98
example of G protein what is the receptor what does the G protein bind to, what does that produced and what does that activate and how
adrenalin - receptor is beta-adrenergic receptor and G protein binds to adenylate cyclase which creates cAMP
cAMP activated protein kinase A (PKA) by causing release of negative regulatory subunits as activated catalytic subunits
99
List 5 regulatory points on adrenalin pathway
1) The adrenalin concentration in blood diminishes and the adrenalin-receptor conjugate on the plasma membrane dissociates.
2) The GTP bound to Gα hydrolysis to GDP and the "ground state" G protein reforms resulting in the deactivation of adenylate cyclase.
3) Degradation of cAMP is catalysed by specific a phosphodiesterase
4) Arrestin (protein) binds to the G protein-coupled receptor and block further G-protein-mediated signalling and target receptors for internalisation
5) Intracellular protein phosphatases remove the phosphate groups from the key enzymes affected by their addition in the first place.
Phosphodiesterase enzyme also has inhibitors such as caffeine that leads to elevated levels of cAMP
100
regulation of adrenalin pathway via other hormones
1) Glucagon binds to its receptor on liver cells and also activates adenylate cyclase and elevates cAMP levels in the same liver cells that adrenalin acts on - ADDITIVE EFFECT
2) Prostaglandin acts antagonistically as also acts upon adenylate cyclase but inhibits it.
Prostaglandin receptor promotes dissociation of different G protein which releasing an inhibitory GαGDP subunit and once bound prevents activation via adrenalin or glucagon
101
disruption of regulation from toxins such as cholera toxin what occurs, what cell type involved and what leads to
- The toxin catalyses ADP-ribosylation protein of the dissociated G protein
○ The covalently modifies Gα derivative behaves normally and activates adenylate cyclase but decays very slowly
○ Therefore once adrenalin activation cascade started cannot be switched off
- Main cell types are gut epithelial cells as adrenergic activation at these cells results in activation of molecular pump that actively secretes Cl- and water into lumen of gut
○ Causes severe osmotic diarrhoea which leads to dehydration
102
nitric oxide signalling what are the steps involved and example
1) Binding of acetylcholine to Gq protein linked receptors on endothelial cells causes IP3 production.
2) IP3 releases calcium ions from endoplasmic reticulum and other cytoplasmic Ca2+ stores
3) Ca2+ ions and calmodulin form a complex which activates NO synthase which converts arginine to citrulline and NO.
4) NO rapidly diffuses from endothelial cell into adjacent smooth muscle cells.
5) Acts only locally - quickly converted to nitrates and nitrites (half-life 5-10 sec).
6) NO activates a soluble guanylyl cyclase (in the cytoplasm) to make cyclic GMP (cGMP) from the nucleotide GTP.
7) cGMP activates protein kinase G which phosphorylates several muscle proteins to induce muscle relaxation resulting in vasodilation and increased blood flow
Example - Viagra enhances penile erection by blocking the degradation of cGMP prolonging the NO signal
103
catalytic enzyme receptors what occurs and the two main types
- Ligand activates enzyme receptor directly or forms complex with another protein that acts as an enzyme
- They are transmembrane proteins but unlike G-proteins only have 1 transmembrane segment and are unable to undergo conformational change
- Instead causes the two receptor molecules to form together as a dimer which activates their kinase function and allows them to phosphorylate each other
1) receptor tyrosine kinase
2) tyrosin kinase linked receptor
104
receptor tyrosine kinase example and what occurs, and how regulated
insulin
1) insulin binds to receptor
2) autophosphorylation
3) phosphorylates other intracellular proteins
4) activate phospholipase C which activates PIP2 pathway
5) phosphorylate other enzymes that activate RAS on GTPase which results in MAP-kinase cascade carries signal to nucleus
6) end of pathway MAP-kinase phosphorylated and phosphorylates gene regulatory sequences to alter gene expression
- terminated by tyrosine phosphatases or by
internalization of ligand bound receptors.
105
tyrosine kinase linked receptors what molecules use and how different from tryosin kinase receptors
cytokine receptors
| receptors are linked receptors so dimerize then bind to cytoplasmic tyrosine kinase before phosphorylate targets
106
nuclear receptors what also called, what hormones important for what occurs
hormone-responsive elements (HRE)
- Important for steroid hormones, thyroid hormones and Vitamin A and B
- Binding to intracellular receptors located within cytoplasm or nucleus which themselves are transcription factors that regulate expression of target genes by binding to specific DNA sequences termed hormone response elements
107
what are the 3 parts of the nuclear receptor structure
1) The carboxy-terminus or ligand-binding domain: This is the region that binds hormone.
Hormone binding to this region changes the conformation of the DNA-binding domain and increases the DNA-binding affinity
2) DNA-binding domain (HRE) Amino acids in this region are responsible for binding of the receptor to specific sequences of DNA.
- Contains two zinc fingers
3) N-terminal portion. In most cases, this region is involved in activating or stimulating transcription by interacting with other components of the transcriptional machinery.
108
what are the 2 main classes, examples of hormones that use these, their receptors and how they work
Cytoplasmic receptors - class 1 nuclear receptors (steroid hormones)
- Are bound to heat shock proteins (HSPs) that dissociates when hormone binds which allow receptor to dimerise and become active
- Then moves into the nucleus (active transport) where bind to DNA and activates RNA polymerase or inhibits certain genes
Nuclear receptors - class 2 nuclear receptors
- Receptor (such as thyroid hormone receptor) bound to corepressor protein (OFF)
- Ligand binding causes dissociation of corepressor and recruitment of coactivator protein (ON)
- Activate RNA polymerase
