Inflamation

Question 1

What are the 5 cardinal signs of inflamation?

Answer 1

heat, redness, swelling, pain, loss of function

Question 2

Difference between chronic and acute swelling?

Answer 2

acute swelling is short lasting, chronic swelling refers to the build up over time, commonly concurring in cycles of inflammation and healing, this can cause damage to tissues resulting in fibrosis and is linked to rheumatoid arthritis.

Question 3

What is dales criteria for an inflammatory mediator? (4)

Answer 3

effect can be replicated invivo
antagonists can counter the effect
removal of the mediator will increase or decrease inflamation
endogenous mechanisms can turn off the mediated inflamatory responses.

Question 4

How do mediators tend to act?

Answer 4

They tend to act via paracrine like release, either on the releasing cell (autocrine) or neighboring cells (juxtacrine

Question 5

Give me the 5 broad examples of mediators?

Answer 5

kinins, histamine, cytokines, complement, eicosanoids

Question 6

what is the purpose of inflammation?

Answer 6

this is to promote the healing of tissue, vasodilation and increasing the permeability of the vessels increase blood flow to damaged regions.

this also increases the arrival of leukocytes to fight any infection. neutrophils tend to be followed by macrophages. after phagocytosis they will present the antigens of their cell surface and then go on to activate lymphocytes in the lymph nodes via clonal expansion. essentially proliferation of one lymphocyte so that all will have specificity for the same antigens.

Question 7

How is histamine produced?

Answer 7

histamine is produced from histidine via histadine decarboxylase

Question 8

Where are the main areas of histamine production?

Answer 8

they tend to be found in the connective tissues due to the high amount of mast cells present. this involves the lungs, blood vessel and GI tract. histamine is also produced in the CNS by histaminergic neurons in the hypothalamus which projects to the thalamus hippocampus, and cortex.

Question 9

Outline the release mechanism of histamine?

Answer 9

the presence of allergens promotes Ige release. (TH2 cells also promote an environment to facilitate this)

Ige will bind the allergen and then bind its receptors on mast cells. this promotes calcium influx into the mast cell causing the degranulation of histamine granules, resulting in the exocytosis of histamine.

Question 10

outline how histamine is metabolised and its link to cAMP?

Answer 10

Histamine is metabolised by acetylation. cAMP levels promote lower levels of histamine, hence why the extra effect of B1 adrenoceptor agonists for asthma.

Question 11

Outline the function of kinins? (give example)

Answer 11

Kinins exist as kininogens which are hydrolysed by plasma enzymes and kalikreins to produce active kinins. they main inflamtory mediator is bradykinin.

They will cause vasodilation and an increase in vessel permeabilty.

To turn off their function we can give kininase II or ACEs
this is why giving things like ACE inhibitors which prevent the breakdown of bradyklinin can cause angiooedema.

Icabitant is a antagonist of kinins.

Question 12

Outline the function of cytokines?

Answer 12

cytokines essentially will promote the immune response. E.g. Interleukin 1 will promote the immune response and inflammation by inducing eicosanoid formation and cytokine production as

Question 13

Outline the function of complement?

Answer 13

complement recognizes sugars or antigens of bacterial cell surfaces and then begins to combine with several complement units to form a membrane attack complex on the cell. this then cause cell lysis. our own cells are protected from this because we can break down compliment.

this explains the dangers of some snake venoms that promote the formation of complement subunits that we cannot break down.

Question 14

What are the 2 types of Immuno deficiency?

Answer 14

these are the result of a immune system mutation, leading to conditions like SCID

or these can be acquired mutations to increase an individuals susceptibility. this is what HIV does.

Question 15

Histamine effects: different receptors?

Answer 15

H1: histamine will cause vasodialtion and an increase in vessel permeability, however it only does so in the arteries. it will cause constriction of bronchiole smooth muscle and have inotrpic effects on the heart. hence why we observe a reduction in BP after the action of histamine, the threat of histamine is it can cause a steady decline in the BP after the baroreceptors facilitate some recovery, this can lead to death. H1 is also found in the brain. H1 is a Gq

H2: this has its action in increasing the gastric acid secretion. this is an Gs

Question 16

Types of Histamine antagonists and their application? Examples

Answer 16

H1 is antagonised in 2 ways: 1st generation Diphenyl hydrazine, these can cross the BBB and cause tiredness.
2nd gen like terfenadin or loratidine which cannot cross the BB so this side effect is abolished.

H2 antagonists are commonly used alongside proton pump (K+/H+ ATPases) in order to treat peptic ulcers. this drugs were made slective to stop systemic effects. exmaples are cimitedine and ranitidine

Question 17

What are the main causes of peptic ulcers? (4)

Answer 17

stress, alcohol, h-pylori bacteria, NSAIDS

Question 18

What is a eicosanoid?

Answer 18

these are inflammatory mediators stemming form lipid precursors

Question 19

how are eicosanoids produced?

Answer 19

these are produced from lipid precursors. the main one is arachandonic acid.

this is produced via the action of phospholipase A2. cytosolic PLA2 is phosphoryled to convert arachadonate to arachadonic acid

Question 20

How do we produce prostanoids or leukotrienes?

Answer 20

once arachadonic acid has been released, either Cyclooxygenase will work to produce the precursors of the prostanoids, which are then produced by synthase enzymes. or lipoxygenase (mainly acting in the lungs and white blood cells) produce leukotrienes from arachadonic acid.

Question 21

difference in Cox1 and 2 expression?

Answer 21

Cox1 is constitutively expressed, where as cox 2 is expressed at induced sites. which tends to be at sites where inflammation is needed.

Question 22

role of Phopholipase?

Answer 22

phopholipase A2 produces arachadonic acid.

Also has large role in the activation of platelet activating factor. PAF precursor acyl PAF is released. at this point PLA2 will act on acyl PAF converting it to Lyso-PAF. this is then acetylated to form the active PAF.

This drives platelet agregation and causes vasodilation and increases permeability.
it can be related to hyperalgesia and leukocyte accumulation.

Question 23

What are the prostanoids?

Answer 23

The prostanoids encompass all the prostaglandins and thromboxane which are produced by COX action of arachadonic acid.

TX:GI/GQ TP: receptor
PgE2: E1,2,3,4, (Gq,GS,GI,GS)
PGD2: GS DP
PGI2: GS/GQ IP
PGF2 alpha:GQ FP

Question 24

How do each of the prostanoids exert their function? application?

Answer 24

PGE2:
EP1: this acts via a Gq g-protein. its main effects are constriction of bronchial and GI smooth muscle, aswell as pain activation.

hence why PGE2 production is associated with the hyperalgesia of nociceptors.

EP2: this acts via Gs. its main effects are vasodilation and bronchodialtion

EP3: this acts via Gi: it has most of its function in the gut, increasing the secretion of gut mucous and decreasing the secretion of gastric acid . it also decrease autonomic NT signalling (inhibitor) and is related to uterus contraction in pregnancy

EP4: acts via Gs: this causes bronchial contraction but vasodilation and suppresses leukocyte activity.

PGE2 is produced by the thalamus in response to interleukins produced due to infections. hence PGE2 action in the ventricles is what triggers the increase in temperature associated with fevers.
these also cause oedema incraesing blood flow and essentially potentiating the response by increasing the arrival of immune cells, and of other inflamatory mediators.
PGD: works by Gs: this causes vasodialtion and inhibits platelet aggregation. However in the brochial smooth muscle it acts on TP causing vasoconstriction. also acts as a chemotractant for TH2 cells.

PGF2 alpha: works via Gq and causes bronchospasm and is related to uterus contraction.

PGI2: known as prostacyclin, this works via Gs. this causes vasodilation and inhibits platelet aggregation.

TX: acats via Gi or Gq. this will promote vasoconstriction, brochial constriction, and platelet aggregation.

PGI and Tx are the main influences out of the prostanoids on platelet aggregation, as PGI is produced in the endothelium and TX mainly in the platelets. hence the natural balance of their expression has a close relation to thrombosis. commonly there is damage to the endothelium by platelet and macrophage activation and the appearance of plaque, reducing PGI expression. in addition lipid peroxides will break down PGI. this shifts the balance towards TX causing thromobosis.

Question 25

How do NSAIDS work? evaluate them

Answer 25

NSAIDS work by inhibiting the formation of all prostanoids, by inhibiting COX. This allows them to have an analgesic effect by a stopping the action of PGE2 on EP1 receptors. allows them to have a anti thrombosis effect. key example is Asprinin. this irreversibly acetylates cox meaning that new protein synth is required to overcome the effect. this cannot occur in the platelets where TX is produce but can in the endothelium where PGI is produced. hence this shifts the balance in the favor of PGI resulting in an inhibition of Platelet aggregation. obviously counter inflammation. However these will stop the role of PGE in stopping gastric acid release in the gut via the action of the EP3 receptor causing peptic ulcers. When treating asthma this can actually force the eicosanoid metabolism down the leukotriene route triggering an asthma attack. COX2 selective anatgonists do exist like Celecoxhib, hwowever this commonly causes headaches. also Cox 2 has been associated with healing as so this shouldn't be given to injured patients. Can be dangerous to use with warfarin patients as it will greatly increase the pottency by inhibiting aggregation and removing plasma binding proteins.

Question 26

Apart from NSAIDS how else can we treat thrombosis?

Answer 26

reduce the saturated fat content of diet, as this increase lipid peroxide. more eicopentanoic acids: these are metabolised to from prostanoids with more double bonds, forming more TXA3 which has no influence on platelet agregation anti-coagulants like heparin or warfrin or fibrinolytics like urikinase or streptokinase

Question 27

how can we apply prostanoids and leukotrienes to therapeutic use?

Answer 27

PGE2 and PGF2 are related to inducing labour and forcing abortions, by causing uterus smooth muscle contraction bronchial dilation: leukotrienes are the main cause of bronchospasm with cysteinyl leukotrienes acting ion the C4 receptor to cause pulmonary vessel contraction and and D4 and E4 causing bronchospasm

Question 28

What is the HPA axis?

Answer 28

This is the the axis down which glucocorticoids are produced. the hypothalamus releases corticotrophin factor which drives the anterior pituitary to produce ACTH which will then drive the adrenal cortex to produce glucocorticoids these then cause feedback inhibition on the hypothalamus and anterior pituitary.

Question 29

How do glucocorticoids work? give example)

Answer 29

an example is cortisol which exists in an inactive form cortisone before conversion. OH swapped for double bonded carbon. these clucocorticoids are bound by chaperpone proteins HSP90, the binding to a glucocorticoid receptor leads to the dissociation from the chaperone and the movement to binding sites on DNA to regulate gene transcription. theinfluence on the DNA is through A GR dimer tethering to other TFS to corepress or express genes. Over all effect is reduced T-leukocyte expression and expansion, reduced neutrophill migration, hence they reduce the inflammatory and immunological response. However they do decrease osteoblast production which usually lay down bone.

Question 30

Risk of too much steroid treatment or rapid removal?

Answer 30

this can cause cushing syndrome: there is bruising a hump, poor wound healing and redistibution of fat to the abdomen rapid removal can lead to dangerous adrenal crisis as the adrenal cortex glands have been reduced in size due to the lack of ACTH stim meaning it cannot produce glucocorticoids itself.

Question 31

What are biologics? give examples?

Answer 31

these are biomolecules taken from biological systems and used to create biosimmilars which can be used to control inflmatory mediators. one of the main ones targeted is TNF alpha. we can used antibodies like infleximab which have been humanised to stop rejection, that can bind to tnf alpha and stop its action on its receptor. also have things like cterncept which which acts as a decoy receptor how ever these are expensive and have issues of redundancy due to how specific their action is and the range of cytokines acting in the inflammatory response.

Question 32

What is haemostasis?

Answer 32

this is the response of the body to a breach in the system they will attempt to create a haemostatic plug in the ruptured vessel. this can occur spontaneously and it related to CV disease and thrombosis.

Question 33

3 natural molecules that stop spontaneous coagulation of blood?

Answer 33

Thrombomodulin: This reversibly binds to thombin preventing it from driving the formation of fibrin. instead it activates protein kinase C and stimulates fibrinlysis ANTI-thrombin III- this neutralises serine residues on thrmobin factors preventing serine protease action and preventing the formation of thrombin factors Heparin co-factors: Works alongside antithrombin to inhibit the role of thrombin .

Question 34

Outline the coagulation cascade?

Answer 34

The thrombin factors exist as zymogens. these are the facotrs in their inactive state. they will undergo proteolysis driving the production of active suffix of thrombin factors. these are hydrolysed by serine proteases to drive the production of each subsequent factors, until thombin is formed. Thrombin will cleave fibrinogen to formed fibrin which bind to form the finrin mesh , the production of facotr XIIIA will increase the stabiltity of thisinsoluble fibrin complex as it is a fibrinoligase. There is 2 routes: intrinsic or contact which relies only on the factors in the blood which is triggered when blood comes into contact with a artificial surface like blood or the extrinisic pathway which is triggered when tissue fluid factors and coagulation factors are involved.

Question 35

role of the platelets in haemostasis?

Answer 35

This is mainly involved in the extrinsic pathway. this relies on a small initial IIA factor presence which is then amplified by positive feedback. rupture of a artery will elad to platelet activation aqnd there adherence to the phosplipids on the exposed enedothelium. they will increase the tissue factor release and thrombin production. thrombin production then had a positive effect on platelet aggregation

Question 36

Application of coagulation promoters?

Answer 36

Vitamin K: this is a co-factor of gamma-glycosyaltion of a glutamat residue of the n-terminus of the precursor glycoprotein which leads to zymogen formation. we can look at the dangers of liver disease which causes a fall in VK and this also can be an issue with the overuse of anticoagulants. we can also give factor V111 OR IX to treat haemophillia A and B respectively.

Question 37

Application of coagulation demoters?

Answer 37

heparin: this will bind antithrombin III to pottentiate its action usually giving via injection of IV in the case of surgery to stop depp venous thrombosis. (we control the supply by looking at the partial thromboplastin time. can cause hameorhage hepradin can be given if immune to heparin Warfarin this is commonly used as orally active and long lasting. works by preventing vitamin K production. However this can cause execssive bleeding and vitamine K deficiency, both can be countered by increasing VK intake. hence we monitor dose by comparing the prothromnin time to the standard thromboplastin time. we also have direct thombin inhibitors like Dabigitran, this has more predictive effects than the likes of warfrin so is a go to as it does not need monitoring. drivers of fribrinolysis. the activation of coagulation usually also leads to the activation of fibrinolysisn. this invoves the cleavge of a betea globulin plasminogen to form the active form. this is done by activators like urinokinase. so we can give urinokinase or to boost its effect give streptokinase which will bind the fibrin and act like an antigen. this can cause bleeding.

Question 38

what is partial thromboplastin time and prothrombin time?

Answer 38

prothrombin time compares the extrinisc ration of prothrombin to coagulation factors, want to keep 2-4:1 whilst PTT is for the intrinsic route.

Question 39

what can influence anti-coagulant effectiveness?

Answer 39

contraceptives can reduce the response drugs that displace the plasma binding proteins or reduce platelet aggregation like aspirin can potentiate the response. hence also liver disease.