Term
| What is inflammation initiated in response to? (4) |
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Definition
Microbial infection
Noxious exogenous chemical stimuli e.g. acid
Neoplasm (tumour)
Trauma |
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Term
| What is the aim of the pathophysiological process of inflammatory response? |
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Definition
| Attempts to destroy, dilute or wall off the inflammatory initiating agent, prepare to 'clean' the tissue for wound healing and/or educate/stimulate the adaptive immune system to produce an appropriate response to various exogenous antigens (except for autoimmune inflammation then it is endogenous antigens) |
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Term
| Why is inflammation considered a complex process? |
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Definition
| Because it is controlled by a variety of mediators, which are controlled by a myriad of inter-dependent cellular processes which are controlled by a host of extracellular inflammatory mediators and intracellular signalling metabolic pathways |
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Term
| What are the 5 cardinal signs of inflammation? |
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Definition
Heat
Redness
Swelling
Pain
Loss of Function |
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Term
| How is inflammation initiated? |
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Definition
| Detection of a causative agent. This involves detection of a chemical/antigen by a SPECIFIC receptor e.g. Pathogen-associated-molecular-patterns (PAMPS) by pathogen recognition receptors (PRRs) [components of the innate immune system] |
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Term
| What happens in the microcirculation stage of inflammation? |
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Definition
-Pathogen is recognised
-Resident macrophages activated
-Increased vasodilation (swelling)
-endothelial cells express cellular adhesion molecules(CAM)
-CAMs cause leukocytes to stick to the endothelium and migrate out of the vessel into the cell |
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Term
| What happens during the first part of the cellular phase of inflammation? |
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Definition
-polymorphnuclear cells (PMNs) usually neutrophils first enter the cell. Phagocytocise microbial material
-they also release proteases which have anti-microbial activity
-release mediators which can recruit more leukocytes |
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Term
| What happens to monocytes to in the cellular phase if inflammation |
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Definition
-monocytes differentiate into macrophages enter the site after neutrophils
-remove microbes by phagocytosis and release inflamm. meds. like reactive oxygen species, lipid mediators and cytokines which can regulate inflamm. response and produce their own inflamm. mediators
-Macrophages can also present antigens to lymphocytes |
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Term
| What do inflamm. mediators do? |
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Definition
-regulate the inflamm response.
-will directly modulate 1 of 5 cardinal signs
-follow Henry Dale's criteria for a chemical mediator
-synergistic and inhibitory interactions, positive and negative feedback pathways/cascades
changes in the cellular and mediator composition of the inflamm lesion |
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Term
| What are the physiological processes and mediators involved in causing redness and heat? |
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Definition
-Increased blood flow, increased local metabolism, local haemorrhage
-Histamine, 5-hydroxytryptamine (5-HT), platelet activating factor (PAF), Bradykinin, Nitric oxide, PGI2, PGE2 |
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Term
| What are physiological processes and mediators of swelling |
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Definition
-increases vascular permeability, exudates and cell infiltration
-anaphylatoxins C3a C5a, LTB4, TNFa, IL-1, VEGF, PGE2, PAF, Bradykinin |
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Term
| What are the physiological processes of pain and what are the mediators? |
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Definition
-Sensory Neuron firing, PNS windup
-Subtance p, calcitonin, gene-related-peptide (CGRP), bradykinin, hear, protons, prostaglandins |
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Term
| What are the physiological processes of 'Loss of Function' and what are the mediators? |
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Definition
Dysfunction, destruction of parenchyma and stroma tissue
-Lipases, proteases, free radicals, bradykinin, LTD4, LTC4, histamine |
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Term
| What kinds of histamine receptor are there and how is histamine stimulated? |
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Definition
H1-4, H1 is the main target of anti-histamines
-released by mast cells or basophils or by a variety of stimuli
-IgE cross linking
-anaphylatoxins C5a & C3a
-morphine
-Substance P, VIP
-Tubocurarine |
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Term
| How is histamine metabolised? |
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Definition
Oxidation, by Diamine oxidase
N-methylation by N-methyltransferase
Acetylation by gut flora |
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Term
| What are H1 antagonists used for? |
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Definition
-drugs crossing blood brain barrier: diphenhydramine, chlopheniramine
Purpose: sedation, tratement of motion sickness, Allergies (e.g. hayfever) but not preferred because of drowsiness
drugs not entering CNS: ranitidine
Purpose: Surpression of gastric secretion leads to healing of duodenal ulcers |
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Term
| How do antihistamine's work and what are their main targets |
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Definition
Insect bites, Allergic rhinitis, drug hypersensitivity, urticaria
-immediate or anaphylactic hypersensitivity
-Cross CNS causing dizziness, tinnitus and fatigue
-new h1 antihistamines do not cross CNS: astemizole, terfenadine, cetirizine |
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Term
| What causes peptic ulcers and how are they treated? |
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Definition
Ulcers are x4 more common in the duodenum than the stomach
-use of NSAIDS blocks function of cycloxegenase and increases risk of gastric ulcers
-H2 antagonists used to treat ulcers |
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Term
| How are kinins formed and what is their half-life? |
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Definition
Bradykinin and kallidin.
Kinins are formed from kininogens by enzymes (plasma and tissue kallikreins which split the active kinins from the precursors.
-metabolised by carboxypeptidase N and angiotensin converting enzyme
-20min half life |
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Term
| What are the function of kinins? |
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Definition
vasodilators, increase venular permeability
-cause pain
-contract smooth muscle
-actions mediated by B2 receptors but B1 receptors also used.
-some actions indirectly mediated by histamine or prostaglandin release
-Icatibant is a B2 antagonist |
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Term
| What is Arachidonic acid a precursor for? How are the subsequent fatty acids named? |
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Definition
eicosatetraeonic acid (ETE), Prostaglandin (PG), Thromboxane (TX), Leukotriene, Hydroxyeicosatetraeonic acid (HETE) Hydroperoxy ETE (HPETE)
-the letter following the prefix denotes what stage of metabolic process
-number indicates parent fatty acid |
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Term
| How are Prostaglandins made and what is their structure? |
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Definition
Involves two enzymes from arachidonic acid to prostanoid cyclooxygenase (Prostaglandin H syntase) and the relevant synthase
-20 carbon molecules with an OH group at C15 which is essential for activity.
-Very potent at low nanomolar-high picomolar levels
-rapidly metabolised |
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Term
| What are the receptors for prostanoids? |
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Definition
-Lack of selective antagonists makes classification difficult
-Agonist activity used for classification
-All are GPCR |
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Term
| What are the Prostanoid inflamm mediators? |
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Definition
-Prostaglandin E2
-Prostaglandin I2
-Prostaglandin D2
-Thromboxane A2
-Prostaglandin F2a |
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Term
| What do the 4 types of PGE2 do? |
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Definition
EP1-contraction of bronchial and GI smooth muscle
EP2-Bronchodilation, vasodilation (mainly in arterioles) stimulation of intestinal fluid secretion and GI smooth muscle contraction
EP3-COntraction of Gi smooth muscle, inhibits GI acid section, inhibition of lypolysis, inhibition of autonomic NT release, contraction of pregnant uterus
EP4-Contraction of bronchial and vasodilation |
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Term
what do
a) IP receptors do
b)DP receptors
c)TP receptors
d)FP receptors do |
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Definition
a) PGI2-vasodilation, inhib platelet aggregation, renin release
b) PGD2-Vasodilation, ",Relax GI and uterine muscle
c) Bronchoconstrictor with PGD2, vasoconstriction, platelet aggregation with TXA2
d)PGF2-Myometrium contraction (midlayer of uterine wall) |
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Term
| What are the vascular effects of prostaglandins? |
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Definition
| PGE2 is a vasodilator of arterioles.It produces little increase in vascular (postcapillay vanules) permeability but promotes increases in permeability produced by other agents eg histamine by increasing flow into permeabilized vessel |
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Term
| What are the leukocyte effects of PGs? |
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Definition
PGE2 can also inhibit monocyte activation and suppress T cell activation. PGD2 appears to be an important regulator of (T helper) TH2 lymphocytes.
The leukotriennes, particularly LTB4 cause leukocyte chemotaxis and represent important targets in asthma |
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Term
| How are PGs produced in Fever? |
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Definition
| -hypothalamus produces PGE2 in response to interleukin 1 which is generated by bacteria interact with leucocytes |
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Term
| Where do bacteria act to cause temperature rise in fever? |
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Definition
-PGE2 into ventricles causes temperature to rise when bacteria are injected
-Injecting PGE2 into ant hypothalamus causes temp to rise
-no other PG active
-PGE mediates rise in temp in response to pyrogens in circulation |
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Term
| What role do PGs play in pain? |
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Definition
| PGE2 causes the sensitization of sensory neurones, enhancing the generator current (eg via TRPV1) and increasing the likelihood of the neuron eliciting an action potential |
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Term
| What effects do Non steroidal anti inflammatory drugs (NSAIDS) have? |
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Definition
-ANalgesic
-Anti-inflammatory
-Anti-pyretic (stop temp increase by over-riding an interleukin based increase in temp controlled by hypothalamus) |
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Term
| What is the mechanism of NSAID action and how has it changed over the years? |
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Definition
-Inhibit COX.
-COX-1 is a constituitive enzyme (produced constantly by the cell
-COX-2 is induced at site of inflammation
-Most old NSAIDS are unselevtive for COX 1/2 or act mainly on COX1
-NSAID toxicity thought to be assc. with COX1 inhib., COX2 does appear to have a protective role in the CV system
-Newer NSAIDS may have reduced toxicity on GI tract but CV side effects are a prob |
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Term
| What are the anti-pyretic effects of NSAIDs? |
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Definition
Exogenous pyrogens eg bacteria are engulfed by macrophages
-macrophages make endogenous pyrogen (IL-1, TBFa)
-endogenous pyrogen causes PGE2 formation in hypothalamus
PGE resets the body's thermostat in the hypothalamus to a higher level
-Inhib, by NSAIDS, of PGE2 formation in the hypothalamus causes the thermostat to be set back to normal level |
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Term
| What are the analgesic actions of NSAIDs? |
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Definition
-At the site of inflamm, PGE2 is formed
-PGE2 sensitizes sensory nerves, lowering pain threshold
-pain is increased
-NSAIDS reduce PGE2 formation, reducing the sensory neuronal sensitization and lowering pain.
There is also an effect on the CNS |
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Term
| What anti-inflammatory actions do NSAIDs have? |
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Definition
PGE2, PGD2 and PGI2 are all vasodilators and promote oedema formation- the heat, redness and swelling of inflammation
NSAIDS inhibit the formation of these prostanoids and reduce the heat, redness and oedema of inflammation |
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Term
| What are the main toxic effects of NSAIDs? |
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Definition
-particularly those that act on COX-2-damage to upper GI tract
-PGE2 from COX-1 in the stomach inhibits gastric acid secretion and promotes protective mucus formation and bicarbonates release
-Inhib. of COX1 increases acid secretion and reduces mucus and bicarb.
-mucosa ulcerates and bleeds
COX-2 selective drugs cause less intestinal damage |
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Term
| What are the effects of asprin on the GI tract? |
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Definition
-In a 7 year period, aspirin caused 40 deaths from GI haemorrhage
-One asprin tablet increases GI bloodloss from 2ml to 12ml per day due to ulceration and bleeding
-Annual bloodloss caused by asprin is 20,000 gallons |
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Term
| What is the naturally occuring glucocorticoid, what are sythenic alternatives and what do they do? |
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Definition
naturally occuring=hydrocortisone. It has roughly equal potency as an antiinflammatory and a mineral corticoid.
-Synthetic compounds offer a)improved potency and b)greater selectivity for anti-inflamm action over mineral corticoid action (action on salt and water balance)
e.g. prednisolene, betamethasone |
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Term
| What is the inflamm actions do Glucocorticoids suppress? |
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Definition
a0anti-inflamm and b)immunosuppressive. Supress early events on inflammation- vasodilation, oedema, leucocyte infiltration and activation
later events of inflammation are also suppressed-cell proliferation, macrophage activity, fibroblast activity, angiogenesis |
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Term
| What do glucocorticoids suppress the production of? |
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Definition
| Some of the anti-inflamm effects are caused by suppression of the production of autocoids (mediators of inflamm) e.g. PGs, LTs TX PAF. Histamine release from basophils is also inhibited |
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Term
| How do glucocorticoids get in to and administer their effects on the cell? |
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Definition
| Glucocorticoids are lipid soluble so easily cross the cell membrane. Here, they bind the glucocorticoid receptor (gr). This results in the loss of hsp complex revealing a translocation and DNA binding region on GR. The receptor enters the nucleus |
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Term
| What are the effects of activated GR on the cell nucleus? |
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Definition
1.binds glucocorticoid regulatory element (GRE) and activates gene transcription of anti-inflammatory proteins eg Lipocortin-1 (calcium regulated annexin IkB
2. Binds GRE which negatively regulate pro-inflammatory gene transcription eg IL-1
3. Transrepression of NFkB at DNA
4. Direct bind of soluble transcription factors or transactivators. |
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Term
| What is the time scale for anti-inflammatory steroids? |
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Definition
| synthesis of new protein or the suppression of protein synopsis are not immediate effects, the anti-inflamm effects of steroids do not manifest for several hours |
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Term
| What COX and lip oxygenate products do anti inflamm steroids reduce? |
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Definition
Reduced COX products: PGE2 PGF2a PGI2 and PGD2 results in reduced oedema, reduced blood flow and reduced pain at site of inflamm
Red. Lipoxygenase products:LTB4 LTC4 LTD4 results in reduced leucocyte infiltration, reduced bronchoconstriction, oedema blood flow and pain |
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Term
| Reduction of the expression of COX2, NOs, adhesion molecules and some cytokines results in: |
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Definition
Reduced cyclooxygenase products
Reduced blood flow
Reduced cellular infiltration (adhesion molecules IL5 IL8)
Reduced pro-inflammatory effects of cytokines IL1 and TNF |
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Term
| What is TNF and what is its function |
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Definition
TNF a is a cut okie (trimmer made up of about 3x 17k. da peptide) which is a key regulatory in the inflammatory response
In particular it is associated with chronic inflammatory diseases |
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Term
| What are the effects of TNF a? |
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Definition
Induces fever
Stimulates acute phase protein release
Cytotoxic/cytostatic for cells
Activates granulocytes and macrophages
Promotes bone resorption by osteoclasts
Inhibits collagen synthesis and promotes breakdown
Induces cytokines synthesis
Promotes fibroblast proliferation
Activates endothelial cells
Promotes angiogenesis |
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Term
| What is the mode of Action against TNF? |
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Definition
Preventing it from binding to its receptor
Humanised TNF antibodies - infliximab, cdp571, adalimumab, |
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