Hannah's attempts Flashcards

Question

What cytokines regulate fibroblasts?

Answer 1

* PDGF - platelet derived growth factor, enhances cell proliferation and chemotaxis * FGF - fibroblast growth factor, enhances proliferation * TGFβ - transforming growth factor beta, promotes fibroblast proliferation and collagen deposition

Answer 2

* Small proteins (5-20kDa) that are important in cell signalling * Alter the behaviour of cells in an autocrine, paracrine or systemic manner, and have important effects on the immune response * Include: * Chemokines - induce directed chemotaxis * Interferons - released in response to virus, induce and enhance anti-viral properties in target cells * Lymphokines - produced by lymphocytes (typically T cells), helps to coordinate the immune system * Monokines - mainly produced by monocytes and macrophages, act as chemoattractants for leukocyte recruitment * Tumour necrosis factor - plays a role in cell survival, proliferation, differentiation and death * These are not hormones and are generally considered to be different to growth factors * Act through receptors and are very important in immune responses * Modulate the balance between the humoral and cell-based immune responses * Regulate the growth, maturation and responsiveness of target cell populations (e.g. immune cells) * Some will inhibit or enhance the action of other cytokines (cross-interactions)

Answer 3

* Transgenic mice defective in endogenous glucocorticoid synthesis (GR^dim mice) * These show increased mass of granulation tissue in early wounds (glucocorticoids have anti-inflammatory action, and their excess can prevent wound healing - lack of presence therefore causes mass production of tissue?) * CX3CL1 Fractalkaline and CX3CR1 KO mice * The former is a chemoattractant cytokine (chemokine) that recruits monocytes to the site of injury * The latter is the receptor through which the fractalkaline exerts its effects on monocytes and macrophages through (GPCR) * Has anti-apoptotic effects on monocytes and other cell types via CX3CR1 (Greaves, 2012) * Graph and data attached shows wound repair in WT and CX3CR1 KO mice (initial rate in wound closure is similar, but at approx day 3 there is a statistically significant difference in wound area reduction rate between the two strands) * **NB KO mice can be limited by the embryonic lethality of certain genes - newer technologies have allowed for more refined models, however**

Answer 4

* Expression of type I collagen taken at 0, 3 and 6 days * Expression in KO mice reduced at days 3 and six * Beta-actin was used as a control (cytoskeleton, therefore always present) * When mRNA saples taken, levels of type I collagen significantly lower at days 3 and 6 in the KO mice * This suggests the important role of the Fractalkaline receptor in cutaneous wound healing

Answer 5

* Mouse wounds heal by contraction as opposed to collagen deposition and remodelling/scar formation * No accepted models of scarring in mouse wounds, they either heal completely or fail to do so * No good models of keloid or non-healing wounds * Even if it was ethically appropriate to have these, which it arguably is not HOWEVER, diabetic mice have identified changes in cytokine production in cutaneous skin wound repair, which has been beneficial.

Answer 6

* Newts, salamanders and axolotls are all able to regenerate limbs after sterile amputation * Formation of blastema at site of amputation, with cells within being able to differentiate and reform the limb over time, replacing cells and reforming structures * Recapitulation of embryonic development occurs * The planarian (flat worm) can form neoblasts (non-differentiated cells) if the head or tail is amputated * Formation of a wound epidermis and blastema, resulting in the outgrowth of the structures * Zebrafish form a blastema and apical epithelial cap is a fin is cut off, from which it can then be regrown * Amphibians exhibit blastema that can restore structures of amputated limbs

Answer 7

* No inflammation in foetal wound repair * No adaptive immune response in utero * Foetal fibroblasts tend to secrete collagen III instead of collagen I * Altered TGF-beta production in embryos * This is an important cytokine in development and wound repair, but has altered production and possibly altered action in embryos * Foetal cells have greater proliferative capacity * Adult and late-gestational wounds heal with a scar, whereas early gestation embryos are remarkable for scar-free healing * Fibromodulin is essential for scar-free healing, and restoration of recombinant Fm in late-gestational rat embryos was shown to restore scar-free healing capabilities * In a mouse embryo, a limb was amputated in utero - healing process involved sheets of epithelial cells sweeping over the wound and resulting in the formation of no scar tissue

Answer 8

* Organisation and scarring * Failure of hepatic regeneration and fibrotic response to toxic insult * E.g. cirrhosis of the liver, causing hepatocytes to die and be replaced by fibroblasts * Results in islands of healthy, functional hepatocytes surrounded by scarring * Excessive fibrotic response to foreign bodies * E.g. silicosis - working with silica in the air and aerosols can result in the build-up of shadows on the lung, which are the result of massive swathes of fibrosis * Replacement of normal tissue with fibrous scar * E.g. folling ischaemia, seen in MIs as injury in the myocardium causes replacement with fibroblasts * Repeated injuries * Repeated head collisions resulting in traumatic brain injury * These build up over time to result in chronic trauma encephalopathy (CTE) * Classic signs of CTE can be seen in autopsy, reduction in brain tissue due to repeated inflammation/CNS injury * Continued ulceration * Venous and arterial ulcers

Answer 9

* An ulcer is an open sore caused by a break in the mucosal lining or skin that then fails to heal * This is a failure to restore normal function and develop due to a lack of ability to restore blood flow to the area/a lack of circulation * Poor blood flow can occur as a result of diabetes, atherosclerosis and vein/valve issues * When valves in the leg veins become damaged/are weak, there is a lack of blood flow back to the heart and accumulation of blood in the skin * These are varicose ulcers * Leg swelling and skin breakdown will result in formation of ulcers * This can cause leakage of blood from the veins into the skin * Diabetic ulcers are related to failures in arterial flow, causing ischaemic areas to develop and ulcers to form * Ulcers can also form as a result of pressure, which is often caused by prolonged immobility

Answer 10

* Their regeneration and presence is important for wound healing, and this is seen through: * VEGFR3 (vascular endothelial growth factor receptor 3)-expressing lymphatic vessels found in early granulation tissues, with regression in later stages * The ligand for VEGFR3 (VEGFC) increases in response to tissue injury * Wounds with impaired lymphatic systems are more susceptible to infection and a failure to heal properly * This is because a function of the lymphatic system is to remove debris from a site of infection - preventing this could increase bacterial colonisation and trap other growth factors/matrix proteins * Excessive oedema can also compress other vessels and limit blood flow, causing the area to become ischaemic * The lymphatic system is also closely linked to the immune response, and so is necessary to fight infection

Answer 11

* Blood clots form at sites of injury to prevent bleeding * This occurs within minutes or even seconds * They prevent further blood loss, which is obviously beneficial * Blood clots also seal off a potential entrance into the body for pathogens

Answer 12

* Vascular spasm/vasoconstrictin * This is a brief and intense contraction of blood vessels to limit blood flow through this vessel - and therefore blood loss - through drastically increasing the resistance * This is caused by thromboxane A₂, which is produced by activated platelets and injured epithelial cells, which causes the vascular smooth muscle to contract * This will also occur after direct injury to vascular smooth muscle and somewhat in the nervous system reflex to pain * This vasoconstriction is brief, due to the inflammatory processes that follow, including the release of vasoactive cytokines * Vasoconstriction should last until the fibrin plug is formed * Vasoconstriction and haemostasis end as wound healing begins * Formation of a platelet plug * Subendothelial collagen is exposed due to damaged epithelial cells, and releases von Willebrand Factor (vWF) * This causes platelets to form adhesive filaments which will bind to the subendothelial collagen on the damaged endothelial wall * Binding to the collagen activates the platelet, causing it to release a series of chemical mediated and cytokines (degranulation) * This includes: ADP, vWF (positive feedback), thromboxane A₂, VEGF, serotonin and coagulation factors * Platelets then aggregate into a barrier-like plug, as receptors on the platelets bind to vWF and fibrinogen molecules to hold platelets together * In small wounds, this mesh may be enough to prevent blood loss, but in larger wounds the coagulation cascade will also be needed, which strengthens this platelet plug * Coagulation * Series of reactions that are divided into three pathways: * Contact/intrinsic pathway, where a negatively charged particle initiates a cascade resulting in the formation of factor X * Tissue factor/extrinsic pathway, where tissue damage caulses the release of tissue factor, creating a smaller cascade to facilitate the formation of factor X * Common pathway, which merges both pathways in the production of thrombin from prothrombin due to the action of factor X * Vitamin K, calcium and phospholipids are necessary cofactors for this process * Production of thrombin then allows the cleavage of fibrinogen into fibrin, which forms the mesh that will adhese to and strengthen the platelet plug, therefore completing haemostasis

Answer 13

* Infection of the wound triggers the body's immune response * This causes tissue damage and inflammation, alongside slowing down the healing process * Prolonged inflammation in response to incomplete microbial clearance in an infected wound results in the prolonged elevation of inflammatory cytokines * This elongated inflammatory phase prevents the transition to a healing phase * Metalloproteases are also released as a result of inflammation, which degrade ECM * Bacteria are also likely to form biofilms, which will slow healing

Answer 14

* They **slow** wound repair * They are used as anti-inflammatories, which inhibit wound repair through global anti-inflammatory effects and suppression of cellular wound responses * This includes fibroblast proliferation and collagen synthesis * Systemic steroids cause wounds to heal with incomplete granulation tissue and reduced wound contraction

Answer 15

* Carbohydrate, energy, protein, fat, mineral and vitamin deficiency can all affect the healing process * Energy sources (especially glucose as can be respired in anaerobic conditions) allow the synthesis of cellular ATP, which is needed for angiogenesis and deposition of new tissue * Protein is needed for the synthesis of a number of components, with deficiency impairing angiogenesis, fibroblast proliferation, proteoglycan synthesis, collagen synthesis and wound remodelling * Co-factors of iron and vitamin C are also needed for collagen synthesis * Notable amino acids are arginine and glutamine * Vitamins C, A and E show potent anti-oxidant and anti-inflammatory properties * C and A deficiencies have also been shown to impair the wound healing process * Magnesium, copper and zinc are all cofactors for various enzymes that are necessary for wound healing, iron is needed in some processes * Mg in protein and collagen syntehsis * Cu in cytochrome oxidase, superoxide dismutase (anti-oxidant) and optimal cross-linking of collagen * Zn in RNA and DNA polymerase * Fe is needed in hydroxylation of proline and lysine, which is necessary for collagen production * Deficiency in vitamin K will also result in a failure of blood clotting * So would hypocalcaemia, in theory, but toxic effects on the heart become significant before this has a chance to occur in vivo

Answer 16

* Irradiated tissue will becoe hypoxic and fibroblasts will become dysfunction * This leads to increased wound healing complications * Radiation is more effective on dividing cells - as wound healing requires mass proliferation, radiation would therefore have an effect

Answer 17

* This is where the wound itself closes/the two edges of the wound draw together * Wound fibroblasts and myofibroblasts work together to draw the wound close * They then contribute to the synthesis, bundling and alignment of collagen fibres, which are the primary constituent of scar tissue, that will eventually replace granulation tissue

Answer 18

* This is essential for restoration of full functionality and a 'normal' appearance to the tissue * Migrating and proliferating keratinocytyes meet at the wound edge as it seals * They then stop and restratify (full mechanism yet to be elucidated) * Epidermal appendages (e.g. hair follicles and sebaceous glands) must also be regenerated, as these do not readily form in scar tissue * Thought to require re-enactment of the epidermal developmental program, of which Wnt signalling is essential * Dense, unorganised ECM deposited in would healing is remodelled and reorganised * Blood bessels also undergo refinement and maturation * Most myofibroblasts undergo apoptosis at this stage * Imperfect regulation of wound resolution can result in hyperproliferation and/or persistence of inflammatory reactions * These can result in fibrosis and excessive scar formation * Lasting scar formation is also particularly likely if the wound extends beyond the epidermis

Answer 19

* Therefore, if the inflammatory response is suppressed through treatment, it may result in the same suppression occurring in the processes for host defence and repair * [EXTRA] For example, COVID appears to give prolonged, residual and innappropriate inflammatory response, even long after the virus has been cleared * This may give rise to some of the damage seen in late stages of an acute infection, or the pathology (e.g. pericarditis) seen in long-term COVID infections

Answer 20

* Injury – inflammation is likely to be protective * Arthritis – inappropriate inflammatory response gives rise to tissue destruction * Infection and allergy – inflammation is likely to be protective * Psoriasis – inappropriate inflammatory response gives rise to tissue destruction * Heartburn * Peptic ulcer – acquired accumulation of innate inflammatory cells * Myocarditis * Nephritis * Spinal cord injury * Ulcerative colitis * Alzheimer’s – one of the archetypal features of Alzheimer’s is the activation of microglial cells (astrocytes) in the brain, leading to inflammation and contributing to the disease * Asthma – treatment is to relieve inflammation

Answer 21

* PU1 KO mice have no macrophages * Experiments on them found that a lack of macrophages had no effect on wound healing * This highlights that maybe too much emphasis is placed on the contribution of inflammation to wound repair * However, if the immune system is impaired in any way, susceptibility to infection is largely increased * AIDS sufferers experience persistent infection and even the development of cancer * Chronic granulomatous disease (CGD) leads to defective respiratory bursts by neutrophils, which, if left untreated, will result in the individuals succumbing to infection

Answer 22

* Increased blood flow, causing: * Calor (increased temperature, increased local vasodilation) * Rubor (redness as more blood) * Tumour (swelling, small amount of tissue oedema) * Dolor (pain, due to cytokines) * Loss of function (usually from swelling and tissue oedema)

Answer 23

* Features differ between different tissues * There is a unique molecular profile of inflammation that will differ between different lesions in different locations * There is no dominant signal * Signals within particular lesions also change over time * This makes inflammaion difficult to target with one therapeutical treatment throughout the entirety of the pathology * [EXTRA] For example, anti-TNF therapy is useful to treat IBD and RA, but exacerbates MS

Answer 24

* LHS image shows inflamed lung, animal was sensitised to an antigen and then exposed * Excessive inflammatory response then occurs, causing the alterations in the tissue * RHS image shows response of the tissues to injection with IL-1β, in red circles * Spinal cord has a different response to the cytokine, as here it causes blood-spinal cord barrier breakdown and the infiltration of leukocytes, as seen by the large stained/brown region * In the brain, there is very little BBB breakdown or recruitment of leukocytes

Answer 25

* Upon entry, there is local tissue damage * This activates complement systems (C5a and C3a, targeting mast cells) and generation of bradykinin (through the production of kinins from precursor molecules within the tissue) * Pathogens may be introduced on the end of the thorn, which will bind to TLRs present of macrophages and other immune surveilling cells * Depending on what the damage is, different responses will occur (see diagram) * Initial responses are shown in pink on the diagram, downstream a series of responses will kick off very rapidly and via many different pathways, as shown in blue * Effects spread to local neurons, which contribute to local inflammation through release of substance P (acts on mast cells) and CGRP * Cytokines interact with fibroblasts, which will rapidly change their shape and start proliferating to aid repair * These will release proteases to remodel the extracellular matrix (metalloproteinases, MMPs) * Immature (type III) collagen is secreted initially and eventually replaced with type I collagen to reform the ECM * Recruitment of leukocytes occurs through cytokines acting on local endothelial cells

Answer 26

* This is thought to be due to the chemical cocktail of chemokines released at each location by macrophages, and possibly by endothelial cells * There is a suggestion that there is a chemokine/leukocyte-attractant gradient, with high levels surrounding the macrophages * Chemokines are then translocated from the abluminal to the luminal surface of endothelial cells, where they are then presented to select leukocyte populations * This selection of leukocyte populations has been shown to occur, but the presence of a gradient has been more difficult to identify due to hepatic control

Answer 27

* After tissue injury, there is both a local and a peripheral response * Signals are transported to the Kupffer cells of the liver, which response by activating NF-κB and upregulating the production of acute phase proteins * These are responsible for the mobilisation of leukocytes from bone marrow into the circulation * The acute phase response then regulates the systemic response to the tissue injury or disease * [Circulating chemokines eliminate any evidence of a concentration gradient, as their concentration will be higher in the circulation as opposed to the injured tissue]

Answer 28

Inflammation can result in a number of effects, including: * Mood * Sleep patterns * Eating habits Alongside local production of inflammatory mediators, there are peripheral changes (e.g. in the liver, spleen and lungs) as well as de novo synthesis of cytokines in the brain

Answer 29

* This includes cytokines such as IL-1 * They are able to alter neuronal function and change behaviour * Inflammatory disease/injury is associated with downstream changes in the CNS, which affects neurotransmitter release * Cytokines expressed in the brain have a completely different function to that which they have in the periphery * They have evolved to have other functions in the brain as if they carried out the same processes, it would be destructive on the neuronal tissue, which has low regenerative ability

Answer 30

* Prostaglandins * Leukotrienes * Derivatives of ceramide

Answer 31

* Through the action of phospholipase A₂ isoforms * These are activated by many different mechanisms * Enzyme is recruited to the cell surface by calcium-dependent translocation of its C2 domain * The enzyme is then able to act on membrane phospholipids * [Administration of glucocorticoids targets this translocation, causing the dissociation of heat-shock proteins from the receptors and therefore inhibiting its action] * Diagram attached shows different functions of PLA₂ isoforms

Answer 32

The wide range of products generated means that derivatives can be pro- or anti-inflammatory

Answer 33

* These enzymes synthesise prostanoids, which are pro-inflammatory mediators * They convert arachidonic acid into PGG₂, and then PGH₂ * This is achieved through the enzyme complexes having both cyclooxygenase and peroxidase activity * From here, specific synthases can then generate thromboxanes, prostaglandins, prostacyclins, PGI₂ and PGE₂

Answer 34

A subclass of eicosanoids that contain thromboxanes (mediators of vasoconstriction), prostaglandins (mediators of inflammation and anaphylaxis) and prostacyclins (active during the resolution phase of inflammation)

Answer 35

* It is the principal pro-inflammatory prostanoid * Synergises with other inflammatory mediators to augment the perception of pain

Answer 36

* COX-1 * Constitutive * COX-2 * Inducible and generally associated with inflammation

Answer 37

* Non-steroidal anti-inflammatory drugs, such as aspirin * These drugs work through inhibiting the action of cyclooxygenase * Aspirin specifically binds to acetyate cyclooxygenase and alters its function, but is not irreversibly bound

Answer 38

* Binds to acetylate cyclooxygenase to alter its function, but is not irreversibly bound * Is generally non-selective, but appears to be weakly more selective for COX-1, which produces pro-inflammatory molecules * This means it weakly selects against COX-2, which produces anti-inflammatory molecules and is therefore beneficial to the action of NSAIDs * Aspirin is anti-inflammatory and has a positive effect on the vasculature (so may be protective against heart attacks?)

Answer 39

* If taken orally and not enterically coated, will inhibit COX-1 action in the stomach and prevent prostaglandin synthesis * Prostaglandins help to protect the stomach lining and maintain the mucosal barrier to protect the tissue from damage by the acidic contents of the organ * Inhibition of production therefore leads to damage of the stomach lining and the formation of gastric ulcers, which can subsequently lead to gastroenteric bleeding and haemorrhage if severe

Answer 40

* NSAIDs cannot cure or slow the progression of the disease but are able to alleviate symptoms * Through inhibition of COX-1 and COX-2, the production of prostaglandins and other inflammatory mediators is greatly lessened, causing a decrease in swelling, fever and inflammation * This should hopefully reduce pain and allow some function to be retained

Answer 41

Paracetamol is classified as an analgesic only, NOT anti-inflammatory. It inhibits a specific COX (thought to be only in the CNS) with analgesic and antipyretic (reduces fever) effects only. Paracetamol will not reduce the underlying inflammatory processes in rheumatoid arthritis.

Answer 42

* Prostanoids (prostaglandins, prostacyclins and thromboxanes) * Leukotrienes

Answer 43

* Converted by 5'-lipoxygenase * This produces LTB₄, which is then converted into LTC₄, LTD₄or LTE₄ by P450 enzyme * LTB₄ is a potent neutrophil chemoattractant * Choice in conversion depends on which cell type the reaction occurs in * This pathway is targeted in the treatment of asthma (alongside treatment using glucocorticoids/steroids), as the derivatives of LTB₄ cause potent bronchoconstriction in asthmatic attacks

Answer 44

* Released from mast cells, increases blood vessel permeability and dilatation * Both involved in local immune response and able to act as a neurotransmitter

Answer 45

* Synthesised by decarboxylation of histidine * Release in periphery is from mast cells and is stimulated by the release of IgE antibodies responding to foreign antigens in the body * Mast cells may also release histamine due to neurogenic inflammation, marked by the release of CGRP and substance P from terminal axons of C fibres * The release mechanism is modulated through phospholipase C, which generates IP3 and DAG to then activate protein kinase C * This causes the granules to become swollen and the contents to be released into the environment

Answer 46

* In the periphery, either stored in mast cells or inactivated by diamine oxidase (notably so during the inflammatory response) * In the CNS, inactivation is carried out by histamine-N-methyltransferase * However this is a cytosolic enzyme, and it is not yet confirmed how histamine reaches the enzyme for degredation after being released into the synapse

Answer 47

* H1 histamine receptor * Found on smooth muscle, endothelium, and CNS tissue * Activation results in vasodilation, bronchoconstriction, smooth muscle activation, and separation of endothelial cells (to increase vascular leakage) * H2 histamine receptor * Found on parietal cells * Regulates gastric acid secretion * If targeting H2 receptors, blocking them is a very effective way of reducing gastric acid secretion * H3 histamine receptor * Found in CNS * Regulates the release of other neurotransmitters * H4 histamine receptor * Found in the CNS * Recently discovered in different parts of the body including organs of the digestive tract, basophils, and bone marrow cells

Answer 48

* Sensitisation: initial interaction between the host and the allergen * Early phase reaction: occurs within minutes of exposure to the allergen and lasts for 30-90 minutes * Histamine release occurs during this phase, but is often only short-lived (as is seen in asthma) * Leukotrienes quickly become dominant if the allergen is quickly removed, so targeting histamines is not overly effective in treating asthma * Targeting histamine is effective when treating allergens present in the environment, however * Late phase reaction: begins 4-8 hours after sensitisation and can last for several days, may lead to chronic inflammatory disease * Treatment with anti-histamines are far less effective in this case

Answer 49

* Small, lipophilic molecules that can cross the BBB * This causes them to also block histamine receptors in the brain that are associated with arousal, therefore causing drowsiness * Not specific to the H1 receptor * Often inverse agonists and suppress beyond the natural action of histamine at the receptors * Groups include: * Ethylenediamines * Ethanolamines * Alkylamines - **e.g. chlorphenamine (on spec)** * Piperazines * Tricyclics

Answer 50

H1 receptors

Answer 51

* Increases vascular permeability and subsequently causes vasodilation * Involved in the acute phase of inflammation * Mediator of itching

Answer 52

* Modifications were made to first generation to eliminate the side effects (e.g. drowsiness) * They are more selective for peripheral H1 receptors, therefore unlikely to cross the BBB and cause side effects * Examples include (none on spec) * Terfenadine * Loratadine * Cetirizine * Mizolastine * Astemizole * Fexofenadine

Answer 53

* Metabolite derivatives or active enantiomers of existing drugs * Safer, faster acting or more potent than second generation * Examples: * Desloratadine * Levocetirizine/Xyzal * Less sedating

Answer 54

* First generation antihistamine * Brand name: Piriton * Relieves symptoms of continuous allergic reactions, such as hay fever, or itching * Able to cross BBB, so causes drowsiness * This type of drug can be used to manage/prophylactically treat asthma, but is not useful in asthmatic attacks

Answer 55

* Molecule generated in any inflammatory response and helps to drive inflammation * Also provokes neurogenic inflammation * Produced in tissue through actions of pro-kallikrein * Converts low molecular weight kininogen (LMWK) into Lys-bradykinin * Excess lysine residue is then cleaved to form bradykinin * In plasma, plasma kallikrein converts high molecular weight kininogen (HMWK) into bradykinin * B1 or B2 receptors, present in both central and peripheral tissue * Different response in CNS than in periphery, no vascular effects * Important mediator of pain in the periphery, also brings about tissue oedema * Poor pharmacological target

Answer 56

* TLR agonists can be used to promote clearance of tumours and potentially of pathogens, in an attempt to alter the natural response * Test subjects were given a CD28 super-co-stimulator/super-agonist * Essentially provided a potent stimulatory signal to T cells * This caused a profound peripheral inflammatory response, resulting in multi-organ failure and for the test subjects to become critically ill * This trial changed the method by which future methods were carried out * Initial injection in trial study is only given to a single patient at one time to prevent the entire cohort from being exposed to any negative unforseen side effects * In study described above, all 6 test subjects given the injection within a short time frame

Answer 57

* Macrophages secrete plasminogen activators, collagenases (aka MMPs) and elastases, these are downstream of cytokine activation. * Have potential to be targeted in the future as an anti-inflammatory drug target

Answer 58

* IL-1 and TNF * These are secreted by activated macrophages * They are present near the beginning of the inflammatory cascade, therefore are good targets

Answer 59

On LHS spec: * Anti-TNF antibodies, e.g. adalimumab, golimumab, infliximab * Anti-IL-6 (receptor) antibodies, e.g. tocilizumab (anti-IL-6R) On RHS spec: [EXTRA] * Rituximab (Rituxan) - Anti-CD20, monoclonal antibody that is able to deplete B cells * Abatacept (Orencia) - Binds to B7 protein on antigen presenting cells, CTLA-4 fusion protein, blocks activity of T cells

Answer 60

* Very high specificity * Therefore are able to target and initiate the destruction of particular targets throughout the body * But due to this and high molecular weight, often not cleared as quickly so therefore have the potency to remove the target entirely * Suppressing the inflammatory response and immune system will result in the relief of symptoms and potentially slow/halt the progression of the disease, as it is autoimmune * Suppressing the immune system will have other consequences, however

Answer 61

* IL-1 is expressed in the CNS, and is a potential target for treating inflammation alongside being important in the perception of pain, as is shown on the graphs * If IL-1 is knocked out, the hind paw withdraw threshold is dramatically increased, meaning that the animal is significantly desensitised to pain * If the accessory protein is knocked out (it is essential for IL-1 signalling), the same effect is seen * If IL-1RA is overexpressed (the endogenous IL-1 antagonist), the increase in hind paw withdrawal threshold is again seen * These IL-1RA is analogous to anakinra (non-glycosylated IL-1RA), so giving the drug may also have an effect on pain, alongside the anti-inflammatory effects

Answer 62

* ANAKINRA (IL-1 receptor antagonist) for the treatment of RA, which has not responded to methotrexate alone * LUTIKIZUMAB (anti-IL-1alpha and anti-IL-1beta), dual variable domain immunoglobulin * CANAKINUMAB (anti-IL-1beta) sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis (SJIA) and active Still’s disease * Still’s disease is very rare in the UK but is associated with a cytokine storm due to an over-production of IL-1β

Answer 63

* ADALIMUMAB (humanised anti-TNF monoclonal antibody) for RA and IBD * Also progressive psoriatic arthritis and severe active ankylosing spondylitis that have not responded adequately to other disease-modifying anti-rheumatic drugs (DMARDs) * INFLIXIMAB (chimeric anti-TNF-alpha monoclonal antibody) has become a standard therapy for Crohn’s disease (CD) and is also likely to be beneficial for ulcerative colitis (UC), and RA. * ETANERCEPT (soluble TNF receptors) approved to treat rheumatoid arthritis (RA), psoriasis, ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis * Xpro1595 (dominant negative TNF)

Answer 64

The endogenous anti-inflammatory agent present to suppress inappropriate inflammation within the body. Inhibition is reduced by: * Reduced (pro-inflammatory) gene transcription * Reduced activity of neutrophils and macrophages * Decreased proliferation of T cells * Decreased production of prostanoids, cytokines and histamine

Answer 65

Wound repair and healing is inhibited

Answer 66

IL-1β (part of the inflammatory response) upregulates this through increasing circulating levels of ACTH Experimental evidence [EXTRA]: * Giving human recombinant IL-1β to a mouse orally results in increased serum ACTH and therefore increased glucocorticoids * If human IL-1 iven to mice, ACTH and glucocorticosteroid levels again increase * Glucocorticoid levels are decreased by an antibody to IL-1 * This is needed in cases of infection with Newcastle disease virus, where glucocorticoid levels are increased in resposne to factors released by human leukocytes

Answer 67

Both mineralocorticoid and glucocorticoid receptors, but binds to the former at a far lower concentration - this causes them to be referred to as the high and low affinity receptors respectively.

Answer 68

Through a circadian rhythm. If this is disturbed - for example, through illness or therapeutics - the amplitude of this rhythm can change, causing a number of other effects (including anti-inflammatory)

Answer 69

* Modulate protein synthesis (receptors are nuclear receptors, affecting gene expression) * Result in the reduced activity of PLA₂ * This reduces the synthesis of prostaglandins, leukotrienes and platelet activating factor * This enables steroids to have systemic effects in reducing inflammation * Glucocorticoid receptor: Nuclear receptor that will result in anti-inflammatory changes * Mineralocorticoid receptor: Nuclear receptor that will result in changes in electrolyte and fluid balance (similar effect to aldosterone)

Answer 70

* Steroids have a huge range of negative side effects, including the development of Cushing's disease * Therefore it is necessary to develop other treatments or give patients 'steroid holidays'

Answer 71

Steroid inhalers: contain glucocorticoids * Largely effective, useful for treating type 2 asthma (most effective here)

Answer 72

* Type 2 asthma is a response to allergens involving a large number of eosinophils, with IL-4 and IL-5 dominating * Steroids are highly effective * Non-type 2 asthma is more common in older people * Pattern of disease is very different, involving neutrophils and Th17 cells * Become very steroid-insensitive

Answer 73

* Immune depression increases susceptibility to viral infection * Hypertension can occur through effects on fluid and electrolyte balance * Has mineralocorticoid action (can mimic aldosterone) * Suppression of vasodilatory systems, activation of the RAAS, intrinsic mineralocorticoid activity, enhancement of vasoactive substances * Bone resorption * Diabetes * Cushing's * Peptic ulcers * Effects on the skin

Answer 74

Dexamethasone * Widely used corticosteroid with anti-inflammatory and immunosuppressant actions * Has been found to help critically ill COVID19 patients [EXTRA] * Able to bind to glucocorticoid or mineralocorticoid receptors * Used to treat certain forms of arthritis, intestinal disorders (e.g. colitis), severe allergies and asthma

Answer 75

* Disease-modifying anti-rheumatic drugs * Depress the immune response over time * Full effect will take several months * Includes immunosuppressants * E.g. anti-metabolites that depress the production of immune cells

Hannah's attempts Flashcards

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