Inflammation Flashcards

Question

Other Integrins involved in Leukocyte Extravasation:

Answer 1

Other Integrins involved in Leukocyte Extravasation: a4b1 expressed on eosinophils, monocytes, T cells Binds vascular cell adhesion molecule VCAM-1 similar molecule to ICAM VCAM-1 Induced by cytokines

Answer 2

Transmigration: - Usually paracellular (i.e. between endothelial cells at cell-cell junctions) - Can also cross through endothelial cells (i.e. transcellular) - Mediated by the complex interaction between CAMs, integrins, junctional proteins and other endothelial cell molecules eg. PECAM-1, JAMs - Chemoattractants direct migration

Answer 3

Matric Metalloproteinases in Transmigration: Zinc binding metalloproteinases degrade extracellular matrix. - Promotes migration through cellular tight junctions - Also modulate expression of adhesion molecules and chemokines

Answer 4

Chemotaxis & Chemoattractants: The process by which cells move directionally in response to a chemical gradient. Signalling molecules that guide the movement of cells.

Answer 5

Molecules that specifically induce chemotaxis Often from the site of inflammation Vary in the cell types they attract Non-selective - C3a, C5a, LTB4 Selective - chemokines

Answer 6

Chemotactic cytokines Structurally defined group of chemotaxins Produced in response to IL-1, TNF, bacteria G-protein coupled receptors (unlike most cytokines) Originally named according to their function Systematic names according to chemokine structure

Answer 7

CXC Chemokines - mainly neutrophil & T cell attractants CC Chemokines – Not neutrophil attractants

Answer 8

Chemokine receptors Bind to chemokines 20 different types 7 transmembrane structure that couples to G-protein for signal transduction 4 different families CXC, CC, CX3C and XC

Answer 9

Cells migrate at different rates Neutrophil associated with acute inflammation Monocytes, lymphocytes associated with chronic inflammation

Answer 10

Selectivity in inflammatory response-tissue: Different selectin and CAM expression Different chemokine expression

Answer 11

Selectivity in the Inflammatory Response – Leukocytes: Express different integrins Express different chemokine receptors

Answer 12

Adhesion molecules & chemokine receptors in disease: Leukocyte adhesion deficiency is caused by a defect in adhesion molecule expression HIV uses CXCR4 and CCR5 chemokine receptors to enter T-cells

Answer 13

- Reduce inflammation and swelling - Also reduce pain (by preventing inflammation) - Reduce pain by preventing inflammation, not action on the CNS - Histamine also induces wakefulness, meaning anti-histamines may cause drowsiness. - Newer drugs are not lipophilic, making access to the brain harder, reducing drowsiness.

Answer 14

Block H1 receptors Anti-histamines Used for allergies, conjunctivitis, reactions to insect bites Chlorpheniramine (chlorphenamine, ‘Piriton’) Cetirizine Loratadine (Clarityn) Fexofenadine (Allegra) Promethazine

Answer 15

Cyclooxygenase triggers production of prostaglandin H2, which acts in inflammatory response. Aspirin targets Cyclooxygenase to prevent this. Cyclooxygenase exists in two isoforms (encoded by separate genes): COX-1 Constitutive “Housekeeping enzyme” products important in normal function of stomach, intestine, kidney and platelets COX-2 Induced: especially during inflammation

Answer 16

- Arachidonic acid causes COX 1 perform homeostatic functions & 2 to induce a variety of cytokines & growth factors used in inflammation. Due to this, it is attempted to inhibit only COX 2 to limit only inflammation. - Arachidonic acid enter catalytic site, causing PGH2 to be produced. - Aspirin binds to catalytic site, preventing Arachidonic acid from binding to the site. This is irreversible, meaning a new enzyme must be synthesized. - This also results in free salicylic acid, which also has anti-inflammatory effects.

Answer 17

Ibuprofen can act in the catalytic site of COX 1 and 2, whilst celecoxib cannot fit into COX 1, hence it only bins to COX 2. This results in Ibuprofen causing digestive issues, whilst celecoxib does not. However, more Cox 1 selectivity increases the risk of GI risk, whilst more Cox 2 selectivity increases the risk of Cardiovascular issues.

Answer 18

1. Gastric irritation : PGE2 involved in inhibition of gastric acid secretion, increased gastric mucus production 2. Bleeding: TXA2 involved in platelet aggregation & vasoconstriction 3. Renal toxicity: PGEs involved in regulating kidney blood flow, direct damage to renal papillae, kidney inflammation

Answer 19

Normal TxA2 from the platelets PGI2 from vessel wall endothelium BALANCE – controlled thrombus formation Aspirin-treated COX is inactivated by low-dose aspirin Platelet COX-1 inactivated for the life of the platelet (week) – no TxA2 Blood vessel COX rapidly resynthesized (hours) PGI2 levels maintained Decreased thrombus formation

Answer 20

Suppress T cell activation and cytokine production Suppress mast cell degranulation Decrease capillary permeability indirectly by inhibiting mast cells and basophils Alter phospholipase A2 activity and reduce prostaglandin and leukotrienes synthesis eg. hydrocortisone, prednisolone, dexamethasone For treatment of asthma, arthritis etc.

Answer 21

Glucocorticoids bind to glucocorticoid receptors Complex migrates to cell nucleus Influences gene transcription Increase or decrease transcription Decrease transcription of pro-inflammatory molecules eg. COX-2 Increase transcription of anti-inflammatory genes eg. lipocortin

Answer 22

Blocking the enzyme prevents all leukotrienes forming, but blocking a receptor will block only a specific leukotriene. Leukotrienes are the cause mast cell induced bronchoconstriction in asthma. By targeting their receptor antagonists, it is possible to prevent an asthma attack.

Answer 23

Blocking the enzyme prevents all leukotrienes forming, but blocking a receptor will block only a specific leukotriene. Glucocorticoids can inhibit arachidonic acid synthesis, preventing prostaglandin production. Zileution acts on Lipoxygenase, preventing leukotrienes formation, preventing them inducing inflammation. Zafirlukast montelukast acts as a leukotriene receptor antagonist, resulting in a decrease in inflammation.

Answer 24

Cizanlizumab anti-P-selectin sickle cell disease Etrolizumab anti- α4b7 and anti- αEb7 gut selectivity inflammatory bowel disease (Crohn’s/ulcerative colitis) Vedolizumab anti- α4b7 inflammatory bowel disease Natalizumab anti- α4b7 monoclonal antibody against a4 integrins inhibits T lymphocyte interactions with brain endothelium multiple sclerosis Lifitegrast αLb2 antagonist prevents binding to ICAM-1 keratoconjunctivitis (dry eye)

Answer 25

Plerixafor CXCR4 inhibitor non-Hodgkins's lymphoma and multiple myeloma Mogalizumab anti-CXCR4 monoclonal antibody T cell leukaemia and T cell lymphoma Maraviroc CCR5 antagonist HIV-1

Answer 26

Autoimmune disease: occurs from dysregulation of the immune system with loss of self-tolerance. In autoimmune conditions, your immune system mistakenly attacks healthy tissues. Rheumatic diseases can cause inflammation, tissue degeneration, and autoimmune dysfunction.

Answer 27

Clinical 1. malaise, fatigue, weight loss 2. myalgia (muscle pain) 3. arthritis 4. anemia of chronic disease Course Multisystem, chronic, relapsing with disease & treatment related morbidity & mortality. Immunological Presence of disease specific autoantibodies.

Answer 28

Rheumatoid arthritis: presence of synovitis in minimum one joint, absence of better alternate diagnosis, & a score of ten from: Number & site of involved joints 2-10 large joints 1 point 1-3 small joints 2 points 4-10 small joints 3 points >10 joints 5 points Serological abnormality (RhF or ACPA) Low positive (above the upper limit of normal) 2 points High positive (>3 times the Upper limit of normal) 3 points Elevated acute phase response 1 point Symptom duration at least six weeks 1 point

Answer 29

1. Genetic factors may be involved in the development of RA 2. Environment may trigger (eg a virus or bacterium, smoking, periodontitis) 3. Hormones or hormonal deficiencies may promote the development of RA

Answer 30

1. Disease onset occurs over weeks to months 2. Painful, stiff joints due to inflammatory synovitis 3. Predominately symmetrical swelling in small joints 4. Large joints sometimes affected 5. Fatigue 6. Flu-like symptoms 7. Morning stiffness

Answer 31

1. It is a polygenic disorder, & many genes may contribute to it, meaning having family members with RA, doesn't guarantee you will have it. 2. HLA genes encode MHC class II, the molecule responsible for presenting peptides to the immune system to be recognised. 3. There are some HLA genes strongly linked with the development of rheumatoid arthritis. 4. e.g. HLA-DR4 & HLA-DR1 contains amino acid sequences which provide the risk. 5. e.g. you smoke, your proteins are citrullinated, the HLA binds to these more strongly, which causes the immune system to produce anti CCP autoantibodies, which target citrullinated proteins.

Answer 32

1. Inflammation of the blood vessels (vasculitis & ulceration) 2. Nerve problems due to compression of the nerves because of joint swelling, or inflammation of the blood vessels that supply the nerves. 3. Eye inflammation, or dry eyes. 4.. Lungs: Pulmonary nodules, Diffuse interstitial fibrosis, Obliterative bronchiolitis 5. Heart & pericardium: Ischaemic heart disease 6. Blood: haemolytic anaemia

Answer 33

1. Radiology: X rays, MRI to measure amount of damage & risk, measure scoring tools, e.g. Sharp score 2. Disease activity: ACR response criteria, disease activity score (how active disease is) 3. Functional status: Health assessment questionnaire – how easy do patients find certain tasks

Answer 34

Look at 1. Radiology 2. Anti CCP body positive 3. How many inflamed joints 4. How patient feels 5. Full blood count

Answer 35

The joints included in the Disease activity score & the form used for recording disease activity consists of: a tender joint count, swollen joint count, measure of inflammation & a visual analogue score of global health (1–100). The calculation is complex, but calculators are readily available. Provides a number on a scale from 0 to 10 which indicates the current activity of the disease. Used to recommend treatment.

Answer 36

1.ACR Response Criteria: 20%, 50%, 70%, 70 is improvement. 2. Tender and swollen joint score 3. 3/5: patient global, physician global, patient pain, HAQ, acute phase reactant (sed rate, CRP) 4. Typically used in clinical trials

Answer 37

Patients report how much difficulty they are having in performing various activities and these are scored as follows: 0 – No difficulty 1 – Some difficulty 2 – Much difficulty 3 - Unable

Answer 38

1. Prognosis of RA can vary considerably between individuals, but untreated is generally poor 2. The aggressive nature of RA can lead to a rapid decline in the patient’s quality of life (QoL) 3. Patients with RA have increased risk of comorbidity & mortality 4. multiple known indicators of poor outcome such as genetics, lab tests, clinical assessment

Answer 39

1. Genetics 2. High inflammatory markers beginning 3. Positive Rheumatoid Factor & anti-citrullinated protein antibodies 4. Many active joints 5. Poorer functional scores (e.g. Health Assessment Questionnaire) 6. Earlier radiological lesions 7. Adverse socio-economic circumstances & lower educational level

Answer 40

1. Patient with RA is assessed, if they're not in remission, increase treatment. 2. Iterative process, repeat. 3. Patient returns: If worse, increase treatment. But if they're in remission you don't make any changes. 4. Continuous iterative cyclical process. 5. Ensure patient is in remission, if they're not you increase treatment.

Answer 41

Patho-mechanism of RA: 1. Inflammation induced by T cells from lymph nodes or citrullinated Antigen-presenting cells. 2. T cells activate macrophages & fibroblasts via secretion of pro-inflammatory mediators (TNF-α, IL17, IFN-γ), & receptor activator of RANK-L. 3. Macrophages secrete pro-inflammatory cytokines (TNF-α, IL-1β, & IL-6), which establish & maintains region of inflammation. 4. T cells help B cells produce anti-citrullinated protein antibodies & rheumatoid factor autoantibodies, which drive inflammation by activating macrophages or activating complement cascade. 5. RANK-L promotes differentiation of osteoclasts from macrophages. With osteoclasts & antibodies, neutrophils can mediate inflammation-dependent cartilage damage.

Answer 42

Synthetic: 1. Conventional - Methotrexate 2. Targeted - Tofacitinib Biological: 1. TNF(R) inhibitors - Certolizumab 2. IL-6(R) inhibitors - Sarilumab 3. B cell depletion - Rituximab 4. Inhibition of T cell co-stimulation - Abatacept

Answer 43

1. Pain relief. - paracetamol 2. NSAIDS: fall into non-selective short acting & then the selective Cox two inhibitors. 3. Steroids help people recover quickly. 4. DMARD which reduced damage. 5. Creatinine measured monthly

Answer 44

1. Substitutes as Folic Acid 2. Interferes with the production of Tetrahydrofolate & the de novo synthesis of purines 3. Affects cells rapidly turn over e.g. Hair follicles 4. Folic Acid supplementation: may help with nuisance side effects (nausea, mouth sores) 5. Avoid: Pregnancy – Teratogenic, Alcohol 6. Creatinine measured monthly

Answer 45

1. Highly [in] cells 2. Increases intracellular pH 3. Interferes with cell’s ability to degrade & process proteins 4. Avoid: May increase sensitivity to the sun 5. Creatinine measured monthly

Answer 46

1. Antibiotic: Sulphapyridine 2. Sulfasalazine consists of salicylic acid and sulphapyridine joined by an azo bond. 3. Sulfinpyrazone is thought to be the active ingredient although, in RA, the mechanism of action is not understood 4. Creatinine measured monthly

Answer 47

1. Prodrug which is converted in GI tract & liver 2. Inhibits dihydro-orotate dehydrogenase, enzyme in de novo synthesis of pyrimidines. 3. Avoid: Pregnancy – Teratogenic, Alcohol 4. Creatinine measured monthly

Answer 48

1. Antigen presenting cell here & through major estate compatibility complex and T-cell receptors. 2. Then activate T cells which activate B cells & macrophages which release more inhibitors. 3. No Biologics are being combined due to the increase in toxicity

Answer 49

1. Infection: Tuberculosis, serious resulting in death 2. Malignancy: Increased risk of lymphoma – early data, solid tumors (cancer patients can’t take) 3. Neurological: Multiple Sclerosis, seizures, inflammation of the ocular nerve 4. Autoimmune: Antibody formation – SLE like illness 5. Worsening of Congestive Heart Failure

Answer 50

1. Inject fluid & light into the joint 2. Trim away damaged cartilage 3. Effective for knee/shoulder replacement, can restore some mechanical effect. 4. Joint replacement

Answer 51

1. Steroids are hormones derived from mevalonic acid. 2. The enzyme producing mevalonic acid is statins target, used to treat high cholesterol. 3.Many steroid hormones derived from cholesterol by modification or ring & sidechain. 4. Receptors inside nucleus, & 1 binding steroid ligand in/decrease gene transcription. 5. Causes change of protein level, causing different phenotype.

Answer 52

Different steroid structure imparts selectivity of receptors, meaning steroids bind not just based on recall shape.

Answer 53

1. Lanosterol (C30) to Cholesterol (C27)2. Cholesterol (C27) converted to Pregenolone (C21), then into Progestagens, precursor for all other steroids. 3. Can be converted into Glucocroticoids, Mineralocorticoids, & Androgens (convertible into Oestrogens). 4. Glucocorticoids promote gluconeogenesis, glycogen formation & reduce inflammation.

Answer 54

1. Steroids have a basic 4 ring structure (6:6:6:5) with side-chains. 2. Different steroids arise due to functionalisation of the rings & changing side-chains. 3. A-D rings,. 4. β-hydroxy configuration. 5. Steroids with anti-inflammatory properties will be derivatised by a carbon 11.

Answer 55

1. Cortisol (reduced Cortisone) & Cortisone: stress hormones which promote gluconeogenesis 2. Prednisolone & Methylprednisolone: synthetic derivatives, & another C=C bond increase activity relative to cortisone. 3. Prednisolone made from prednisone (keto derivative) by drug metabolism. 4. All these used to reduce inflammation (suppress the immune system). 5. Excessive use results in Cushing’s syndrome, sudden withdraw can cause adrenal insufficiency.

Answer 56

1. NSAIDs reduce production of leukotrienes & thromboxane (lipids which mediate inflammatory response) 2. Inhibits Cyclooxygenase 1 & 2 (COX-1 & -2); these control synthesis of leukotrienes & thromboxane 3. COX-1 is constitutive (produced at low levels in all tissues). 4. COX-2 is inducible (produced in response to injury). 5. Most NSAIDs inhibit both COX-1 & -2. 6. Selective COX-2 inhibitors may suffer from serious cardio side effects

Answer 57

1. Aspirin is an irreversible, selective COX-1 inhibitor. 2. Drug disappears from blood rapidly but has extended action duration due to covalent modification of target. 3. Effect is potentiated by caffeine. 4. Long-term low doses reduces blood clotting (decreases risk of heart attacks by reducing COX-1). 5. Not recommended for use in children due to risk of Reyes’ syndrome.

Answer 58

1. Reversible inhibitors of COX-1 & -2. 2. Analgesic, anti-inflammatory & antipyretic activity largely due to COX-2 inhibition. 3. Only S-enantiomer active. Naproxen is manufactured as the S-enantiomer, all others as the racemate. 4. Some risk of ulcers (due to COX-1 inhibition).

Answer 59

1. Diclofenac is stronger inhibitor COX-2 than COX-1 (approx. 10-fold). 2. Use increases risk of cardiovascular complications (as with other COX-2 inhibitors). 3. Reduced risk of ulcers (due to lower activity against COX-1). 4. Duration of action is 6-8 hours (despite a short half-life), in part due to accumulation in synovial fluid.

Answer 60

1. Selectively inhibits COX-2. 2. Increased risk of cardiovascular complications. 3. Effectiveness for pain-relief is similar to that of Ibuprofen, Naproxen, & Aspirin. 4. Naproxen has lower cardiovascular risk (& cheaper) but less widely used.

Answer 61

1. Ibuprofen & other drugs given as racemic mixtures. 2. Conversion is specifically R- to S-. 3. Acyl-CoA esters can acylate other proteins (gives rise to allergic reactions & other toxicities). 4. Naproxen given as pure S-enantiomer; R-Flurbiprofen converted to S. 5. Mixture is fine as all ends up as S-Ibuprofen. R is inactive. 6. Just S of NSAID can avoid toxicity, as it avoids Acetyl coA esters, which are good electrophiles & may isolate proteins, causing allergic reactions.