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Inflammation Flashcards

1
Q

What is the ‘Triple Therapy’ for RA?

A

A treatment with 3 csDMARDS

Methotrexate, Sulfasalazine and Hydroxychloroquine

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2
Q

What are Matrix Metalloproteinases (MMPs)?

A

Enzymes that break down collagen

Active at neutral pHs, and require Zn2+

Activated by the removal of propeptides by other proteases

Can be inhibited by Tissue Inhibitors of Metallo-Proteinases (TIMPs)

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3
Q

What are the main ‘risk’ genes for RA?

A

Genes in the MHC region

Eg, HLA-DRB1

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4
Q

Explain the Reactive Oxygen Species pathway

A
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5
Q

What is LAD-1?

A

An adhesion deficincy

Leukocytes do not adhere to extracellular material or endothelium

Leukocytes deficient in the B2 integrin

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6
Q

What is Rheumatoid Arthritis?

A

The persistant joint inflammation (of synovium) of at least 3 joint areas

Early morning stiffness of at least 30 min duration

1% of people in the UK have RA

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7
Q

What are Anti-Citrullinated Protein Antibodies (ACPA)?

A

These are highly specific for RA

Can be found in the body up to 14yrs before the onset of RA symptoms

Can predict erosive and progressive disease

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8
Q

What is the main active ingrediant in Sulfasalazine?

A

Sulfinpyradone

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9
Q

What is Leflunomide?

A

A new DMARD

Inhibits dihydro-oroate dehydrogenase –> used in the ynthesis of pyrimidines

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10
Q

Explain Prostanoid receptors

A

PGE2 (prostaglandins)–> EP1 - 4 Act on very specific GPCRs on target cells

PGI2 (prostacyclin) –> IP

Thromboxane receptor = TP

PGD2 –> DP1 + 2

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11
Q

What are the effect of RONS?

A

Activation of inflammatory gene transcription

Amino acid modifications

DNA damage –> cell apoptosis

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12
Q

What is the EP3 receptor?

A

A prostaglandin receptor

Activates leukocytes and mast cells

Promotes oedema formation

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13
Q

What are Chemokines?

A

Chemotactic Cytokines

Produced in responce to bacteria, TNF and IL-1

Act on GPCRs

2 Types

CXC –> Neutrophil attractants

CC

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14
Q

What are eicosanoids?

A

Oxidation products of 20carbon long fatty acids

Primerily from Arachidonic Acid

Main type is prostaglandins

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15
Q

What are chemotaxins?

A

Molecules that attract and activate leukocytes (increasing integrin avidity and affinity)

2 types…

Non Selective

Selective = Chemokines

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16
Q

Explain how low dose aspirin is beneficial……and how therefore taking a COX-2 selective NSAID can have adverse effects

A

Aspirin is selective to COX-1, and so prevents (pro-thrombotic) thromboxane from platelets, which will decrease the chances of clotting)

This is effective as platelets cannot remake proteins as they have no nucleus, so this effect occurs for a period of time. Also the endothelial produced PGI2 is unaffected

However, when a COX-2 inhibitor is used, PGI2 production stops, and so clotting becomes much more common, as the pro-thrombotic thromboxane is still present (as COX-1 isn’t inhibited)

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17
Q

What are the key indications of poor outcome in RA?

A

Genetics –> eg, the HLA-DRB1 genotype present

Lab Results –> RF or ACPA presence…..high CRP level

Clinical Assessment –> Many active joints and poor scores

Low educational / social-economical circumstances

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18
Q

What is Rheumatoid Factor?

A

Antibodies that bind to the Fc domain of IgG

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19
Q

What are the 2 neuropeptides that can positively feedback on histamine release and oedema formation?

A

NKA (Neurokinin A)

CGRP

20
Q

Explain which each of the 3 selectins are

A

L - Expressed on inactivated leukocytes

This causes leukocyte activation, which increases avidity (stickability)

There is rapid shredding of the selectin by proteolytic cleavage (shedase)

P - Expressed on platelets and endothelium

Start in granules, and are rapidly translocated to the cell surface upon activation

E - Endothelial expression is induced by cytokines or LPS

Required ‘de novo’ synthesis –> made on demand –> so takes time (hours)

Their expression is inhibited by glucocorticoids

21
Q

What is Rituximab?

A

A B cell depleting monoclonal anti-CD20 antibody

22
Q

What are the 5 cardinal signs of inflammation?

A

Heat

Redness

Swelling

Pain

Loss of Function

23
Q

What is the enzyme that primarily controls steroid biosynthesis?

A

HMG-CoA Reductase

Produces mevalonic acid

24
Q

What are the 3 things that plasma proteases are used to create, in reference to inflammation

A

Kinins (Bradykinin) –> Increases permeability/vasodialtion and pain

Complement –> Activates leukocytes, mast cell degranulation, and bacterial lysis and opsonisation

Clotting Cascade –> Amplifies the kinin and complement pathways

Also causes thrombosis and platelet activation

25
What are Leukotrienes (LTs)? And what are their actions?
A classic eiconisoid **Bronchoconstriction** **Oedema** **Chemotaxis** **Present in inflammation**
26
What is a **selectin**?
A lectin-like adhesion molecule So bind to carbohydrate molecules weakly **Important in the tethering of leukocytes to the endothelium**
27
What is **leukocyte adhesion deficiency II (LAD-II)**?
Patients have **defective fucose (a CHO) metabolism** So leukocytes do not express the correct ligands for selectins..... which causes a **reduced 'rolling' response** (for E/P selectins only) So less white blood cells where the inflammation has taken place **Reccurent infections without pus**
28
What are **integrins**?
Heterodimeric proteins that re expressed on the surface of leukocytes Important for 'Firm Adhesion' When leukocytes are activates, a conformational change of the integrin occurs, increasing avidity (stickiness) and affinity
29
What is **Angioedema**?
Deep cutaneous and mucosal swelling Can be induced from ACE inhibitors Driven mainly from mast cell degranulation (release of histamine) --\> due to the activation of plasma proteases
30
How does **Oedema** (swelling) occur?
H1 receptor binding of histamine causes endothelial-derived **Nitric Oxide** to be released, causing arteriolar dialation The endothelium then contracts, which makes venules leaky --\> increasing permeability
31
What are fevers regulated by?
PGE2 in the anterior hypothalamus
32
What do **Aspirin** and **Ibuprofen** do?
**Aspirin** - Acetylates COX irreversibly (covalent bond) **Ibuprofen** - Competitive inhibitor of COX, preventing arachidonate from binding
33
Explain anti-LT therapies
**Glucocorticoids** - Indirect inhibition of the formation of anachidonic acid (and so all other pathways) **Zileutin** - Blocks the conversion of anachidonic acid to leukotrienes via the enzyme 5-lipoxygenase **Montelukast/Zafirlukast** - A leukotriene receptor antagonist
34
What is Abatacept?
Blocks the interaction of CD80 and CD86 on CD28 of T cells
35
What are the 2 ways that **plasma leakage** can occur?
**Neutrophil** Dependent H1 receptors and histamine This means that just using an H1 antagonist will not remove all inflammatory mediaters!!
36
What do **Serine and Cysteine proteinases** do?
**Break down matrix proteins**, like Elastin, proteoglycans and chondroitin sulfate Inhibited by serpins Eg, **Neutrophil Elastase**
37
What type of **MMP inhibitor** targets the active site Zn2+?
Hydroxamate
38
What are the 4 main physiological functions of **prostanoids**?
Initiation of labour Inhibition of of gastric acid secretion, increased gastric mucus production Inhibition of platelet aggregation and vasodialation (PGI2 - Prostacyclins) Platelet aggregation and vasoconstriction (TXA2 - Thromboxane)
39
What is the **effect of proteases in angioedema**?
ACE inhibitors **block the breakdown of bradykinin** --\> increasing the inflammation Hereditary factors can include **increased complement and bradykinin activation** --\> by i**ncreasing kininogenase and decreasing protease inhinitors**
40
What is **ICAM** and **VCAM**?
Ligands for integrins **ICAM - Intracellular Adhesion Molecule** ICAM-2 = Expressed basally on endothelium ICAM-1 = Induced by cytokines Binds **B2** integrins **VCAM - Vascular Cell Adhesion Molecule** Induced by cytokines Binds **A4 integrins**
41
What is a lectin?
A molecule that binds to carbohydrates
42
What is the **DAS28** score? And what is the **HADQI** score?
**DAS28** - Provides a number on a scale of 1-10 which indicates the current activity of the disease **HADQI** - A score 0-3 which tells us how much difficulty they are having in performing various activities
43
Explain the stages of inflammation over time after a local injury (eg, seconds --\> mins --\> hours)
**Seconds** - Pre-formed substances like histamine are released NKA, CGRP (peptides) and eiconisoids (lipid membranes) are released/produced **Minutes** - Production of bradykinin and complement fragments following proteinase activation Infiltration cell products are released **Hours** - Transcription/translation of proteins like COX-2 and cytokines
44
What are the **5 main types of drug treatments for RA**?
**Analgesics** --\> Paracetamol **NSAIDs** --\> Ibuprofen (COX) and Celecoxib (COX-2) **Glucocorticoids** --\> Prednisolone **csDMARDS** --\> Methotrexate **bDMARDS** --\> Biologics
45
What are the 4 stages of **Leukocyte Diapedesis**?
**Circulating** **Tethering/Rolling** **Firm Adhesion** **Transmigration**
46
What is the monoclonal antibody that targets the **A4 integrin**?
**Natalizumab (Tysabri)** Inhibits T lymphocyte interactions with brain endothelium

PA20309 (6 decks)

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