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2 - MC > 3-4: Acute Inflammation > Flashcards

3-4: Acute Inflammation Flashcards

1
Q

State the “Big Picture” steps of inflammation

A

Recognise -> Recruit -> Vascular Changes -> Inf. Cells enter tissues -> Repair

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2
Q

What is the general timeframe and extent of an acute inflammation response (and what are the common causes)?

A
  • Minutes to hours after injury/infection
  • Often self-limiting
  • Pathogens
  • Tissue necrosis
  • Physical (e.g. splinters)
  • Chemicals
  • Hypersensitivity (e.g. cold air)
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3
Q

Describe three macroscopic features of an inflamed area?

A

Purulent (pus containing dead/dying neutrophils)

Fibrinous (exudate contains fibriongen, which leads to fibrin -> polymerisation -> scarring if not broken down)

Pseudomembranous (appearance of a false membrane)

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4
Q

Name the characteristic vascular and systemic effects of acute inflammation

A

Vascular:
- Red, Wheal (permeability), Flare (axon reflex)
- Loss of function

Systemic:
- Fever
- Loss of appetite
- Lethary
- Leukocytosis and APPs

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5
Q

What recognise offending agents and what are the two groups that they recognise?

A

PRRs (pattern recognition receptors) recongise PAMPs (Pathogen Associated Molecular Patterns)

and DAMPs (Damage associated molecular patterns)

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6
Q

Give some examples of PAMPs and DAMPs

A

PAMPs
- highly conserved structures in viruses and bacteria, e.g., LPS

DAMPs
- intracellular or ECM proteins
- uric acid
- K+
- ROS
- HSP70/90

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7
Q

Name 7 families of PRRs

A

Pentraxin
Toll-Like Receptors (TLRs)
NOD-Like Receptors (NLRs)
Mannose-binding Lectin
C-type lectin receptors (CLRs)
RIG-I-like receptors
AIM-2 like receptors

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8
Q

Where are pentraxins found and what do they recognise? (and give 1 example)

A

Pentraxins (e.g. C-Reactive Protein) are Extracellular, and recognise Phosphocholines in microbial membranes

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9
Q

Where are TLRs found and what do they recongise?

A

Plasma membrane (recognise LPS, flagellin, HSPs, ECM components, oxLDL)

Endosome membrane (recognise Microbial RNA/DNA)

Location is tailored to best respond to ligand

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10
Q

How many TLRs are there?

A

13 (1-10 are found in humans), 3/7/8/9 are found in the endosome, rest in PM

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11
Q

Describe the general structure and function of a TLR

A

Leucine-rich repeats (LRRs) form the extracellular domain - a horseshoe shaped ligand binding domain (often requiring an accessory molecule, e.g. MD2 links LPS to LRR)

Toll/IL-1 intracellular domain which initiates downstream signalling

TLRs dimerise upon ligand binding

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12
Q

Summarise the TLR signalling pathway(s)

A
  1. Upon dimerisation, MYD88 or TRIF is recruited (depending on TLR)
  2. -» activate MAPKs/JNK/p38
  3. -» activate NFkB or IRFs
  4. -» activated TFs translocate to nucleus and activate transcription (NFkB -> Pro-Inf Cytokines; IRFs -> INFa and INFß)
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13
Q

Describe the NLR group

A

A major family of CYTOSOLIC PRRs consisting of 4 families - NLR A/B/C/P

B, C and P function in the innate immune system, with P including NLRP3 (-> Inflammasome -> Casp1)

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14
Q

Describe the general structure of NLRs

A
  • A C-terminal Leu-rich domain
  • A central Nucleotide-binding Oligomerisation Domain (NOD)
  • An N-terminal effector domain (depends on family, nlrP = Pyrin)
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15
Q

Describe the first part of the processthat leads to NLRP3 activation

A

Signal 1 = Priming

-> NFkB activated by TLRs
-> NF-kB activates transcription of NLRP3, pro-IL-1ß and pro-IL-8

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16
Q

Describe the second part of the response to NLRP3 activation

A

Signal 2 = Activation!

NLRP3 oligomerises -> INFLAMMOSOME -> recruits and oligomerises ASC -> Casp1 activation

Casp1 then cleaves (pro-)IL-1ß, IL-8 and Gasdermin-D, activating them all

Active Gasdermin-D forms pores in cell membrane, allowing others to leave and sometimes induce pyroptosis

17
Q

Name some common signals that can act as Activators for NLRP3 (and comment on the diversity thereof)

A

Fatty Acids, Ceramides, Uric Acid, ß-amyloids, Cholesterol

It is unclear exactly how NLRP3 can respond to so many - possibly an integration signal?

Also, unclear why evolution selected NLRP3 (read more for essay)

18
Q

What diseases are associated with NLRP3?

A

Mutations in NLRP3 -> recurrent inflammation (due to excessive Casp1 activation), leading to Cryopyrin-associated periodic syndromes/CAPS

This contributes to Alzheimer’s, Parkinsons, Atherosclerosis, Type II, Multiple Sclerosis

Potentially a drug target?

19
Q

What are the main vascular changes seen in Acute Inflammation?

A
  1. Vasodilation + increase in blood flow
  2. Increase in endothelium permeability to allow leukocytes + plasma proteins to enter tissues
20
Q

What are the main two vasodilators of VSM in acute inflammation?

A

Nitric Oxide (NO) and Histamine

21
Q

Describe the pressure changes that cause extravasation of leukocytes into tissues during acute inflammation

A
  • Endothelial cells contract, allowing exudate to leak through (containing Edema, then neutrophils (6-24h), then monocytes (24-48h)
  • Vasodilation -> Increased flow -> Increased HYDROSTATIC PRESSURE
  • Osmotic pressure decreases due to proteins leaking out into tissues
  • Overall, MORE PRESSURE OUT, forcing leukocytes into tissues (extravasation)
22
Q

Define the difference between Exudate and Transudate (which is Edema, and which is pus?)

A

Exudate = high [protein] and cellular debris, associated with inflammation

Transudate = low [protein] and no cell debris

Edema can be either, PUS is an inflammatory exudate

23
Q

State the order of steps in leukocyte vasation + migration

A

Capture, Rolling, Arrest, ADHESION (Cascade), Crawling, Migration

24
Q

Name all the components that might be found in Exudate during inflammation

A
  • Edema
  • Leukocytes (Neutrophils 6-24h and Monocytes 24-48h)
  • Erythrocytes
  • Proteins, 50g/L [CRP, Complement, Immunoglobulins and Fibrinogen]
25
Q

Name the 5 (mentioned) Endothelial molecules involved in Leukocyte adhesion, and the Leukocyte molecule they bind to

A
  1. P-selectin (P-s glycoprotein ligand-1, PSGL1)
  2. E-selectin (E-s ligand-1, ESL1)
  3. GlyCam1/CD34 (L-selectin)
  4. ICAM1/2 (Integrins, LFA1)
  5. VCAM1 (Integrins, VLA4)
26
Q

Describe the steps of the Adhesion cascade

A
  1. Macrophages that have detected pathogens secrete cytokines (e.g. TNF, IL1) to upregulate P/E/L-selectins and their ligands
  2. Loose attachment between selectins and their ligands (capture + rolling)
  3. Chemokines switch on leukocyte integrins, TNF/IL1 induce expression of integrin LIGANDS on endothelium
  4. Adhesion between leukocyte integrins + adhesion molecules (ICAM1/2 and VCAM1)

Note: ICAM1/2 also play roles in arrest and transmigration

27
Q

[If time, make FCs from Supplementary Info on Inflammatory Cells)

A

Okay (thumbs up emoji)

28
Q

Name the drug that prevents pain crises in sickle-cell disease, and how it functions

A

Crizanlizumab

It is a monoclonal antibody that binds to P-selectin and prevents binding to its ligand PSGL1, thus reducing vaso-occlusion and sickle-cell crisis

29
Q

Which types of cells carry out phagocytosis?

A

Neutrophils and Macrophages

30
Q

Name and describe the three groups of local hormones (autacoids) that are VASOACTIVE in acute inflammation

A
  1. Histamine and Serotonin (preformed + stored for FAST release, both induce vasodilation and endothelial gaps)
  2. Kinins e.g. Bradykinin (increases prostaglandin and NO production -> indirect vasodilation and PAIN)
  3. Eicosanoids e.g. PGs, TXs, Lipoxins, LTs (NOT preformed, on demand, various functions)
31
Q

Describe the pathway(s) that activates the Eicosanoids

A

Cell Damage -> Phosphorylation of Phospholipase A (PLA) -> Activation of Arachidonate:

-> Cyclooxygenase -> Prostaglandins
-> Lipoxygenase -> Leukotrienes
-> Lipoxins

32
Q

Describe what Platelet Activating Factor does and how it is activated

A

It is a more potent vasodilator than histamine (also a bronchoconstrictor and chemotaxin)

Prodced by platelets, basophils, masts, neutrophils, macrophages AND endothelial cells;
Like eicosanoids, it is activated downstream of Phospholipase A, but it is activated by Lyso-glyceryl-phosphorylcholine instead of Arachidonate

33
Q

Name some key groups of cytokines (plus examples) and what cells are the main manufacturers of them?

A

Interleukins (IL1, IL10)
Chemokines (IL8, MCP1)
Interferons (INFa/ß,y)
Plus TNFa

Many cell types manufacture these, but especially Macrophages

34
Q

What are the effects of IL-1ß and TNFa?

A

Upregulation of endothelial adhesion molecules, Secretion of other cytokines, Systemic effects (due to upregulating APPs)

IL1ß also causes Fever

35
Q

What are the effects of IL6, IL8 and CXCL8?

A

IL6 = Systemic Effects (Fever, Leukocytosis, upregulates APPs)

IL8 and CXCL8 (plus other chemokines) = Recruits Leukocytes

36
Q

Describe two specific local effects of IL-1ß and TNFa (besides Adhesion and Leukocyte Activation)

A

Increased Procoagulent activity; Increased Proliferation of Fibroblasts and Collagen Synthesis (REPAIR)

37
Q

What causes the upregulation of Acute Phase Proteins?

A

Interleukins, e.g. IL1, Il6, TNFa

38
Q

Name 5 Acute Phase Proteins that are upregulated by pro-inflammatory interleukins, and state their effects

A
  1. Fibrinogen (Coagulation)
  2. Mannose-binding lectin (a PRR for Mannose)
  3. Complement (Complement Cascade)
  4. Serum amyloid (Leukocyte recruitment)
  5. C-Reactive Protein (a pentraxin PRR that acts as an opsonin to enhance phagocytosis)
39
Q
A

2 - MC (5 decks)

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