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Biochemistry > #1 and #4 Mediators of Inflammation: > Flashcards

#1 and #4 Mediators of Inflammation: Flashcards

1
Q

Why are they called leukotrienes?

A

B/c they are made by leukocytes and they all have a conjugated triene in their structure

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2
Q

Prostaglandins, thromboxanes, leukotrienes are autacoids

A

True

  • Made on demand
  • Biosynthesis is latent
  • Short-lived
  • Local, not systemic actions

NOT HORMONES

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3
Q

What is the structure of leukotriene receptors?

A

Membrane spanning proteins with 7 domains

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4
Q

Receptor and ligand:

CysLT1 (receptor) prefers _____

A

LTD4>LTC4

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5
Q

Receptor and ligand:

CysLT2 (receptor) prefers _____

A

LTC4=LTD4

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6
Q

CysLT2 vs LTD4 etc

A

Cys refers to the receptor and starting with LT refers to compound

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7
Q

What happens when neutrophils encounter a “threat”?

A

Neutrophils near the “threat” make LTB4 (via 5-LO) which augments their adhesion to endothelium and their chemotaxis toward the threat

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8
Q

What is the main leukotriene made by neutrophils and what does it do?

A

LTB4

A potent chemotactic agent for neutrophils, themselves

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9
Q

Neutrophils are mostly circulating, not in tissues

A

True

LTB4 will make a chemical gradient and will attract the neutrophils into the tissue

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10
Q

What are “pyogenic” infections?

A

They have neutrophil-rich pus.

An infection gets in, you need neutrophils. Monocytes or macrophages will attempt to degrade it, they will make small amounts of LTB4 which will create a gradient telling neutrophils where to go. IL-8 also helps. LTB4 also changes endothelium, making it more adhesive so more neutrophils will stick.

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11
Q

Neutrophils in bloodstream

A

Those that stick are the “marginating pool”. They will stop and see if there is a problem

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12
Q

Inflammation, phagocytes and LTB4 etc

A

In inflammation phagocytes and granulocytes attack the “threat” and use signals like PGE2, PGI2, and LTB4-which send autocrine and paracrine signals telling leukocytes to engage and neutralize the threat, and also telling epithelial and mesenchymal cells in the inflamed area to adapt, migrate or perish. The host uses lipid mediators to limit damage that is inseparable from inflammation.

Proteins that help: IL-8
Lipids: LTB4

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13
Q

What lines the airways?

A

Ciliated columnar epithelium (moves stuff)

Has brushes that brush it upwards. Goblet cells release mucous which traps particles and epithelium pushes it up.

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14
Q

There are 2 major elements in asthma: airway inflammation and airway hyper-responsiveness

A

Th-2 → IL-13 (asthma)

Person with asthma has more Th2 state. They have a different composition of lymphocytes in lungs and you are trying to get them back to Th1 state.

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15
Q

Asthmatic airway

A

Inflammation because of Th2 state (excessive leukotrienes)

Airway inflammation: leukotrienes

Joint inflammation: prostaglandins

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16
Q

LTB4 and chemotaxis

A

Chemotaxis with LTB4(receptor is BLT). LTB4 creates chemotactic gradient for neutrophils.

In asthma, LTB4 draws in eosinophils. If they are drawn into the airway from circulation, they are looking for something to do. They are designed to attack parasites and they can be destructive. They are aggravating things because they don’t need to be there

So in asthma, it’s the neutrophils AND the eosinophils

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17
Q

Where is histamine stored?

A

Substances in these granules and cells (heparin) form complexes with histamine that keeps histamine stored as an inactive complex

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18
Q

Mast cells and histamine are concentrated in certain areas of the body because of their role in host defense. These areas are anatomically vulnerable to antigen or pathogen exposure

A

True

Nose, lungs, skin, gut (stomach, intestines etc)

19
Q

Massive release of histamine

A

We know that histamine causes bronchioconstriction. It stimulates mucous secretion (clogs airway), increased heart rate.

Anaphylaxis: you aren’t getting enough O2 to your organs. Relaxation of blood vessels makes pumping blood very inefficient

Fix: use epinephrine (constricts blood vessels and relaxes bronchial smooth muscle)

Leukotrienes and histamine constrict bronchial smooth muscle

20
Q

What are the “resident” inflammatory cells in tissues?

A

MΦ, mast cell, eosinophil

*“transient” cells come, do their job, then leave

21
Q

Inflammatory cells circulating in blood

A

Basophil (circulating mast cell), eosinophil, neutrophil, monocyte

22
Q

Gout Etiology (causes) and Mediators

A

1 and 2. MΦ/monocytes ‘engulf’ uric acid crystals, trigger IL1β and IL8 release

  1. IL1β (pro-inflammatory effects) INDUCES EXPRESSION of adhesion molecules on endothelium, COX-2 in MΦ, monocytes, connective tissue and endothelium
  2. Together IL1β and IL8 initiate the recruitment of neutrophils from the blood toward the locale of activated MΦ/monocytes
  3. IL1β induces COX-2 in cells at the site of inflammation and in adjacent endothelium. COX-2 and COX-1 generate prostaglandin mediators that cause dilation and increase permeability of vessels (especially post capillary venules). You get redness, swelling, pain, heat. (amplification)
23
Q

COX 1, PGs and Inflammation

A
  1. IL1β STIMULATES AA release
  2. COX-1 converts AA → PGE2
  3. PGE2 causes symptoms (erythema, edema, pain)
  4. IL1β INDUCES COX-2 expression
  5. COX-2 converts AA into PGE2, PGI2…
  6. PGE2, PGI2 amplify symptoms
24
Q

“Leaky vessels”

A

Leaky vessels allow plasma extravasation (leakage out of container) into Interstitial space → localized edema (makes the infection area protein rich which helps)

Most leaky are post-capillary venules (not major venules-the small ones, that’s where fluid comes from)

Why do you get edema?
-PGI2: vasodilation
PGE2: permeability

25
Q

What does IL1β do?

A

Induces adhesion molecules on adjacent endothelium.

This ↑ neutrophil sticking…expands the pool of marginating neutrophils. (Makes this region REALLY sticky for neutrophils)

Some in circulating pool→marginating pool→go into tissue

26
Q

Gout inflammation- why does it ‘build up’?

A

There is a failure to eliminate uric acid crystals- proteases and lysosomal enzymes do not digest uric acid; the ‘oxidative’ burst from granulocytes does not ‘degrade’ uric acid. In gout, inflammation may even aggravate the problem because uric acid precipitates more easily at acidic pH in an abscess.

*Evolution shaped the inflammatory response to manage bacterial (infectious) ‘threats’

27
Q

Inflammation in Bacterial infection

A

Bacteria and components (e.g. LPS) provoke an inflammatory response

LPS itself, TNFα, IL1 induces expression of adhesion molecules on endothelium and COX-2 in MΦ, monocytes, connective tissue, and endothelium

28
Q

In bacterial infections, the innate response is usually effective in an immunocompetent host.

Myeloid cells (eventually becoming neutrophils) ‘digest’ bacteria or degrade their components. We use clorox (bleach) to inactivate bacteria…we stole the idea from neutrophils…

A

True

29
Q

A big difference compared to gout…

A

LPS (gram negative) induces expression of adhesion molecules on endothelium, and COX-2 in macrophages, monocytes, connective tissue and endothelium

e. g. If a gram negative bacterial infection→ blood stream→SEPSIS→systemic inflammation
* In SEPSIS, an overwhelming inflammatory response → septic shock, multi-organ failure, death

30
Q

In sepsis bacteria (LPS) and cytokines (TNFα) → systemic inflammation. Induction of COX-2 and adhesion molecules →widespread damage to host. Systemic vasodilation and extravasation of plasma from the blood to interstitial space leads to a drop in blood pressure- a feature of septic shock

A

True

31
Q

In regards to allergic reactions, when the respiratory tract and lungs become involved, the mediators can cause Anaphylaxis- a life-threatening condition, involving additional mediators

A

True

32
Q

What are the mediators of anaphylaxis?

A

Histamine
Leukotriene C4 and D4
PGD2

33
Q

Anaphylaxis steps (magnification of a normal allergic reaction)

A
  1. Respiratory tract exposed to excess histamine→ **Airway compromised, Breathing impaired
  2. Peripheral vasculature exposed to histamine **Airway compromised, Breathing impaired, Hypotensive shock
34
Q

What do H1 receptors do in the nasal/bronchial regions?

A

Nasal and bronchial: ↑ mucus secretion

Bronchial muscle: ↑ constriction

35
Q

Anaphylaxis and histamine levels

A

With anaphylaxis, histamine levels in blood rise substantially within 10 min of the start of symptoms and return to normal after 30-60 minutes. This increase is reflected a short time later in the urine as histamine and its primary metabolite, N-methylhistamine, are excreted

36
Q

Anaphylaxis and histamine

What do the H1 and H2 receptors do in peripheral vasculature when exposed to histamine?

A

Blood pressure: ↓

Heart: ↑ HR

Blood vessels dilate: ↓ peripheral resistance

Blood vessels: ↑ permeability

Peripheral edema: ↑

37
Q

In addition to histamine release, mast cell activation → autacoid lipid mediators- such as LTC4, LTD4 and PGD2. In allergy and anaphylaxis these mediators compound the effects of histamine

A

True

38
Q

How do neutrophils auto-activate chemotaxis?

A

They make LTB-4 in addition to IL-8

39
Q

How do neutrophils degrade pathogens?

A

Myeloid peroxidase: it’s a big chunk of the neutrophil. It takes Cl- ions and OH- and makes hypochloric acid (aka bleach).

40
Q

Leukocyte adhesion deficiency (LAD)

A

Lack of expression of the adhesion molecules. An infection won’t get a full response and they’ll eventually get SEPSIS

41
Q

Uncontrolled diabetes can develop what?

A

Prone to infections. They lose peripheral nerves (lose sensation in nerves) and they develop ulcers in foot because they don’t feel the pain where bacteria can spread

42
Q

Septic shock: good system goes bad

A

Edema is now systemic, the fluid left blood, so less fluid in blood and so heart has less to pump to organs, so if you give them fluids you get more edema because blood vessels are permeable.

43
Q

Peripheral vascular resistance goes ______

A

DOWN

*Dilation → lower BP → heart has to work harder to push fluids leaking out →not delivering as much blood→ not delivering as much O2 to organs → organ failure

44
Q

How to treat anaphylactic shock?

A

Epinephrine

Vasoconstrictor and bronchodilator

It will relax smooth muscle and dilate the airway

Administration of agents to negate the actions of histamine, leukotrienes and eicosanoids.

Biochemistry (41 decks)

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