L10: Treating acute inflammatory conditions and minor injuries

What are the characteristics of the innate non-adaptive inflammatory response?

- Short term acute response

- Defensive

- Quickly resolved

When was innate non-adpative system developed ?

Early in evolution

What is involved in the adaptive immune response ?

1) Acute microvascular change

2) Release of inflammatory mediators

3) Accumulation of inflammatory cells

4) Repair and Healing

What triggers the acute microvascular effects ?

Triggered from a variety of cells and plasma in and around these vessels

What are local hormones ?

Agents that are released locally to act locally (more commonly referred to as inflammatory mediators )

Why is the term inflammatory mediators more common than local hormones ?

In some conditions mediators can be released locally but influence other organs in the body

What makes up the inflammatory soup (inflammatory mediators)

- Histamine

- Bradykinin

- Nitric Oxide

- Eicosanoid

- Neuropeptides

- Cytokines

- Complment

- Platelet-activating factor (PAF)

What do eicosanoids produce ?

Prosaglandins & Leukotrienes

What are the post capillary venules involved in ?

- Oedema formation

- Inflammatory cell accumlation

What is the role of the arteriole in inflammation?

Increased blood flow to the inflamed site

What vasodilators do the following cells produce?

- Endothelial cells

- Inflammatory cells

- Sensory nerves

- Endothelial cells = prostaglandins, nitric oxide

- Inflammatory cells = prostaglandins, nitric oxide

- Sensory nerves = Neuropeptides (Calcitonin gene-related peptide antibodie(CGRP))

What are the two main characteristics of acute inflammation ?

- Increase blood flow

- Inflammatory swelling

What causes inflammatory swelling ?

Increased microvascular permeability

What is the difference between bruising and swelling ?

Bruising = broken blood vessel so red blood vessels come out

Swelling = only plasma comes out and blood vessels remain intact

What are the mediators that stimulate inflammatory swelling?

Direct acting

- Histamine

- Substance P

- Bradykinin

- Platelet-activating factor (PAF)

- Leukotrienes

State the two ways that plasma leaks out of cell ?

1) Oedema producing mediators bind to endothelial cell => contraction and leaking out through the basement membrane

2) Endothelial cells unstick together causing gaps to form allowing fluid to leak out

How do neutrophils cause oedema fluid to leak out ?

- Agents activate neutrophils

- Neutrophils interact with endothelial cell causing leakage of fluid

- (The neutrophil can emigrate out of the cell)

Why do neutrophils emigrate out of the post-capillary venule ?

To help with the defence of the body => phagocytosis of foreign substances

State the steps of neutrophil emigration out of the endothelial cell ?

1) Rolling along venule

2) Stick to the endothelial cell

3) Get more sticky due to Cell adhesion molecule expression (CAM)

4)Adherence

5) Extravasation

6) Phagocytosis

What are the mediators that lead to neutrophil accumulation in tissues ?

Leukotriene B4 (LTB)

Peptide in complement system (C5a)

Interlukin-8 (IL-8)

What are the endothelial adhesion molecule stimulants ?

TNF alpha

IL-1

What is histamine formed from ?

Histidine

What are two major sources of histamine ?

Mast cells

Basophils

When is histamine released?

In allergic / hypersensitivity (IgE) responses

What do H1 receptors mediate ?

- Increased blood flow, increased microvascular permeability, itch

What is an H1 antagonist ?

Non-sedating drugs that are used to combat the effects of histamine used during allergy, hay fever and skin irritations

e.g mepyramine and chlorpheniramine

What are the two roles of sensory nerves ?

1) Transmit sensory info to CNS/initiate reflexes

2) Release neuropeptides such as Substance P, CGRP & VIP

How can sensory nerves be stimulated ?

- Mechanical (pressure)

- Temperature (cold & heat)

- Chemical (mediators & capsaicin found in chilli extract )

What can impact the fast acting histamine response ?

The response is inhibited by histamine H1 receptors antagonist

What is the triple response ?

1) Local reddening

2) Oedema formation

3) Axon reflex flare

What are the features of sensory nerves that mediate itch ?

- Respond to histamine

- Insensitive to mechanical stimuli

- Slow conducting velocities

Where is constitutive nitric oxide synthase found?

Endothelial (eNOS)

Neurons(nNOS)

Where is inducible nitric oxide synthase found ?

Macrophage(iNOS)

How is nitric oxide produced ?

Arginine and Oxygen are converted to Citrulline and NO catalysed by nitric oxide synthase

What are the multiple roles of nitric oxide ?

- Regulation of blood flow/pressure as it is released from endothelial cels

- Host response to infection

- Neurotransmitter

- Pain

What is a negative consequence of NO ?

Can react to produce cytotoxic radicals (e.g peroxynitrite)

What is bradykinin ?

A peptide formed in plasma by the activity of enz on tissue fluid substrates called kininogens

How is bradykinin metabolised ?

By angiotensin converting enz (ACE) and caboxypeptidases

What are the side effects of ACE inhibitors

Cough

Why is ACE inhibitor cough considered to be mediated by bradykinin?

As it is present in the nasal dropping of people who are sneezing a lot (present during allergic rhinitic attacks )

What do B2 receptors mediate ?

- Increased blood flow and increased microvascular permeability

- Nociception

- Broncho-constriction and nasal blockage

What do B2 antagonists inhibit the effects of ?

Some angioedemas (e.g Icatibant - B2 antagonist )

What are B1 receptors induced in ?

- Inflammation

- Mediate similar responses especially pain

What is a fatty acid that leads to the production of inflammatory mediators ?

Arachidonic acid (polyunsaturated fatty acid)

What are the two pathways in the metabolism of arachidonic acid?

1) Cyclo-oxygenase pathway which leads to the production of prostaglandins and thromboxanes

2) Lipoxygenase pathway leads to leukotrienes

What are the two intermediates in the cyclo-oxygenase pathway ?

PGG2 = unstable and short acting

PGH2

State what produces the following prostaglandins

- PGI2 (prostacyclin)

- PGE2

- PGD2

- PGI2 = endothelial cells

- PGE2 = endothelial and inflammatory

- PGD2 = several cells & mast cells

What other system in the body are prostaglandins involved in?

Reproductive

What produces thromboxanes?

Platelets

What type of drug inhibits arachidonic acid metabolism via the cyclo-oxygenase pathway ?

Non-steroidal anti-inflammatory drugs (NSAIDs )

State non-selective NSAIDs ?

- Inhibit COX-1 and COx-2

- e.g aspirin, ibuprofen and indomethacin

What are the side effects of non-selective NSAIDs ?

Side effects = gut and kidney

- especially in the elderly

- cause problems such as internal bleeding and kidney problems

State the COX-2 selective inhibitors?

- Not over the counter

- e.g Celecoxib, Rofecoxib (Vioxx) and Meloxicam

Why do COX-2 selective inhibitors have few gut and kidney side effects ?

As the block COX-2 which is only up-regulated in inflammation

- Use is controversial as they have adverse cardiac effects

What is antipyretic ?

Anti-fever