BIOL21351 L10&15 lol

What cells are abundant in chronic inflammation?

Predominantly monocytes/ macrophages and lymphocytes

What causes chronic inflammation?

- Persistent infection

- Hypersensitivity

- Prolonged exposure to toxins

- Immune-mediated (e.g. antibodies against the myelin sheath)

Give examples of toxic agents that can lead to chronic inflammation

Exogenous e.g. asbestos

Endogenous e.g. uric acid crystals

Where do macrophages come from?

Arise from monocytes in the blood, but differentiate into macrophages when they migrate to tissue

Name some diseases associateed with inflammation

Atherosclerosis

How are acute and chronic inflammation similar?

Many of the same cells, receptors and mediators are involved in both

What happens when the adaptive immune system is involved?

Tissue damage occurs, leading to the cycle of inflammatory events

Give possible treatments to reduce circulating cholesterol

Diet, exercise, stop smoking, reduce alcohol

- Lipid-lowering drugs like fibric acid derivatives (bezafibrrate) and statins

- PPAR activators

Outline the mechanism of lipid lowering drugs (2)

Bezafibrate decreases VLDL and triglycerides

Statins inhibit HMG-CoA reductase (the rate limiting step in cholesterol synthesis)

How do statins treat atherosclerosis?

- They inhibit HMG-CoA (preventing cholesterol synthesis

- They suppress platelet activation

- Plaque stabilisation

- Reduced cytokine production

- Upregulation of IL-10

Mechanism of ApoE?

Inhibits oxidation of lipoproteins, VSM cell proliferation and migration and inhibits platelet aggregation

Results of CANOTS study

- Canakinumab prevents adverse cardia events

- Reduces CRP (dose-dependent)

- Associated with increased risk of fatal infection by sepsis

Mechanism and role of colchicine

Inhibits assembly of the NLRP3 inflammasome and therefore IL-1β secretion, so reduces inflammation

Source of cholesterol

- From diet AND

- Produced by liver

What are chylomicrons?

tiny fatty droplets composed of triglycerides, small amounts of phospholipids, cholesterol, free fatty acids, and some protein.

What is the role of chylomicrons?

Transport cholesterol from the small intestine to the body

Where are chylomicrons synthesised?

In the GI tract

PPAR activation leads to...

Decreased expression of adhesion molecules, foam cell formation and other effects that decrease inflammation and atherosclerosis

List the cells in both chronic and acute inflammation and those in chronic only

Both : Plasma cells, eosinophils and mast cells

Chronic only : Lymphocytes

What is the difference in action of the chronic compared to the acute inflammatory process?

Chronic involves lymphocytes and the adaptive immune system, whereas acute involves the innate immune system.

Risk factors for atherosclerosis that involve the inflammatory response

Increased CRP, interleukins and coagulation factors

What is a fibrous cap?

Result of smooth muscle cell apoptosis during atherosclerosis.

Fibrous cap forms over lipid-rich accumulation.

When fibrous cap ruptures, endothelium is exposed to circulating platelets and coagulants -> acute thrombus forms

What is endothelial dysfunction?

-Change in endothelial cells leading to malfunction

-Implicated in thrombus formation, atherosclerosis & other disorders (Ex. HTN)

-May be rapid or slow in onset & reversibility

Under normal conditions, what does endothelium control?

- The vascular tone

- The balance between thrombosis and fibrinolysis

- Regulates the recruitment of inflammatory cells

How does a plaque develop?

damage to endothelial cells (due to cholesterol, high blood pressures, or LDL)

this damage causes inflammation and hangs artery lining

Steps to plaque development

1. Endothelial Dysfunction

2. Lipid accumulation

3. Inflammatory response

4. Foam cell formation —> Plaque

How do foam cells form?

Oxidised LDL trapped in macrophages forms foam cells

What makes up a tumour (carcinoma)?

Neoplastic cells and non-neoplastic stroma

What can limit cancer growth?

Lack of oxygen (hypoxia) and metabolic waste products)

What is the role of stroma?

Contributes to tumour progression

How does hypoxia alter gene expression?

Mechanism of angiogenesis

1. Pericytes detach

2. BM and ECM degraded by MMPs

3. Endothelial cells migrate towards the angiogenic stimulus

4. Endothelial cells proliferate in a migration column to tumour

5. Endothelial cells adhere to each other and a blood vessel forms

What is stroma, with regards to tumours?

The surrounding tissue of tumours that contains ECM, fibroblasts and immune cells

What is neovascularisation?

natural formation of new blood vessels that is required for tumour growth

Why is tumour vasculature chaotic and leaky?

Fenestrations (small holes) in endothelial cells. This raised hydrostatic pressure within the tumour reduces distribution of chemotherapy

How is neovascularisation achieved?

Through the angiogenic switch

What is the angiogenic switch?

An increase of activity in angiogenesis activators (e.g. VEGF) and a reduction of inhibitors (e.g. endostatin) that results in neovascularisation (for tumour growth)

Give examples of angiogenesis inhibitors and activators

Inhibitors: Statins and Thrombosponin-1

Activators: VEGF, FGF, EGF

Different mechanisms that inhibit angiogenesis

- Inhibiting the signalling cascade

- Inhibiting endothelial cells

- Blocking the ability of endothelial cells to break down ECM

Drugs that inhibit the angiogenesis signalling cascade

Drugs that inhibit VEGF, e.g. avastin and SU6668

Drugs that target endothelial cells directly to prevent angiogenesis

Endostatin,

Thalidomide

Drugs that block the break down of ECM

Marimistat - prevents MMP production

Processes that lead to neovascuarisation

- Angiogenesis

- Vasculogenesis

- Vascular mimicry (cancer cells form vessels themselves)

Mechanism of vasculogenesis

New vessels form de novo from circulating endothelial progenitor cells released from the bone marrow

Where do angiogenic factors come from?

Tumour cells, mast cells, macrophages and ECM

Which lysing processes are increased in cancer?

Glycolysis and glutaminolysis

Why do glycolysis and glutaminolysis increase in cancer?

To maintain high levels of anabolic reactions whilst generating sufficient ATP even under hypoxic conditions

Therapeutic targets for cancer growth

Angiogenesis

Altering cellular metabolism

What is the Warnburg effect?

Aerobic glycolysis carried out by cancer cells that leads to an increased uptake of glucose (4 ATP compared to 2 in anaerobic glycolysis)

How does cancer cell metabolism differ from normal cells?

More glutaminolysis

Results in a shift in metabolism to biosynthesis

Produces proteins and nucleic acids from glycolysis and glutaminolysis as well as ATP

What happens in glutaminolysis?

Q —> D/E/A/CO2/Lactate/Pyruvate/Citrate

Also produces carbon and nitrogen

What is the role of glutaminolysis?

Breaks down glutamine to produce components that can be used in respiration to generate energy (citrate, pyruvate —> lactate)