Chronic Inflammation And Wound Healing

Question 1

What are the 3 phases of wound healing?

Answer 1

1. inflammatory (substrate, lag phase), 1-3/7d
2. proliferate (repair phase, lag phase) 3/5-14d
3. Maturation (remodelling phase) 14d+

Question 2

What is the decline of the inflammatory phase?

Answer 2

Loss of stimulus, altered cellular signals
- as inflammation dies down, fewer inflammatory factors are secreted, existing ones removed and macrophages and neutrophils reduced at the wound site

Question 3

What is the role of macrophages in the decline of the inflammatory phase?

Answer 3

• secrete growth factors and cytokines that attract cells involved in proliferation stage of healing to the tissue
• respond to low oxygen content of their surroundings to produce factors that induce angiogenesis
• recruit cells that re-epithelialise the wound and lay down a new extracellular matrix

Question 4

What is angiogenesis?

Answer 4

Formation of capillary buds to produce new blood vessels - pre-existing blood vessels send out capillary buds to make new vessels

Question 5

How is the process of angiogenesis performed?

Answer 5

1. Migration of endothelial cells towards angiogenic stimulus
2. Remodelling of endothelial cells into capillary tubes
3. Recruitment of peri-endothelial cells, smooth muscle cells
4. Stimulated by TGF𝛃 (transforming growth factor 𝛃), FGF (Fibroblast growth factor), PGDF (platelet derived growth factor)
   - tumours can also stimulate angiogenesis

Question 6

How is tissue repair conducted?

Answer 6

Fibroblasts (activated) and fibrocytes (maintenance) are two states of the same cell
Repair = migration and proliferation of fibroblasts triggered by growth factors - mainly macrophage derived
1. The fibroblast synthesises extracellular matrix and collagen
2. Fibrosis is the formation of excess fibrous connective tissues in an organ

Question 7

What is scarring?

Answer 7

Confluent fibrosis that obliterates the architecture of the underlying organ or tissue

Question 8

What is the effect of scarring?

Answer 8

Altered composition of new tissue affects the function of that organ or tissue
- e.g. heart after myocardial infarction, coal miners lung, cirrhosis of the liver, spinal infuris (prevents the neurons reconnecting).

Question 9

What are the outcomes of chronic inflammation?

Answer 9

Start with acute inflammation then if:

• excessive exudate = suppuration → repair and organisation or the discharge of pus → fibrosis
• excessive necrosis = repair and organisation → fibrosis
• persistant causal agent = chronic inflammation →fibrosis

Question 10

What is purulent or suppurative inflammation?

Answer 10

Persistant or excessive necrosis and cellular exudate - exudate dominated by neutrophils (pus)
- normally induced by bacteria (pyogenic bacteria)

Question 11

What is apoptosis?

Answer 11

Programmed cell death with limited activation of the immune system

Question 12

What is necrosis?

Answer 12

Premature death of cell/tissue caused by factors external to the cell - can cause an abscess leading to granuloma formation

Question 13

What are causes of necrosis?

Answer 13

Injury, infection (flesh-eating bacteria), infarction/stroke (hypoxia), reduced blood flow (gangrene), poisons (snake bite/ spider venoms)

Question 14

What is early phase necrosis?

Answer 14

Massive neutrophil accumulation in tissue cavity in response to necrosis

Question 15

What is late phase necrosis?

Answer 15

Granulation tissue develops around abscess including macrophages and lymphocytes - and an outer layer of fibroblasts and connective tissue

Question 16

What cells are involved in chronic inflammation?

Answer 16

Macrophage, monocytes in the blood are of bone marrow origin, move into tissue (macrophage) 30-60 day life span in tissue

• efficient digestion of particulates, degenerate neutrophils and microorganisms
• produce mediators which regulate inflammation

Question 17

What is the specific type of macrophage present in chronic inflammation?

Answer 17

Epithelioid macrophages (activated macrophages that resemble epithelial cells) - less phagocytic, different markers

Question 18

What are multi-nucleated giant cells?

Answer 18

Formed by fusion of epithelioid macrophages around a chronic stimulus

Question 19

What role do T cell lymphocytes play in chronic inflammation?

Answer 19

Produce inflammatory mediators - regulate chronic inflammation

Question 20

What role do plasma cells play in chronic inflammation?

Answer 20

Differentiated B cells produce antibodies
Both T and B cells are attracted by chemokines to site of chronic inflammation
Fibroblasts produce an extra layer of connective tissue - “walls off” area

Question 21

How does a granuloma form?

Answer 21

An organised collection of giant epithelioid macrophages
- Macrophages clustered around agent or or area of necrosis or accumulation of neutrophils, surrounded by collar of T lymphocytes as parts of the normal adaptive immune response, surrounded by layer of fibroblasts and connective tissue

Question 22

What are the different types of granuloma?

Answer 22

Foreign body granuloma - too big to be phagocytosed
Immune granuloma - prototype is mycobacteria - hard to kill bacteria or parasites
Abscess - surrounds an area of extensive necrosis

Question 23

How would you describe the structure of a granuloma?

Answer 23

Caseous necrosis surrounded by activated macrophages with giant cells clustered throughout. This area is surrounded by lymphocytes which are encased in fibroblast

Question 24

What are consequences of chronic inflammation?

Answer 24

Granulomatous enteritis (cow) - (mycobacterium allium), Johne's disease
- loss of function - interferes with water and nutrient uptake

Question 25

Is it a good idea to block oxygen free radicals?

Answer 25

Phagocytes (neutrophils and macrophages) have an enzyme that produces a ROS, produced in a respiratory burst + kill ingested bacteria

• Enzyme = NADPH (nicotinamide adenine dinucleotide phosphate) oxidase
• process involves oxidation of molecular oxygen to free radicals such as superoxide anion, hydrogen peroxide, hydroxyl radical and hypochlorite - ROS, help to phagocytose bacteria

Question 26

What happens if you block free oxygen radicals?

Answer 26

Block a major phagocytic killing pathway

Question 27

What is chronic granulomatous disease?

Answer 27

CGD = group of hereditary diseases in which immune cells have an impaired ability to form ROS to kill ingested bacteria

Question 28

How does CGD occur?

Answer 28

Defects in enzymes that produce ROS results in failure of phagocytic cells to kill organisms they have engulfed - leads to formation of granulomas
- people who have CGD can be infected by organisms that normally do not affect healthy individuals i.e. athersclerosis

Question 29

What are systemic effects of chronic inflammtion?

Answer 29

• Tissue dysfunction e.g. chronic renal disease, chronic enteritis - altered tissue structure interferes with function
• Persistent infection leads to persistent stimulation of immune system
• Recurrent or persistent production of cytokines (TNP)
• systemic effects of catabolic cytokines (TNF = (cacheocia)), causes wasting and release of cortisol

Question 30

What is neurodegenerative disease?

Answer 30

Stimulus = aggregated host proteins/ damaged neurons
- brain is immuno-privaleged
IL-6 acts a neurotransmitter in the hypothalamus
- induces PGE2, symptoms of infection, fever, sleep
Influx of monocytes and proliferation of microglia (brain macrophages)
Different cytokine profile to macrophages in the periphary