Chronic inflammation

Question 1

What is chronic inflammation?

Answer 1

Chronic inflammation is prolonged inflammation ( >3 months), where tissue injury & attempts at repair coexist, in varying combinations

Question 2

What causes chronic inflammation?

Answer 2

1. Persistent infections - by microorganisms that are difficult to eradicate e.g. mycobacteria, some viruses, fungi & parasites.
2. Hypersensitivity diseases - Autoimmune diseases or Allergic diseases.
3. Foreign material e.g. thorn, hair…
4. Carcinoma - the immune system reacts to abnormal proteins found in tumour cells.

Question 3

What are the morphologic features of chronic inflammation?

Answer 3

• Infiltration by mononuclear cells e.g. macrophages, lymphocytes & plasma cells.
• Tissue destruction
• Attempts at healing - by angiogenesis & fibrosis.

Question 4

What are the cells involved in inflammation?

Answer 4

Macrophages

Lymphocytes

Plasma cells

Question 5

What is the role of macrophages in chronic inflammation?

Answer 5

Dominant cell in most chronic inflammatory reactions.
- Become dominant 2 days after infection or injury.

Role
- They secrete cytokines & growth factors
- Destroy foreign invaders & tissues
- Activate other cells e.g. T-lymphocytes.

Question 6

Where are macrophages derived from?

Answer 6

Derived from haematopoietic stem cells in bone marrow.

Circulate as monocytes before activation.

Question 7

Where are macrophages found inn the body?

Answer 7

-Connective tissue
- CNS (Microglia)
- Liver (Kuppfer cells)
- Lymph nodes (Sinus histiocytes)
- Lungs (Alveolar macrophages)
- Spleen (Sinus histiocytes)

Question 8

Explain the function of the 2 different macrophage subtypes & what activates them?

Answer 8

1. M1 - activated by bacteria or interferon gamma (INF-𝛄) from T-cells. M1 macrophages will:
   - Present antigens
   - Produce NO and ROS
   - Upregulate lysomal enzymes.
   - Secrete cytokines that stimulate inflammation e.g. IL-1, TNF-⍺, IL-6 & IL-12. Interleukin-12 causes T-helper cells to differentiate into TH1 cells.
   - CLASSICAL MACROPHAGE ACTIVATION
2. M2 - activated by IL-4 or IL-13 from T-cells. M2 will:
   - Secrete growth factors e.g. IL-10, TGF-β
   - Stimulate angiogenesis
   - Stimulate collagen synthesis
   - ALTERNATIVE MACROPHAGE ACTIVATION

Question 9

Name the lymphocytes seen in chronic inflammation

Answer 9

1. T lymphocytes
2. B lymphocytes

Question 10

What is granulomatous inflammation? What is a granuloma?

Answer 10

A form of chronic inflammation which the body uses to get rid of pathogens which are difficult to eliminate

A granuloma- collection of activated macrophages also called epithelioid histiocytes.
- Epithelioid= resembling epithelial cells but there are no actual epithelial cells, just macrophages.

Question 11

How can granulomas be classified?

Answer 11

Either caseating or non-caseating.

Caseating:
central region of necrosis
- appear cheese-like
- Usually in lungs

Non-caseating:
- no central region of necrosis
- occur more commonly

Question 12

Give an example of each classification

Answer 12

Caseating granulomas- seen in:
-mycobacterium tuberculosis infection (TB)
- Fungal infection
- Syphilis - Treponema pallidum infection.
- Mycobacterium leprae - cause of leprosy.

Non-caseating granulomas seen in:
- Foreign bodies
- Sarcoidosis - involves the lung & lymph nodes.
- Crohns’ disease - form of inflammatory bowl disease.
- Cat scratch disease - Bartonella henselae infection (bacterial)

Question 13

How do Granulomas form?

Answer 13

1. Macrophages present antigen on their surfaces with MHC II molecules to helper T-cells
2. Macrophages then secrete IL-12 which causes helper T cells to differentiate into TH1 cells
3. TH1 cells secrete interferon gamma (IN-Y) & IL-2
4. Interferon gamma then converts macrophages into granulomas & giant cells- I.e. macrophage activation
5. Macrophages & T-cells secrete TNF alpha
   - Increased accumulation of inflammatory cells

NOTE: interferon gamma production can be detected clinically to help make a diagnosis of tuberculosis.

Question 14

When does process of wound healing occur?

Answer 14

Healing begins when inflammation begins.

Question 15

What does wound healing involve?

Answer 15

Tissue regeneration & repair.

This is dependent on the regenerative capacity of the tissue.

Question 16

What are the 3 types of tissue based on regenerative capacity?

Answer 16

1. Labile - contain stem cells e.g. skin, bowel lining & bone marrow.
2. Stable - quiescent (dormant) but can regenerate in the need arises e.g. liver (hyperplasia).
3. Permanent - lack significant regenerative potential e.g. myocardium, skeletal muscle & neurons.

Question 17

Explain the 4 phases of wound healing

Answer 17

Coagulation Phase:
- Damage to blood vessels brings Hageman factor into contact w/ collagen, which starts clotting cascade.
- Thrombus is formed.

Inflammatory Phase:

1. Platelets:
   - Platelets contribute to clot formation (coagulation).
   - fibrin mesh of the blood clot acts as a scaffold for the immune cells.
   - Platelets degranulate & release growth factors e.g. PDGF. Stimulates proliferation by mitosis of undamaged cells.
2. Neutrophils:
   - Clear* wound of debris & bacteria.
3. Macrophages:
   - Replace neutrophils to continue removing debris & bacteria.
   - They release wound healing mediators e.g. IL-10.
   - Release growth factors that recruit fibroblasts & help promote the formation of new blood supply (angiogenesis).
   - NOTE: angiogenesis occurs in the proliferative phase of wound healing.

Proliferative/ granulation tissue phase;
- Starts 3 days after injury.
- Granulation tissue forms - this is a proliferation of new capillaries & fibroblasts.
- Fibroblasts deposit type 3 collagen.

Remodelling phase:
- 1-2 weeks after injury
- Myofibroblasts remodel the extracellular matrix.
- Remodelling followed by apoptosis & aceullular scar formation.

Question 18

Name the growth factors in healing & their effect

Answer 18

• Transforming Growth Factor alpha (TGF-α) - epithelial & fibroblast growth.
• Transforming Growth Factor beta (TGF-β) - fibroblast growth & inhibits inflammation.
• Platelet Derived Growth Factor (PDGF) - growth of endothelium, smooth muscle & fibroblasts.
• Fibroblast Growth Factor (FGF) - Angiogenesis & fibroblast proliferation.

-Vascular Endothelial Growth Factor(VEGF) - angiogenesis

Question 19

What are the 2 types of surgical wound healing?

Answer 19

Primary Intention - wound edges brought together = minimal scarring.

Secondary Intention - edges not brought together.
- Occurs when there is lots of tissue loss or there is a need to delay wound closure e.g. infection.
- Granulation tissue fills the gap, then myofibroblasts contract the wound = scar forms.

Question 20

What are the 2 types of excess scar formation?

Answer 20

Hypertrophic scar
- excess production of scar tissue that is localised to the would.

Keloid Scar
- Scar overgrows the wound edges.
Due to an excess of Type III collagen
- More common in black people.

Question 21

What can delay wound healing?

Answer 21

Infection - continued production of PAMPs = more acute inflammation.

Ischaemia - cells can’t get to site if blood flow is impaired.

Foreign bodies - act as a ‘nidus’ (nest) for infection.

Diabetes- pathogens love sugar. Diabetes narrows blood vessels & impair growth factor production.

Malnutrition - Vit C is needed for collagen cross linking; Zinc is a co-factor for collengenase (which replaces type III collagen from graulation tissue w/ stronger type I).

Question 22

Name one vitamin & two minerals which are important for wound healing. How do these contribute to the wound healing process?

Answer 22

Vitamin C, copper & zinc.

Deficiencies of vitamin C and copper will delay healing as both are involved in the formation of collagen crosslinks.

Zinc deficiency - zinc is a co-factor for collagenase which is required to replace type 3 collagen with type 1 collagen.