Lecture 3-4 -- Chronic Inflammation and Healing

These flashcards cover key concepts regarding inflammation, healing processes, and outcomes as discussed in the lecture on Inflammation and Healing.

What are the four possible outcomes of acute inflammation?

• Complete resolution

• Progression to chronic inflammation

• Healing by fibrosis

• Abscess formation

What happens if acute inflammation completely resolves?

• Return to normal vascular permeability

• Drainage of fluid and proteins into lymphatics

• Drainage of macrophages (pinocytosis)

  • Macrophages remove remaining fluid and small particles

• Phagocytosis of degenerated neutrophils

  • Dead or dying neutrophils are cleared by macrophages

• Phagocytosis of necrotic debris

  • Macrophages digest damaged tissue and cellular debris.

• Removal of macrophages

  • Macrophages either leave via lymphatics or undergo apoptosis once cleanup is complete

What factors are likely to result in chronic inflammation?

1. Persistent infections

   • Mycobacteria, certain fungi and parasites

2. Prolonged irritation

   • Foreign material, exogenous and endogenous toxins

3. Cellular immune response: Autoimmunity/ Viral infections

Which inflammatory cells are typically seen in chronic inflammation?

• Macrophages

• Lymphocytes

• Plasma cells (Specialised B cells)

• Mast cells (especially in parasitic infections)

• Eosinophils (especially in parasitic infections)

• Sometimes neutrophils (in chronic suppurative 化膿 inflammation)

How do macrophages accumulate in chronic inflammation?

• Continued recruitment of monocytes from circulating blood

  • Once one macrophage is activated, it induces the endothelium to express the right receptors to recruit more monocytes out of the circulating pool

• Local proliferation of macrophages in tissues

• Immobilisation/retention of macrophages at the site of inflammation

  • Cytokines are released to keep those macrophages in place

What are the main roles of macrophages as inflammation progresses?

• Phagocytosis

• Antigen presentation (via MHC II)

  • Macrophages phagocytose bacteria (Extracellular pathogen) → Peptide fragments are produced via lysozyme → Peptide then binds to MHC II molecules → CD4+ helper T cells recognise the complex

• Secretory functions

  • Pro-inflammatory (Produce IL-1, TNF)

  • Pro-coagulatory factors

  • Immune regulatory products

  • Enzymes

• Wound healing / tissue repair

• Regulation of monocyte and granulocyte pools (via growth factors)

What types of cells determine whether tissue can regenerate during repair?

1. Labile cells

2. Stable cells

3. Permanent cells

Give examples of labile cells and their characteristics.

Examples of labile cells:

• Epidermis, GI tract epithelial cells, Haematopoietic cells in bone marrow

Characteristics (= Continuously dividing cells)

• High capacity for regeneration

• Have a large population of stem cells

Give examples of stable cells and their characteristics.

Examples:

• Hepatocytes in the liver

Characteristics (= Quiescent cells)

• Very low level of replication

• Can proliferate when stimulated by injury

• BUT not as good as labile cells

Give examples of permanent cells and their characteristics.

Examples:

• Neurons in the brain

• Cardiac muscle cells

• Skeletal muscle cells

Characteristics (= Non-dividing cells):

• Cannot undergo mitosis

Describe the process of tissue repair after injury.

1. Persistent stimulus / injury → Activates macrophages and lymphocytes

2. Release of growth factors such as:

   • TGF-β (Transforming Growth Factor-β)

   • EGF (Epidermal Growth Factor)

   • FGF (Fibroblast Growth Factor)

   • VEGF (Vascular Endothelial Growth Factor)

3. Growth factor stimulates epithelial cells, endothelial cells, parenchymal cells and fibroblasts proliferation

4. Extracellular matrix deposition

   • VEGF increases vascular permeability → Fibrinogen leaks into the injured tissue → Fibrinogen is converted to fibrin → Fibrin forms a temporary extracellular matrix (ECM) scaffold that allows fibroblasts to migrate into the injury site

5. Granulation tissue formation

   • Fibroblasts produce collagen

   • New blood vessels form (angiogenesis).

   • This creates immature granulation tissue

6. Tissue remodelling and maturation
   As inflammation subsides:

   • Inflammatory cells decrease

   • Collagen fibers re-organise (align parallel to the tissue surface)

   • Blood vessels become more organised (perpendicular to the greatest plane of tension)

   • Epithelialization completes

7. ± Scaring

   • Tissue may return to normal structure or

   • Scar formation (= fibrosis) may occur

How does the extracellular matrix (ECM) contribute to tissue remodeling?

The ECM provides structural support for cells and helps regulate cellular functions, contributing to the strength and stability during and after tissue healing.

What mediates the production of collagen by fibroblasts during tissue repair?

Cytokines, IL-1, IL-4, IL-13 and TNF produced by activated macrophages and lymphocytes

P.S. From immunology lecture, with IL-4 and IL-13 cytokines, macrophages change to phenotype II, which produce RELM-alpha → Help with deposition of ECM and wound healing

What mediates the process of tissue remodeling?

MMPs (Matrix Metalloproteinases) and their inhibitors TIMPs (Tissue Inhibitors of Metalloproteinases) produced by fibroblasts, neutrophils and macrophages etc.

P.S. MMPs break down the ECM; TIMPs prevent excessive break down of ECM

What is the difference between healing by first intention and healing by second intention?

Healing by first intention:

• Occurs in wounds with opposed edges (e.g., surgical wounds)

• Minimal disruption of basement membrane

• Only small inflammatory response in dermis e.g. presence of neutrophil and little formation of new blood vessels

Healing by second intention:

• Occurs in wounds with large tissue defects where edges cannot be closed

• More intense inflammatory reaction (e.g., ulcers, abscesses, infarction)

• Formation of larger amount of granulation tissue to fill the tissue defect → Epithelium may not regenerate to how it was initially → Cause puckering 起皺 of overlying epidermis → Larger scar formation

What is the difference between immature granulation tissue and maturing granulation tissue?

Immature granulation tissue:

• Many inflammatory cells

• No epidermis (Keratinised) on the top layer

• Little collagen

• Oedema (White space between the inflammatory cells)

• Newly blood vessels

Maturing granulation tissue:

• Fewer inflammatory cells

• Epithelialisation completed

• More organised collagen (Parallel to overlying surface)

• More organised blood vessels (Perpendicular to the tissue surface)

What systemic factors influence wound healing?

• Nutrition

  • Poor nutrition slows wound healing

• Hormones

  • Insulin

    • In diabetes mellitus, insulin deficiency or resistance leads to delayed wound healing

  • Steroids

    • High levels of endogenous steroids (e.g., adrenal gland disorders) or steroid medication suppress inflammation and delay healing

What local factors influence wound healing?

• Bacterial infection

• Mechanical factors

  • Movement disrupts healing

  • Example: Immobilising a fractured limb helps healing

• Foreign material

• Size and type of tissue injury

• Location of the wound

• Poor perfusion

What are abnormalities in wound healing?

Deficient granulation tissue and scar formation

• Wound dehiscence = Wound breakdown

• Ulceration

What are abscesses?

Inflammation buried in a confined space, tissue or organ, caused by necrosis

What are the layers of an abscess?

• Inner layer:

  • Purulent exudate (pus) with liquefaction

• Middle layer:

  • Immature, cell-rich granulation tissue

  • Red in colour (Contains lots of blood vessels)

• Outer layer:

  • Mature, cell-poor, fiber-rich granulation tissue

  • Whiter (As the inflammation subsides, collagen dominants and blood vessel decreases)

What are the possible causes of abscesses?

• Bacteria with low hyaluronidase

  • Spread slowly but induce a strong local inflammatory reaction (stasis, thrombosis).

• Tissue necrosis caused by:

  • Bacterial toxins → damage blood vessels

  • Reduced perfusion → hypoxia → necrosis

• Neutrophil emigration

  • Neutrophils phagocytose bacteria → release enzymes → tissue necrosis

What are ulcers?

Full thickness defect in epithelium, surface of a tissue or organ due to sloughing of inflammatory necrotic tissue

What is granulomatous inflammation?

Occurs when the injurious agent cannot phagocytosed and degraded easily

What type of cells dominate in granulomatous inflammation?

Macrophages

What are giant cells?

Giant cells = Multi-nucleated cells formed by epithelioid macrophages fusing together

• Foreign body giant cells

• Langhans’ giant cells

What is granuloma?

Focal area of granulomatous inflammation

What is the typical structure of a granuloma?

• Rim of fibroblasts and connective tissue

• Periphery: Lymphocytes and plasma cells

• Centre: Macrophages and epithelioid cells