LO: Describe the causes of chronic (including granulomatous) inflammation, the cells-mediators which are involved and the process of regeneration and repair

Chronic inflammation

• Prolonged inflammation (weeks to months) due to persistence of stimulus
• Characterised by macrophages, lymphocytes and plasma cells in tissue
• Delayed response but more specific (adaptive immunity)

Causes

• Persistent infection
• Infection with viruses, mycobacteria, parasites or fungi
• Autoimmune disease
• Allergic conditions
• Foreign material
• Carcinoma

Macrophages

• Dominant cell in most chronic inflammatory reactions
• Derive from haematopoietic stem cells
• Circulate as monocytes
• In connective tissue
• Half-life is about a day in monocytes
• Tissue macrophages half life is several months/years
• Dominant within 2 days post-insult

M1

• Activated by bacteria or by interferon gamma from T-cells
• Stimulate inflammation

M2

• Activated by IL-4 or IL-13 from T-cells
• Stimulate repair

Lymphocytes

• T and B cells
• Produced in bone marrow - T cells mature in thymus
• Thymus
  • CD4+ helper T cells
  • CD8+ cytotoxic T cells
  • Produced from progenitor T cells
• T cells use TCR complex (TCR+CD3) for surveillance
• Recognise antigen bound to MHC molecule and need a second signal for activation

CD4+ helper T cell activation

• Extracellular antigens processed by antigen presenting cells and presented in association with MHC class II on cell surface
• B7 - provides second activation signal for T helper cells
• TCR complex binds to antigen on MHC II and CD28 binds to B7 - second signal
• T_h1 - secrete interferon gamma and recruit macrophages
• T_h2 - secrete IL-4 and IL-5 and recruit eosinophils

CD8+ cytotoxic T cell activation

• Intracellular antigens
• Proteins processed and presented on MHC I
• Cytotoxic T cells bind to MHC complex
• IL-2 by CD4+ T helper 1 cells provides second activation signal
• Cytotoxic T cells activated for killing
• Secretion of perforin and granzyme
• Perforin - creates pores allowing granzyme to enter
• Granzyme - destroy target cell
• Binding of FAS ligand to FAS on target cell
• Ends with apoptosis

B-lymphocytes

• B cell receptors (BCRs)
• BCR recognises a particular antigen
• Activated - B cells differentiate into plasma cells
• Plasma cells - produce large amount of antibodies that bind specifically to antigen
• Activate - B cells differentiate into memory B cells
• Memory B cells - remain in body and allow faster and stronger response if same antigen encountered again
• Antibodies - tags, flags cells to immune system for destruction
• Neutralise virus and bacteria to stop getting into cells

Eosinophils

• Abundant in immune reactions mediated by T_h2 cells - parasitic infections and some allergies
• Recruitment driven by adhesion molecules
• Granules that contain major basic protein - highly cationic protein that is toxic to helminths but may injure host epithelial cells
• Benefit in controlling helminth infections
• Contribute to tissue damage in immune reactions - allergies

Mast cells

• Widely distributed in connective tissues and are in both acute and chronic inflammatory reactions
• In hypersensitivity reactions - release mediators such as histamine and prostaglandins
• Hypersensitivity type I - allergies
• Secrete cytokines - promote inflammatory reactions in different situations

Granulomatous inflammation

• Collection of activated macrophages/epithelioid histiocytes
• Non-caseating or caseating
• Foreign material, sarcoidosis, Crohn's disease, cat scratch disease

Sarcoidosis

• Enlargement of the hilar lymph nodes bilaterally
• In lungs - granulomas around bronchioles

Wound healing

• Healing initiates when inflammation begins
• Occurs via a combination of regeneration and repair
• Regeneration:
  • Occurs when cells divide
  • Tissue's supporting framework is preserved
• Repair:
  • Damage is extensive, supporting framework is destroyed or tissue has limited regenerative capacity
  • Involved new blood vessel formation, fibroblast activity and collagen deposition

How wounds heal

• Replacement of damaged tissue with native tissue - dependent on the regenerative capacity of the tissue
• Labile - continuously dividing
• Stable - quiescent (not actively dividing)
• Permanent - non-dividing

Phases

• Coagulation

• Inflammatory

• Proliferative/granulation tissue

• Remodelling

• Early phase of wound healing is the transition from acute inflammation - immediate

• Inflammatory phase included coagulation and infiltration of cells that participate in healing

• Fibrin mesh of the blood clot acts as a scaffold for these cells

• Platelets - clot formation and release growth factors that begin the proliferation of undamaged cells

• Neutrophils - clear wound of debris and bacteria, replaced by macrophages

• Macrophages - release wound healing mediators and growth factors, which recruit fibroblasts and help promote formation of a new blood supply (angiogenesis) during the proliferative phase of wound healing

Repair

• Repair needed if stem cells are lost of damaged tissue is a permanent type
• Platelets congregate and degranulate
• Neutrophils arrive and later the macrophages - inflammatory phase
• Damaged epithelial, platelets and macrophages produce growth factors which cause new vessels to grow into the wound - proliferative phase, which forms granulation tissue

Growth factors

• Transforming growth factor (TGF)-alpha - epithelial and fibroblast growth
• TGF-beta - fibroblast growth and inhibition of inflammation
• Platelet derived growth factor (PDGF) - growth of endothelium, smooth muscle and fibroblasts
• Fibroblast growth factor (FGF) - angiogenesis and fibroblast proliferation
• Vascular endothelial growth factor (VEGF) - angiogenesis

Primary intention

• Wound edges brought together (suturing)
• Minimal scarring

Secondary intention

• Edges not brought together
• Granulation tissue fills up the gap
• Myofibroblasts contract the wound
• Scar forms

Hypertrophic scar

• Excess production of scar tissue
• Localised to wound

Keloid scar

• Exuberant production of scar tissue out of proportion of wound size
• Excess type III collagen

Keloid

• Form on head and neck, ear lobes, shoulder and chest - can be quite exuberant
• Grow over the margin of original injury
• Persist for many years before keloids flatten

Delayed wound healing

• Infection - continues production of PAMPs, promoting acute inflammation
• Ischaemia - inflammatory phase is dependent on cells coming out of blood vessels
• Foreign bodies - nidus for infection and impair healing
• Diabetes - sweeter blood, narrows blood vessels due to sugar damaging endothelium, impair growth factor production
• Malnutrition - nutrients essential to healing, vitamin C (collagen cross-linking), copper(collagen cross-linking, zinc (cofactor for collagenase)