Fibrosis
- Excess deposition of collagen and ECM in chronic disease (compared to breakdown)
- Frustrated healing and chronic inflammation
- Persistent stimulus (infection, autoimmune)
- Macrophage/leukocyte activation
- Growth factors – PDGF, FGF, TGF
- proliferation of fibroblasts, endothelial cells and spec fibrogenic cells
- activation of macrophages (IL4, IL 13, cytokines)–> attract monocytes, fibroblast activation and proliferation, increased collagen synthesis, inhibit metalloproteinases
- Eg: cirrhosis, pulmonary fibrosis, chronic pancreatitis, constrictive pericarditis
Wound healing by primary / secondary intention.
Primary intention – when the incision is closed with sutures or glue
- 24hrs -haematoma/scab formation, epithelial cells move from wound edges and fuse in midline, neutrophil migration to edge of wound
- Up to 3d – inflammation: neutrophils, leaky blood vessels–> oedema
- 3-5 days – granulation tissue, neutrophils replaced by macrophages and fibroblasts enter(collagen laid), epithelial cells proliferate and thicken the epidermal layer
- Day 5 – angiogenesis, incision filled with granulation tissue and epidermis recovers its original thickness.
- 2 Weeks – continued accumulation of collagen fibres – decreased leukocytes, oedema and vasularity.
- 1 month – wound contraction(myofibroblasts), connective tissue remodelling, scar is made of connective tissue devoid of inflammatory infiltrate. Intact epidermis.
- Recovery of tensile strength – 10% at 1 week, 70-80% at 3months.
Secondary intention – when the wound is left open and allowed to heal naturally
- Epithelialisation and contraction
- Same steps but slower and more likely to have a larger scar and possibly hypertrophic scaring.
Factors influencing healing.
| Local | Systemic |
| Poor wound approximation | Malnutrition |
| FB | Diabetes |
| Infection | Sepsis |
| Poor blood supply | Smoking |
| Denervation | Immunosuppression |
| Necrotic tissue | Hypoxia |
| Mobility at site | Anaemia |
| Tissue type | Vitamin deficiency |
| Necrotic tissue | Old age |
Pathological aspects of wound repair.
- Hypertrophic scars – within boundary of original scar but can be red, raised and pruritic – often self resolves
- Keloid scars – go beyond original scar, more common in dark skinned people, needs treatment with steroids, surgery etc.
- Chronic wounds – require debridement, irrigation and healing by secondary or tertiary intention.
Angiogenesis
- Formation of new blood vessels in the adult
- Endothelial progenitor cells from marrow
- Branching and growth of existing vessels
- Vasodilation
- Proteolytic degradation of basement membrane
- Endothelial migration to angiogenic stimuli
- Maturation
- Capillary formation
- Recruitment of periendothelial cells for support structure.
- Examples
- Wound healing, growth
- Hypertrophy eg skeletal muscle or uterus in pregnancy.
- Tumours.
Overview of cell cycle
- G0 – at rest, can be influenced by cytokines and growth factors/growth inhibitors to start G1
- G1 – start of cycle, growth in mass, cetrosome duplication, restriction point, check point for dna damage before next stage
- S – chromosome duplication
- G2 – check point for dna faults or incomplete copying
- M – mitosis
- Labile tissues eg skin, GIT continuously cycle
- Quiescent cells like hepatocytes can enter the cycle when required
- Permanent cells eg neurons have lost their ability to proliferate
Collagen: Characteristics of different types
| Collagen type | Tissue distribution | Genetic disorders |
| I | Ubiquitous in hard and soft tissues | Osteogenesis imperfecta, Ehlers- Danlos |
| II | Cartilage, Intervertebral discs, vitreous | Achondrogenesis |
| III | Hollow organs, soft tissue | Ehlers – danlos |
| IV | Basement membrane | Alport syndrome |
| V | Soft tissue, blood vessels | Ehlers Danlos |
Other constituents of extracellular matrix
- Proteoglycan
- Laminin
- Elastin
- Hyaluronan
- Glycoproteins