Fibrosis and Repair

Overview of Tissue Repair - Healing's ABCs

• Goal: Restore tissue structure & function post-injury.
• Two Paths:
  • Regeneration: Complete replacement by original cells; no scar.
  • Repair (Scarring): Fibrous tissue fills defect if regeneration fails.
• Cell Proliferative Potential:
  • Labile: Always cycling (e.g., skin, gut, marrow).
  • Stable: Quiescent (G0), can divide (e.g., liver, kidney).
  • Permanent: No significant regeneration (e.g., neurons, cardiac muscle).
• Outcome: Depends on injury severity & tissue's regenerative capacity.

⭐ Cardiac muscle, being composed of permanent cells, typically heals by fibrosis (scar formation) after an infarction, not by regeneration of myocytes.

Repair Mechanisms & Angiogenesis - New Pipes & Scaffolds

• Repair Phases:
  • Inflammation: Clears debris, initiates repair.
  • Proliferation: Granulation tissue formation, angiogenesis, re-epithelialization.
  • Remodeling: ECM deposition, scar maturation.
• Granulation Tissue: Hallmark of healing.
  • Fibroblasts (collagen synthesis).
  • New thin-walled capillaries (angiogenesis).
  • Loose ECM.
  • Inflammatory cells (macrophages).
• Angiogenesis (New Vessel Formation):
  • Key growth factors: VEGF, FGF-2.
  • Steps: Vasodilation & ↑permeability → Proteolytic degradation of BM → Endothelial cell migration & proliferation → Tube formation → Maturation.

⭐ VEGF (Vascular Endothelial Growth Factor) is the most important growth factor in angiogenesis, stimulated by hypoxia via HIF-1α.

• ECM Deposition & Remodeling:
  • TGF-β: Potent fibrogenic agent; stimulates collagen, fibronectin, proteoglycan synthesis.
  • MMPs (Matrix Metalloproteinases): Degrade ECM, crucial for remodeling. Balanced by TIMPs (Tissue Inhibitors of Metalloproteinases).

Wound Healing & Scars - Skin's Patchwork

• First Intention (Primary Union): Clean, incised, apposed edges (e.g., surgical). Minimal granulation, fibrin clot, rapid re-epithelialization, less scarring.
• Second Intention (Secondary Union): Large defects, infected wounds, ulcers. More intense inflammation, abundant granulation tissue, significant wound contraction (myofibroblasts), larger, more prominent scar.
• Phases of Healing:

• Scar Strength: Reaches ~70-80% of normal skin by 3 months; Type I collagen dominates.

⭐ Hypertrophic scars remain within wound boundaries; Keloids (📌 KEEPS growing) extend beyond, are often familial, more common in darker skin, and rich in Type III collagen.

Pathologic Fibrosis - Scars Gone Wild

Aberrant wound healing: excessive collagen & ECM deposition leading to tissue scarring and organ dysfunction. Caused by chronic inflammation or persistent injury.

• Key Cell: Myofibroblast (activated fibroblast) - primary collagen producer.
• Key Mediator: TGF-β (Transforming Growth Factor-beta) - most potent fibrogenic cytokine.
  • Promotes fibroblast migration, proliferation, & collagen synthesis.
  • Inhibits ECM breakdown (↓MMPs, ↑TIMPs).
• Consequences: Organ failure (e.g., cirrhosis, pulmonary fibrosis), constrictures, keloids.

⭐ TGF-β is the principal profibrogenic cytokine, pivotal in fibrosis development across nearly all tissues.

Healing Factors & Flops - Fixer-Uppers & Fails

• Systemic Factors:
  • Promote: Nutrition (Vit C, protein, zinc), adequate perfusion.
  • Impair: Diabetes, glucocorticoids, poor circulation, advanced age.
• Local Factors:
  • Promote: Good blood supply, no infection, immobilization.
  • Impair: Infection (major delay!), foreign bodies, ischemia, movement.
• Complications (Flops):
  • Deficient Scar: Dehiscence (rupture), ulceration.
  • Excessive Scar: Hypertrophic (raised, within borders), Keloid (grows beyond; 📌 Keloid Klimbs).
  • Contractures: Limits mobility (e.g., post-burn).

⭐ Keloids show haphazard collagen (Type I & III); common in African descent, earlobes, sternum.

High‑Yield Points - ⚡ Biggest Takeaways

• Granulation tissue formation, with fibroblasts, angiogenesis, and macrophages, is absolutely crucial for repair.
• TGF-β is the most potent fibrogenic cytokine, strongly stimulating collagen production.
• Myofibroblasts are key cells for effective wound contraction.
• Type III collagen (early) is replaced by Type I collagen (late, for strength).
• Keloids and hypertrophic scars result from excessive collagen deposition.
• Infection, diabetes, and steroids are major systemic inhibitors of wound healing.