Tissue Repair

4

REGENERATION AND HEALING

1. Tissue repair

a.Regeneration and healing of damaged cells and tissues starts almost as soon as the inflammatory process begins.

b.Tissuerepairinvolvesfiveoverlappingprocesses: hemostasis (coagulation, platelets); inflammation(neutrophils, macrophages, lymphocytes, mast cells); regeneration (stem cells and differentiated cells); fibrosis (macro­ phages, granulation tissue [fibroblasts, angiogenesis], type III collagen); andremodeling (macrophages, fibroblasts, converting collagen III to I).

2.Regeneration

a.Different tissues have different regenerative capacities.

b.Labile cells (primarily stem cells) regenerate throughout life. Examples include surface epithelial cells (skin and mucosa! lining cells), hemato­ poietic cells, stem cells, etc.

c.Stable cells (stem cells and differentiated cells) replicate at a low level throughout life and have the capacity to divide if stimulated by some initiating event. Examples include hepatocytes, proximal tubule cells, endothelium, etc.

d.Permanent cells (fewstem cells and/ordifferentiated cellswiththe capacity to replicate) have a verylowlevel ofreplicative capacity. Examples include neurons and cardiac muscle.

3.Fibrosis and remodeling phases

a.Replacement of a damaged area by a connective tissue scar

b.Tissue repair is mediated by various growth factors and cytokines. Examples include transforming growth factor (TGF-(3), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endo­ thelial growth factor (VEGF), epidermal growth factor (EGF), tumor necrosis factor (TNF-cx) and IL-1.

i.TGF-(3 and EGF are involved in wound healing and regeneration. Both bind to the EGF receptor.

ii.VEGFs are important in inducing new vessel growth during growth, repair, and regeneration

iiiTNF. -cx and IL-1 are both important in wound healing

c.Granulation tissue shows synthetically active fibroblasts and capillary proliferation.

d.Wound contraction is mediated by myofibroblasts.

e.Scar formation

4. Primary union (healing by first intention) occurs with clean wounds when there has been little tissue damage and the wound edges are closely approximated; the classic example is a surgical incision.

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USMLE Step 1 • Pathology

5. Secondary union (healing by secondary intention) occurs in wounds that have large tissue defects and when the two edges of the wound are not in contact. Requiring larger amounts ofgranulation tissue to fillin the defect, it is often accompanied by significant wound contraction and can cause larger residual scars.

6.Repair in specific organs

a.Liver: Mild injury is repaired by regeneration ofhepatocytes, sometimes with restoration to normal pathology. Severe or persistent injury causes formation of regenerative nodules that may be surrounded by fibrosis, leading to hepatic cirrhosis.

b.In the brain, neurons do not regenerate, but microglia remove debris and astrocytes proliferate, causing gliosis.

c.Damaged heart muscle cannot regenerate, so the heart heals by fibrosis.

d.In the lung, type II pneumocytes replace both type I and type II pneu­ mocytes after injury.

e.In peripheral nerves, the distal part of the axon degenerates while the proximal part regrows slowly, using axonal sprouts to follow Schwann cells to the muscle.

ABERRATIONS IN WOUND HEALING

I . Delayed wound healing may be seen in wounds complicated by foreign bodies, infection, ischemia, diabetes, malnutrition, scurvy, etc.

2. Hypertrophic scar results in a prominent scar that is localized to the wound, due to excess production of granulation tissue and collagen.

3.Keloid formation is a genetic predisposition that is more common in Af­ rican Americans. It tends to affect the earlobes, face, neck, sternum, and forearms, and it may produce large tumor-like scars, which often extend beyond the injury site. There is excess production of collagen that is pre­ dominantly type III.

© Richard P. Usatine, M.D. Used with permission.

Figure 4-1 . Keloid on posterior surface of ear (auricle)

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Table 4-1-1. Factors InhibitingTissue Repair

Diabetes

Diseases affecting collagen and elastic fibers

Foreign bodies

Inadequate blood supply

Infection

Large size or extent of damage

Mechanical disruption of healing wound

Malnutrition or specific nutrient deficiency

Malignancy

Medications including glucocorticoids

Obesity

Old age

CONNECTIVE TISSUE COMPONENTS

1 . Collagen (over 29 types)

a.Type I collagen is the most common, has high tensile strength, and is found in skin, bone, tendons, and most organs.

b.Type II is found in cartilage and vitreous humor.

c.Type III is found in granulation tissue, embryonic tissue, uterus, and keloids.

d.Type IV is found in basement membranes.

e.Hydroxylation of collagen is mediated by vitamin C.

f.Cross-linking of collagen is performed by lysyl oxidase. Copper is a re­ quired cofactor.

2.Other extracellular matrix components

a.Elastic fibers are formed when elastin proteins are aligned on a fibrillin framework. Defects in fibrillin are found in Marfan syndrome.

b.Adhesion molecules include fibronectin and laminin.

c.Proteoglycans and glycosaminoglycans include heparan sulfate and chondroitin sulfate.

3.Basement membranes have a net negative charge. The composition of basement membranes includes collagen type IV, proteoglycans (heparan sulfate), laminin, fibronectin, and entactin.

Chapter 4 • Tissue Repair

Clinical Correlate

Scurvy:

•Vitamin C deficiency first affects collagen with highest hydroxyproline content, such as that found in blood vessels

•Thus, an early symptom is bleeding gums

Ehlers-Dantos (ED) Syndrome:

•Defect in collagen synthesis or structure

•9 defects known

•Type IV is a defect in type Ill collagen

Osteogenesis lmperfecta:

• Defect in collagen type I

Clinical Correlate

Marfan Syndrome:

•Defect in fibrillin gene, leading to laxity oftissues (long, lanky frame; lens subluxation; aortic aneurysms)

Clinical Correlate

Loss of negative charge (proteoglycan) of the renal glomerular basement membrane may cause proteinuria (nephrotic syndrome).

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USMLE Step 1 • Pathology

Chapter Summary

•Tissue repair involves regeneration ofthe damaged tissue by cells ofthe same type and healing with replacement by connective tissue.

•Tissue repair involves five overlapping processes including hemostasis, inflammation, regeneration, fibrosis, and remodeling.

•Tissues vary in their regenerative capacities. Labile cell populations that regenerate throughout life include surface epithelial cells, hematopoietic cells, and stem cells. Stable cells that replicate at a low levelthrough life, but can divide ifstimulated, include hepatocytes, proximal tubule cells, and endothelial cells. Permanent cells that cannot replicate in adult life include neurons and cardiac muscle.

•Healing with replacement of a damaged area by a connective tissue scar is mediated by many growth factors and cytokines, primarily from macrophages. Initially granulation tissue forms, which later undergoes wound contraction mediated by myofibroblasts, eventually resulting in true scar formation.

•Wound healing by first intention (primary union) occurs after clean wounds have been closely approximated. Wound healing by second intention (secondary union) occurs in wounds with larger defects in which the edges cannot be closely approximated.

•Problems that can occur with wound healing include delayed wound healing, hypertrophic scar formation, and keloid formation.

•Different types ofcollagen are found in different body sites.

-Type I collagen is the most common form.

-Type II collagen is found in cartilage.

-Type Ill collagen is an immature form found in granulation tissue.

-Type IV collagen is found in basement membranes.

Collagen production requires vitamin C and copper.

•Other extracellular matrix components include elastic fibers, adhesion molecules, and proteoglycans and glycosaminoglycans.

•Basement membranes have a net negative charge and are composed of collagen and other extracellular matrix components.

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