General Pathology

Theme 8: Tissue Healing and Repair

  1. Appreciate the relationship between Cellular Growth, Fibrosis and Wound Healing.
  2. Describe the process and outcome of regeneration.
  3. Describe the process and outcome of fibrous connective tissue repair.
  4. List the factors that influence wound healing and describe the possible complications.
  5. Present an overview of the inflammatory-reparative response.
  6. Discuss the clinico-pathological consequences of damage and healing in specific tissues: liver, kidney, lung, heart, nervous system and bone.

Cell Types and Regenerative Ability

Labile Cells

Cells with a short lifespan that constantly proliferate and are lost from the body: skin, gut, hematopoetic cells. Cells have short G0 (resting, or intermitotic) phase. Continued loss of mature cells is a continuous stimulus for resting cells to enter the mitotic cell cycle.

Permanent Cells

Cells that cannot regenerate once they are destroyed. A destroyed cell will form a scar. Brain, Heart. Cells exit the cell cycle and cannot regenerate.

Stable Cells

Cells that have a long lifespan and a very low rate of division. They remain in G0 phase of the cell-cycle for long periods and don't normally divide, but can enter the mitotic cycle and be induced to divide quickly upon injury. These cells have good regenerative capacity. Liver, Renal proximal convoluted tubule. Unlike labile cells, which are undifferentiated cells that divide frequently and must undergo maturation before becoming functional, stable cells are differentiated functional cells that only revert to a dividing mode at need. Such cells heal by regeneration when (1) enough viable tissue remain to regenerate; (2) connective tissue framework is intact. When necrosis of both the parenchyma and connective tissue framework occurs (e.g. renal infarct), no regeneration is possible and healing occurs by scar formation.
Role of Glycoproteins and Proteoglycans

The extracellular matrix (ECM) consists of the materials over which cells migrate and travel during development and wound-healing. They are:

Collagen

Basement Membrane

Elastic Fibres

Glycoproteins

Integrins

Transmembrane proteins that interact with the ECM. They may act as a communication link between intracellular environment and extracellular matrix. Via integrins, the ECM can modify cell behavior. Integrins are the major family of cell surface receptors that mediate cellular attachment to the ECM. Many integrins are widely expressed, and most cells have more than one integrin on the cell surface. Integrin receptors span the cell membrane and bind to many components (e.g., fibronectin, laminin, and some collagens) of the ECM. Integrin receptors are important both in organizing the actin cytoskeleton of cells at points of focal adhesion and in transduction of signals from the ECM to the cell interior. The mechanical linkage between the integrin receptors and the cytoskeletal signaling system may be a mechanism by which cells convert mechanical force into biochemical signals.

Proteoglycans and Hyaluronan

Proteoglycans are ECM components that consist of a core protein linked to one or more polysaccharides called glycosaminoglycans. Olycosaminoglycans are long repeating polymers of modified disaccharides (e.g., heparan sulfate). Proteoglycans can also be integral membrane proteins, as in the syndecan family, in which the core protein spans the plasma membrane.

Hyaluronan is a huge molecule consisting of many repeats of a disaccharide. It serves as a ligand for core proteins and cell surface receptors. Hyaluronan binds large amounts of water, which helps give connective tissue turgor pressure and the ability to resist compression forces.

Tissue injuries associated with inflammation are eventually followed by some form of healing. Resolution is the ideal result of healing where the tissue is restored to the normal (pre-injury) state. After removal of cellular debris associated with the inflammation, any necrotic parenchymal cells are replaced by new parenchymal cells of the same type in a process known as regeneration.

When resolution and regeneration are not possible, necrotic cells are replaced with collagen in a process called organisation, or repair by scar formation.

Regeneration

Replacement of lost parenchymal cells by division of adjacent surviving cells (regeneration) can restore injured tissue to normal. This depends on:

  1. regenerative capacity of involved cells.
  2. number of surviving viable cells.
  3. presence of a connective tissue framework that will provide a base for restoration of normal tissue structure.
Before regeneration can occur, necrotic cells must be removed. This involves an acute inflammatory response, liquefaction of cells by neutrophil enzymes and removal of debris by lymphatics and macrophages.

Organisation, Repair by Scar Formation

As tissue destruction in wound healing and chronic inflammation involves both parenchymal cells and the stromal framework, repair cannot be accomplished solely by regeneration of parenchymal cells. Repair thus involves in large part the replacement of lost cells and tissues by connective tissue, which, in time, produces fibrosis and scarring. Connective tissue repair is the systematic processes by which unregenerated damage is replaced by fibrosis and scarring. The initial response to a wound consists of the formation of Granulation tissue, which consists of a richly vascular connective tissue, containing new capillaries, proliferating fibroblasts, and variable numbers of inflammatory cells. (Note: Granulation tissue must be distinguished from granuloma, which is an aggregate of macrophages associated with chronic inflammation.)

There are four components to this orderly process:

  1. Formation of new blood vessels (angiogenesis), spanning the wound;
  2. Migration and proliferation of fibroblasts filling and bridging the wound;
  3. Deposition of ECM and;
  4. Maturation and reorganization of the fibrous tissue into a scar, also known as remodeling.

Angiogenesis

Angiogenesis is critical for chronic inflammation, formation of collateral circulation, and tumor growth. Blood vessels are assembled by two processes:
  1. Vasculogenesis, in which a primitive vascular network is assembled during development, and;
  2. Angiogenesis (or neovascularization), in which preexisting blood vessels give rise to capillary buds to produce new vessels. Fibroblast Growth Factor (FGF) is a cytokine that is thought to induce angiogenesis.
Multiple steps underlie angiogenesis:
  1. proteolytic degradation of the basement membrane of the parent vessel basement membrane;
  2. endothelial cell migration and formation of a capillary sprout;
  3. proliferation and maturation of endothelial cells, which includes remodeling into capillary tubes; and recruitment of periendothelial cells, including pericytes for small capillaries and vascular smooth muscle cells for larger vessels to support the endothelial tubes.
The formation, maintenance, and remodeling of blood vessels are controlled by the following:

Fibrosis (Fibroplasia)

Fibrosis occurs within the granulation tissue framework formed at the site of repair and involves two processes:
  1. Fibroblast migration and proliferation: Increased vascular permeability leads to the deposition of plasma proteins, such as fibronectin and fibrinogen, which provide a provisional stroma for ingrowth of fibroblasts. Migration of fibroblasts and their subsequent proliferation is also mediated by growth factors such as PDGF, EGF, FGF, and TGF-ß and the fibrogenic cytokines IL-l and TNF-a.
  2. ECM deposition: As repair progresses, the number of proliferating endothelial cells and fibroblasts decreases. The fibroblasts become more synthetic and deposit increased amounts of collagen and other components of the ECM. Collagen synthesis is stimulated by growth factors (e.g., PDGF, FGF) and by cytokines (e.g., IL-l) secreted by fibroblasts and leukocytes in healing wounds. TGF-ß is thought to play a particularly important role in chronic inflammatory fibrosis. Eventually the granulation tissue scafolding is converted into a scar composed of fibroblasts and collagen.

Tissue Remodelling or Scar Formation

The replacement of granulation tissue with a scar involves transitions in the composition of the ECM. Some of the growth factors that stimulate synthesis of collagen and other connective tissue molecules modulate the synthesis and activation of matrix metalloproteinases (MMPs), enzymes that serve to degrade these ECM components. MMPs consist of interstitial collagenases, which cleave the fibrillar collagen types I, II, and III; gelatinases (or type W collagenases), which degrade amorphous collagen as well as fibronectin; stromelysins, which act on a variety of ECM components, including proteoglycans, laminin, fibronectin, and amorphous collagens; and the family of membrane-bound MMPs, which are cell surface-associated proteases. Secretion of MMPs by fibroblasts and leukocytes is induced by growth factors and cytokines and inhibited by TGF-ß. The enzymes are secreted as proenzymes, which are activated extracellularly. Activated MMPs can be rapidly inhibited by a family of specific tissue inhibitors of metalloproteinase. The net effect of ECM synthesis versus degradation results in debridement of injured sites and remodeling of the connective tissues framework-important features of both chronic inflammation and wound repair.

Wound Healing

Wound healing is a complex but orderly phenomenon involving many of the processes just described:

Healing by First (Primary) Intention

Clean incised wounds and lacterations in which the edges of the wound are in close apposition heal by first intention.

The young scar that becomes visible when the scab separates from the skin is initally pink because of the vascularity of the dermal granulation tissue but over the next few weeks the scar turns white as a result of a decrease in number of blood vessels and an increased amount of collagen in the maturing scar. Eventually the scar assumes normal skin colour as the epidermis matures.

Healing by Second (Secondary) Intention

Healing by second intention occurs when there is more extensive loss of tissue, such as:
  1. lacerations characterized by inability to achieve opposition of wound margins (e.g., uneven cut);
  2. foreign material is present;
  3. necrosis is extensive (e.g., infarction, ulceration);
  4. infection occurs (e.g., abscess formation);
  5. large wounds.
Abundant granulation tissue grows in from the margins to fill the defect, but at the same time the wound contracts; that is, the defect is markedly reduced from its original size. Myofibroblasts contribute to wound contraction.

Debridement

Surgical removal of dead tissue and foreign material from the wound. This aids healing by clearing away the debris associated with inflammation.

Demolition

Wound Strength

Tensile strength of the young scar is only about 10% that of normal skin but increases to 30%-50% of normal skin by 4 weeks and to 80% after several months. The latter is associated with first increased collagen synthesis exceeding degradation and subsequently with the cross-linking and increased fiber size of collagen fibres.

Local and Systemic Factors that Influence Wound Healing

Local Factors

Systemic Factors

Pathologic Aspects of Wound Healing

Complications in wound healing can arise from abnormalities in any of the basic repair processes. These aberrations can be grouped into 3 general categories:

Clinico-Pathological Consequences of Damage and Healing in Specific Tissues

Cirrhosis

Result of a chronically damaged liver. Histologically, it a combination of regenerated liver cells interspersed with fibrosis.

Cardiac Disease

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