Keywords for Chapter 3, Repair, Regeneration, and Fibrosis

Keywords: Chapter 3, Repair, Regeneration, and Fibrosis

angiogenesis

During the formation of granulation tissue, the process of angiogenesis leads to the formation of numerous small capillaries. These capillaries can be seen from the surface of the wound, and resemble small red granules, which accounts for the name. The exuberant growth of new blood vessels is brought about by the influence of fibroblast growth factor (FGF), and perhaps other cytokines. Angiogenesis also occurs during the formation of tumors, both benign and malignant. Certain infections also induce angiogenesis (e.g., Bartonellosis and bacillary angiomatosis).

callus

A callus is a type of granulation tissue that contains bone cartilage.

cirrhosis

The liver heals by regeneration. If chronic injury occurs (e.g., alchoholism, chronic hepatitis, or right heart failure) then a combination of regeneration and fibrosis ensues, due to the fact that the extracellular matrix has become damaged. The regenerating cells don't know how to put themselves back together properly, so they form nodules. Bile ducts proliferate to try to drain bile from these nodules. The nodular appearance of the gross liver is then termed cirrhosis. Sometimes qualifying terms are used, such as "alcoholic cirrhosis" or "cardiac cirrhosis", depending upon the etiology. Occasionally one hears the terms "micronodular cirrhosis" and "macronodular cirrhosis". These terms refer to the gross appearance of the liver. Micronodular cirrhosis is generally considered to be of the alcoholic type, whereas macronodules are associated with chronic active hepatitis. These terms are not really very useful anymore, since other diseases besides alcoholism and hepatitis can result in a cirrhotic liver (e.g., Wilson disease, and primary biliary cirrhosis, see page 416).

collagen

The collagens are a family of closely related proteins, with a triple helix protein structure. Numerous collagen types have been identified (>10); however, the following represent the most important types:

Type I: Type I collagen is the principal component of bone, skin, and tendon, and is the predominant type of collagen in a mature cicatrix (scar)
Type II: Type II collagen is the major type found in cartilage.
Type III: Type III collagen is abundant in embryonic tissues. In the adult it predominates in pliable organs, such as blood vessels, the uterus, and the GI tract.
Type IV: Type IV collagen is found exclusively in basement membranes.

contracture

A contracture occurs when there is an exuberant contraction phase of wound healing. This can result in a deformed scar, sometimes with consequences for the function of a limb. Occasionally, contracture occurs without any injury, for example, in Dupuytren contracture, the hands become deformed for unknown reasons (pg. 92).

cytokine

A vast array of relatively low molecular weight, pharmacologically active proteins that are secreted by one cell for the purpose of altering either its own functions (autocrine effect) or those of adjacent cells (paracrine effect). In some instances, cytokines enter the circulation and have one or more of their effects systemically. TNF-alpha is an example of a cytokine that can have the latter kinds of effects. In many instances, individual cytokines have multiple biological activities. Different cytokines can also have the same activity, which provides for functional redundancy within the inflammatory and immune systems, i.e., it is infrequent that loss or neutralization of one cytokine will markedly interfere with either of these systems. This fact has great significance in the development of therapeutic strategies. Among the cytokine group are a large number of interleukins plus growth and colony-stimulating factors.

dehiscence

Dehiscence is literally the bursting of a wound (page 59). Abdominal wounds are the biggest problem. Systemic factors play a major role in wound dehiscence, since the patient may experience vomiting or coughing (physical factors), or wound infection, or poor nutrition (especially vitamin C). Mortality is high, about 30%. It is treated by using artificial grafts, or large retention sutures to keep the edges of the wound apposed.

elastic fibers

Elastic fibers are composed of a protein called elastin. It is rich in glycine and proline, like collagen, but differs in that it contains almost no hydroxylated amino acids. Its major feature is elastic recoil, therefore, it is found in pliable structures like artery walls and the uterus. Defects in elastic fibers result in the genetic disease, Marfan syndrome.

epidermal growth factor (EGF)

EGF binds to a transmembrane receptor found on most epithelial cells, where it activates a kinase (phosphorylating enzyme). This action induces proliferation of epithelial cells and promotes wound healing. EGF may also serve as a carcinogenic trigger in some instances; for example, it may induce proliferation of breast glandular epithelium in response to estrogen. Over a lifetime of un-interrupted (by pregnancy) stimulation, it may produce an abnormal epithelial growth.

extracellular matrix

A stable complex of macromolecules that surrounds cells. It can be thought of as a framework for cell migration during the embryologic development of the organism. In many ways, the extracellular matrix seems to actually direct cell migration, and/or facilitate cell-to-cell communication. The matrix consists of 5 primary components: 1) basement membrane; 2) elastic fibers; 3) structural glycoproteins such as fibronectin; 4) proteoglycans; and 5) collagen. Fibroblasts actively secrete components of the matrix. Fibronectin and hyaluronic acid are some of the first glycoproteins deposited in a wound.

fibroblast growth factor (FGF)

FGF induces proliferation of fibroblasts, endothelial cells, and smooth muscle. It accelerates wound healing, and may be responsible for much of the process of angiogenesis.

fibronectin

A glycoprotein with specific binding sites for collagen, proteoglycan, fibrinogen, fibrin, bacteria, and DNA. These diverse binding sites allow fibronectin to act as an integrating protein in the extracellular matrix. This cross-linking function is of great importance in the early stages of wound healing, before fibroblasts have laid down any collagen.

granulation tissue

Granulation tissue is the initial response to a wound and consists of a richly vascular connective tissue, which contains new capillaries, abundant fibroblasts, and variable numbers of inflammatory cells. Do not confuse with the term granuloma.

integrins

As the name implies, integrin proteins are involved in the integration of the extracellular matrix. The integrins are a family of transmembrane proteins that serve as receptors for various components of the extracellular matrix. The integrins are closely associated with cytoskeletal proteins, such as actin, and may act as a possible communications link between the internal cell compartment and the extracellular matrix.

keloid

A keloid is a hypertrophic or exuberant scar. If a keloid is excised by a plastic surgeon, it will usually recur in just as an exuberant manner. Keloids are commonly encountered in African-Americans. The reasons for exuberant scar formation in this sub-population are unknown.

labile cells

This subpopulation of cells is constantly turned over. The best examples are found in the epithelial cell population of the skin or gut, and the hematopoetic cells in the bone marrow. These cells have a short, finite life span, and are rapidly replaced.

myofibroblast

These cells migrate into wounds in the first 2 or 3 days after injury, and are involved in wound contraction. Their origin is unclear, but they may derive from the pericytes of capillaries.

permanent cells

Permanent cells are found in the central nervous system and heart. Once they are destroyed, they cannot regenerate. New research indicates that the neurons of the olfactory nerve have some regenerative capacity, but they are the only neurons of the CNS that have been shown to have this ability.

platelet-derived growth factor (PDGF)

PDFG induces proliferation of fibroblasts, microglia, and smooth muscle. It is stored in platelet granules and is released following platelet aggregation. PDGF may also serve as a chemotactic agent for inflammatory cells.

primary intention

When a skin wound has clean, apposed edges (as in most surgical incisions), then it will heal by primary intention. This means that the epithelial cells can easily fill the gap between the edges, and a small scar will result.

proteoglycans

As the name implies, proteoglycans are composed of long polysaccharide chains (glycans) which are covalently bound to a protein core. They are a key component of the extracellular matrix.

regeneration

Regeneration is a type of repair. The best example of healing by regeneration occurs in the liver, which has incredible regenerative properties. It is possible to resect virtually an entire lobe of liver, and the organ will repair itself over a period of months to completely recapitulate its previous structure. The skin is another good example of an organ that heals by regeneration. If the skin is injured, no scar will form unless the basement membrane is destroyed. This is easily seen in cases of chicken pox, where only pocks that become superinfected with bacteria from scratching will leave a scar.

repair

The replacement of lost tissue, either by regeneration of the original tissue, or the formation of a scar. The type of scar formed depends upon the type of tissue. For example, a collagen scar is formed by fibroblasts in most tissues. However, in the brain, scars are formed by glial cells, and a termed glial scars or gliosis.

secondary intention

Wound healing by secondary intention occurs in gouge wounds, or in surgical wounds that are left to heal without approximating the edges. This is often done with bowel surgeries, where feces (i.e., anaerobes) may have contaminated the wound, such as with a ruptured appendix. The wound then "granulates in", or fills with granulation tissue from the bottom up. The epithelium then fills in over the top of the granulation tissue. The result is a large, wide, scar. However, wound infection is avoided. Occasionally, as in 3rd degree burns, a matrix or graft of skin must be layed down to allow the epithelium to fill in.

stable cells

Stable cells are a subpopulation of cells that normally are replaced very slowly, but are capable of rapid renewal after tissue loss. This is most commonly seen in the cells of the liver, which heals by regeneration, and in the cells of the proximal renal tubule. Newly regenerated cells may require some time before they become fully functional, which is demonstrated by the proximal convoluted tubule cells during the polyuric phase of acute tubular necrosis (see page 475).