Inflammation (def)
The inflammatory response is an attempt by the body to restore and maintain homeostasis (def) after injury and is an integral part of body defense. Most of the body defense elements are located in the blood and inflammation is the means by which body defense cells and defense chemicals leave the blood and enter the tissue around the injured or infected site. Inflammation is essentially beneficial, however, excess or prolonged inflammation can cause harm.
1. The Mechanism of Inflammation
As a result of proinflammatory cytokine (def) and chemokine (def) release in response to injury or infection, mast cells in the connective tissue as well as basophils, neutrophils and platelets leaving the blood from injured capillaries, release or stimulate the synthesis of vasodilators (def) such as histamine, leukotrienes, bradykinins, and prostaglandins. Certain products of the complement pathways (def) (C5a and C3a) can also trigger mast cells to release their vasodilators.
Vasodilation is a reversible opening of the junctional zones between endothelial cells (def) of the blood vessels and results in increased blood vessel permeability (see Fig. 1 and Fig. 2; also the scanning electron micrographs of a cross section of a capillary showing an endothelial cell and a capillary with a red blood cell; courtesy of Dennis Kunkel's Microscopy).
2. Benefits of Inflammation
As a result of this increased permeability:
a. Plasma (def) flows out of the blood into the tissue. This has the following benefits (see Fig. 2):
1. clotting factors cause fibrin clots to form to localize the infection, stop the bleeding, and chemotactically attract phagocytes;
2. antibodies (def) enter the tissue to help remove or block the action of microbes;
3. proteins of the complement pathways (def) enter the tissue to: 1) stimulate more inflammation (C5a, C3a, and C4a), 2) stick microorganisms to phagocytes (C3b and C4b), 3) chemotactically attract phagocytes ( C5a), and 4) lyse membrane-bound cells displaying foreign antigens (membrane attack complex or MAC);
4. nutrients enter the tissue to feed inflamed tissue;
5. lysozyme (def) and beta-defensins (def) enter the tissue to degrade peptidoglycan and cytoplasmic membranes; and
6. transferrin (def) enters the tissue to deprive microbes of needed iron.
b. Leukocytes enter the tissue through a process called diapedesis (def).
1. First, molecules called selectins (def) cause the circulating leukocytes to slow their flow and roll along the inner blood vessel wall.
2. Proinflammatory cytokines such as Il-1 and TNF-alpha produced by cells at the injured or infected site then stimulate the endothelial cells that form blood vessels to produce chemokines (def) such as interleukin-8 (IL-8). The chemokines are held on the inner surface of the endothelial cells where they interact with chemokine receptors on the surface of the rolling leukocytes. This interaction, in turn, trigger the activation of molecules called integrins (def) on the surface of the leukocytes.
3. Activation of these integrins by chemokines enables the slowly rolling leukocytes to strongly bind to adhesion molecules such as ICAMs (intercellular adhesion molecules) and VCAMs (vascular cell adhesion molecules) on the inner surface of the vascular endothelial cells (see Fig. 3, step 2). (Macrophage-produced cytokines such as IL-1 and TNF-alpha induce the expression of these adhesion molecules on the vascular endothelium.)
4. Once bound to the endothelial cells, the leukocytes then flatten and squeeze between the endothelial cells to leave the blood vessels and enter the tissue (see Fig. 3, step 3).
5. The leukocytes are then chemotactically attracted to the injured site by the chemokines and other chemotactic factors mentioned earlier.
The process of diapedesis, also known as emigration, is summarized in Fig. 3.
Benefits of diapedesis include:
1. phagocytosis (neutrophils, monocytes/macrophage, and eosinophils are phagocytes);
2. more vasodilation (basophils, neutrophils, and platelets promote inflammation);
3. exposure of immunocompetent cells (B-lymphocytes (def) and T-lymphocytes (def)) to microorganisms and other antigens (discussed in Unit 3);
4. killing of infected cells and cancer cells by cytotoxic T-lymphocytes (CTLs) (def) and NK cells (def) (discussed in Unit 3).
Cytokines called chemokines are especially important in this part of the inflammatory response. They play key roles in enabling white blood cells to adhere to the inner surface of blood vessels, migrate out of the blood vessels into the tissue, and be chemotactically attracted to the injured or infected site. They also trigger extracellular killing by neutrophils.
Finally, within 1 to 3 days, macrophages release the cytokines Il-1 and TNF-alpha that stimulate a proliferation of endothelial cells and fibroblasts. The endothelial cells form a fine network of new capillaries into the injured area to supply blood, oxygen, and nutrients to the inflamed tissue. The fibroblasts deposit the protein collagen in the injured area and form a bridge of connective scar tissue to close the open, exposed area. This is called fibrosis or scarring, and represents the final healing stage.
Inflammation is regulated by cytokines. Proinflammatory cytokines such as interferon-gamma and interleukin-12 enhance the inflammatory response whereas the cytokine interleukin-10 inhibits inflammation by decreasing the expression of proinflammatory cytokines.
So as can be seen, acute inflammation is essential to body defense. Chronic inflammation, however, can result in considerable tissue damage and scarring. With prolonged increased capillary permeability, neutrophils continually leave the blood and accumulate in the tissue at the infected or injured site. As they discharge their lysosomal contents and oxidizing agents, surrounding tissue is destroyed and eventually replaced with scar tissue. Anti-inflammatory agents such as antihistamines or corticosteroids may have to be given to relieve symptoms or reduce tissue damage.
To view a QuickTime video animation showing inflammation, see "Ouch!" under the CELL'S ALIVE web page.