Inflammation

Inflammation is a local defensive response to tissue injury of any kind, including trauma and infection. Its general purposes are (1) to limit the spread of pathogens and ultimately destroy them, (2) to remove the debris of damaged tissue, and (3) to initiate tissue repair. Inflammation is characterized by four cardinal signs—redness, swelling, heat, and pain. Some authorities list impaired use as a fifth

7opson = food scyto = cell + lysis = split apart, break down

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Glassical pathway

Antibody binds to foreign cell, exposes complement-binding sites

Alternate pathway

Antibody binds to foreign cell, exposes complement-binding sites

Antibody binds complement proteins G1, G2, and G4

Complement factors B, D, and P bind to polysaccharides of microbial cell walls

Gomplement protein G3

Splits into fragments G3a and G3b

G3b I

Stimulates mast cells and basophils

Activates complement proteins G5b to G9 (membrane attack complex)

Goats bacterial surfaces

Secrete inflammatory chemicals

Inflammation

G5b to G9 bind to enemy plasma membrane, creating a hole

Gytolysis

Binds neutrophils and macrophages, promotes phagocytosis

Opsonization

Figure 21.14 Complement Activation. Both the classical pathway and the alternate pathway produce complement fragments C3a and C3b. The process is the same from that point to the end. The C3a and C3b fragments promote inflammation, cytolysis, and opsonization.

sign, but this may or may not occur and when it does, it is mostly because of the pain.

Words ending in the suffix -itis denote inflammation of specific organs and tissues: arthritis, encephalitis, peritonitis, gingivitis, and dermatitis, for example. Inflammation can occur anywhere in the body, but it is most common and observable in the skin, which is subject to more trauma than any other organ. Examples of cutaneous inflammation include an itchy mosquito bite, sunburn, a poison ivy rash, and the redness and blistering produced by manual labor, tight shoes, or a kitchen burn.

The following discussion of the process of inflammation will account for the four cardinal signs and explain how the three purposes of inflammation are achieved. These processes are mediated by several types of cells and inflammatory chemicals that are summarized in tables 21.1 and 21.2 at the end of this section. Some of these inflammatory chemicals are also classified as cytokines9—small proteins secreted by leukocytes, macrophages, mast cells, and several other cell types, which mediate the body's immune and nonspecific defenses. Cytokines include interferons, chemotactic factors, growth factors, inter-leukins, tumor necrosis factor, and other chemicals you will soon encounter in this discussion.

Inflammation involves three major processes: mobilization of the body's defenses, containment and destruction of pathogens, and tissue cleanup and repair.

acyto = cell + kine = action, response

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Mobilization of Defenses

Some inflammatory chemicals are vasoactive—they stimulate vasodilation, causing hyperemia, or elevated blood flow to the damaged tissue. Among them are histamine, bradykinin, and leukotrienes, which are secreted by basophils of the blood, mast cells of the connective tissue, and damaged cells of the inflamed tissue. These chemicals also cause endothelial cells of the blood capillaries and venules to separate a little, increasing the permeability of the vessels and thus promoting exudation (filtration) of fluid from the blood into the interstitial spaces of the tis

Membrane Attack Complex

Figure 21.15 The Membrane Attack Complex. Complement proteins form a doughnutlike ring in the plasma membrane of an enemy cell, thus causing cytolysis.

In what way does the action of the membrane attack complex resemble the action of perforin?

Figure 21.15 The Membrane Attack Complex. Complement proteins form a doughnutlike ring in the plasma membrane of an enemy cell, thus causing cytolysis.

In what way does the action of the membrane attack complex resemble the action of perforin?

sue. The collective effect of these changes is to speed the delivery of cells and chemicals needed to combat pathogens and repair damaged tissue, and to wash away toxins and metabolic wastes more rapidly.

Hyperemia accounts for the redness and heat of inflammation, and the increased filtration of fluid into the tissue accounts for its swelling (edema). Extravasated erythrocytes—RBCs that escape from the blood vessels into the tissue—contribute to the redness (as in sunburn). Pain results from direct injury to the nerves, pressure on the nerves caused by edema, and the stimulation of noci-ceptors (pain receptors) by bradykinin, prostaglandins, and some bacterial toxins.

In an area of injury, endothelial cells of the blood vessels produce cell-adhesion molecules (CAMs) that make their membranes sticky and snag leukocytes arriving in the bloodstream. Leukocytes adhere loosely to the CAMs and slowly tumble along the endothelium, sometimes coating it so thickly that they obstruct blood flow. This adhesion to the endothelium is called margination. The leukocytes then undergo diapedesis10 (emigration), in which they crawl through the spaces between the endothelial cells into the interstitial fluid. Most dia-pedesis occurs across the walls of the postcapillary venules. Also filtering through the capillary and venule walls are antibodies, fibrinogen and other clotting proteins, and complement, all of which aid in combating the pathogens as described next.

_Think About It_

Review eicosanoid synthesis (p. 665) and explain why aspirin eases the pain of inflammation.

10dia = through + pedesis = stepping

Table 21.1

Cellular Agents of Inflammation

Agents

Action

Basophils

Secrete histamine, heparin, bradykinin, serotonin, and leukotrienes

Endothelial cells

Produce cell-adhesion molecules to recruit leukocytes; synthesize platelet-derived growth factor to stimulate fibroblast activity

and tissue repair

Eosinophils

Attack parasites too large to phagocytize; phagocytize antigen-antibody complexes

Fibroblasts

Promote tissue repair by secreting collagen, ground substance, and other tissue components; produce scar tissue

Helper T cells

Secrete interleukins that promote inflammation and activate specific immunity

Macrophages

Phagocytize bacteria, tissue debris, dead and dying leukocytes and pathogens; act as antigen-presenting cells, which activate

specific immunity

Mast cells

Same actions as basophils

Neutrophils

Phagocytize bacteria; secrete bactericidal oxidizing agents into tissue fluid; secrete cytokines that activate other cells

Platelets

Secrete clotting factors, which initiate tissue fluid coagulation, and platelet-derived growth factor

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Table 21.2 Chemical Agents of Inflammation

Substance

Sources

Effects*

Bradykinin

Plasma and basophils

Pain; vasodilation; increased vascular permeability; neutrophil chemotaxis

Clotting factors

Plasma, platelets, and damaged cells

Coagulation of tissue fluid; isolation of pathogens; formation of temporary framework for tissue repair; include fibrinogen and clotting enzymes

Cytokines

Leukocytes, macrophages, mast cells

Mediation of immune and nonspecific defenses; include interferons, interleukins, growth factors, and other signals

Colony-stimulating factors

Macrophages and T cells

Leukopoiesis; increased WBC count

Complement

Plasma

Enhanced histamine release; neutrophil chemotaxis; promotion of phagocytosis

Heparin

Basophils and mast cells

Inhibits clotting in area of infection or injury; thus promotes WBC mobility

Histamine

Basophils and mast cells

Vasodilation; increased vascular permeability

Leukotrienes

Damaged cells, mast cells, and basophils

Vasodilation; increased vascular permeability; neutrophil chemotaxis

Platelet-derived growth factor

Platelets and endothelial cells

Stimulation of fibroblast activity; cell division; replacement of damaged cells

Prostaglandins

Damaged cells

Pain; enhanced action of histamine and bradykinin; neutrophil diapedesis

*Some inflammatory chemicals have additional roles in specific immunity, as described in table 21.6.

*Some inflammatory chemicals have additional roles in specific immunity, as described in table 21.6.

Containment and Destruction of Pathogens

One priority in inflammation is to prevent introduced pathogens from spreading through the body. The fibrinogen that filters into the tissue fluid clots in areas adjacent to the injury, forming a sticky mesh that sequesters (walls off) bacteria and other microbes. Heparin, the anticoagulant, prevents clotting in the area of the injury itself, so essentially bacteria or other pathogens are trapped in a fluid pocket surrounded by a gelatinous "capsule" of clotted fluid. They are attacked by antibodies, phagocytes, and other defenses, while the surrounding areas of clotted tissue fluid prevent them from escaping this onslaught.

The chief enemies of bacteria are the neutrophils, which begin to accumulate in the inflamed tissue within an hour of injury. After emigrating from the bloodstream, neutrophils exhibit chemotaxis—attraction to chemotac-tic chemicals such as bradykinin and leukotrienes that guide them to the site of injury or infection. As they encounter bacteria, neutrophils avidly phagocytize and digest them, and destroy many more by the respiratory burst described earlier. The four major stages of neutrophil action are summarized in figure 21.16.

Neutrophils also recruit macrophages and additional neutrophils by secreting cytokines, like shouting "Over here!" to bring in reinforcements. Activated macrophages and T cells in the inflamed tissue also secrete colony-stimulating factors, cytokines that pro mote the production of more leukocytes (leukopoiesis) by the red bone marrow. Within a few hours of the onset of inflammation, the neutrophil count in the blood can rise from the normal 4,000 or 5,000 cells/^L to as high as 25,000 cells/^L, a condition called neutrophilia. In the case of an allergy or parasitic infection, an elevated eosinophil count, or eosinophilia, may also occur. The task of eosinophils was described earlier.

Tissue Cleanup and Repair

Monocytes are major agents of tissue cleanup and repair. They arrive within 8 to 12 hours of an injury, emigrate from the bloodstream, and turn into macrophages. Macrophages engulf and destroy bacteria, damaged host cells, and dead and dying neutrophils. They also act as antigen-presenting cells, activating immune responses as described later in the chapter.

Edema also contributes to tissue cleanup. The swelling compresses veins and reduces venous drainage, while it forces open the valves of lymphatic capillaries and promotes lymphatic drainage. The lymphatics can collect and remove bacteria, dead cells, proteins, and tissue debris better than blood capillaries can.

As the battle progresses, all of the neutrophils and most of the macrophages die. These dead cells, other tissue debris, and tissue fluid form a pool of yellowish fluid

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Inflammation Saladin Text

Blood capillary or venule

Figure 21.16 Leukocyte Behavior in Inflammation. Chemical messengers are released by basophils, mast cells, blood plasma, and damaged tissue. These inflammatory chemicals stimulate leukocyte margination (adhesion to the capillary wall), diapedesis (crawling through the capillary wall), chemotaxis (movement toward the source of the inflammatory chemicals), and phagocytosis (engulfing bacteria or other pathogens).

Blood capillary or venule

Figure 21.16 Leukocyte Behavior in Inflammation. Chemical messengers are released by basophils, mast cells, blood plasma, and damaged tissue. These inflammatory chemicals stimulate leukocyte margination (adhesion to the capillary wall), diapedesis (crawling through the capillary wall), chemotaxis (movement toward the source of the inflammatory chemicals), and phagocytosis (engulfing bacteria or other pathogens).

called pus, which accumulates in a tissue cavity called an abscess.11 Pus is usually absorbed, but sometimes it forms a blister between the epidermis and dermis and may be released by its rupture.

Blood platelets and endothelial cells in an area of injury secrete a cytokine called platelet-derived growth factor, an agent that stimulates fibroblasts to multiply and synthesize collagen. Hyperemia, at the same time, delivers the oxygen, amino acids, and other necessities of protein synthesis, while the heat of inflamed tissue increases metabolic rate and the speed of mitosis and tissue repair. The fibrin clot in inflamed tissue may provide a scaffold for tissue reconstruction. Pain also contributes importantly to recovery. It is an important alarm signal that calls our attention to the injury and makes us limit the use of a body part so it has a chance to rest and heal.

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