InflammationA Coordinated Response to Invasion or Damage

When tissues have been damaged, such as when an object penetrates the skin or when microbes produce toxic compounds, a coordinated response called the inflammatory response, or inflammation occurs. Everyone has experienced the signs of

386 Chapter 15 The Innate Immune Response inflammation; in fact, the Roman physician Celsus described these four cardinal signs of inflammation in the first century A.D. They are swelling, redness, heat, and pain. A fifth sign, loss of function, is sometimes present.

The vital role of inflammation is to contain a site of damage, localize the response, and restore tissue function. Early inflammatory activation quickly recruits neutrophils, followed by monocytes and other cells, to assist the local macrophages and eosinophils at the site of damage.

Factors that Initiate the Inflammatory Response

Inflammation is initiated in response to invading microbes or tissue damage. In the case of a surface wound, the action that caused the tissue damage is likely to also introduce microbes either residing on the offending instrument or on the skin's surface. Therefore, both factors are often involved in eliciting the response. Events that initiate inflammation include, either singly or in combination:

■ Microbial products such as LPS, flagellin, and bacterial DNA trigger the toll-like receptors of macrophages, causing these cells to produce pro-inflammatory cytokines. One of these, tumor necrosis factor alpha, induces the liver to synthesize a group of proteins, termed acute-phase proteins, that facilitate phagocytosis and complement activation.

■ Microbial cell surfaces can trigger the complement cascade, leading to the production of the C3a and C5a, both of which stimulate changes associated with inflammation. The complement components also induce mast cells to release various pro-inflammatory cytokines, including tumor necrosis factor alpha, and other substances.

■ Tissue damage results in the activation of two enzymatic cascades. One is the coagulation cascade, which results in blood clotting, and the other produces several molecules such as bradykinin that elicit changes involved in inflammation. Current research is seeking to determine if some of the substances released during tissue damage are recognized by toll-like receptors, causing the production of pro-inflammatory cytokines.

The Inflammatory Process

Initiation of the inflammatory process leads to a cascade of events that result in dilation of small blood vessels, leakage of fluids from those vessels, and the migration of leukocytes out of the bloodstream and into the tissues (figure 15.10).

The diameter of local blood vessels increases during inflammation due to the action of certain pro-inflammatory chemicals. This results in an increase in blood flow to the area, causing the heat and redness associated with inflammation, accompanied by a decrease in the velocity of blood flow in the capillaries. Because of the dilation, normally tight junctions between endothelial cells are disrupted, allowing fluid to leak from the vessels and into the tissue. This fluid contains various substances such as transferrin, complement proteins, and antibodies, and thus helps to counteract invading microbes. The increase of fluids in the tissues causes the swelling and pain associated with inflammation. The direct effects of chemicals on sensory nerve endings also cause pain.

Some of the pro-inflammatory cytokines cause endothelial cells in the local area to produce adhesion molecules that loosely adhere to phagocytes. The phagocytes normally flow rapidly through the vessels, but slowly tumble to a halt as they attach to the adhesion molecules. The phagocytic cells themselves then begin producing a different type of adhesion molecule that strengthens the attachment. Then, in response to other cytokines and complement components that function as chemoattractants, phagocytes migrate from the blood vessels into the area. They do this by squeezing between the cells of the dilated permeable vessel, the process of diapedesis. Neutrophils (PMNs) are the first type of phagocyte to be lured from the circulation, and soon they predominate in the area of inflammation. After the influx of neutrophils to the area, monocytes and lymphocytes accumulate. Both neutrophils and monocytes, which mature into macrophages at the site of infection, actively phagocytize foreign material. Clotting factors, which are in the fluid that leaks into the tissues, initiate clotting reactions. This helps prevent further bleeding and halts spread of invading microbes, which get caught in the clot. As the inflammatory process continues, large quantities of dead neutrophils accumulate. Along with tissue debris, these dead cells make up pus. A large amount of pus constitutes a boil or abscess (see figure 22.3). ■ boil, p.537

The extent of inflammation varies, depending on the nature of the injury, but the response is localized, begins immediately upon injury, and increases over a short period of time. This short-term inflammatory response is called acute inflammation and is marked by a prevalence of neutrophils. Then, as inflammation subsides, healing occurs. During healing, new capillary blood vessels grow into the area and destroyed tissues are replaced; eventually, scar tissue is formed. If acute inflammation cannot limit the infection, chronic inflammation occurs. This is a long-term inflammatory process that can last for years. Chronic inflammation is characterized by the prevalence of macrophages, giant cells, and granulomas. ■ giant cells, p. 409 ■ granulomas, p. 409

Outcomes of Inflammation

The inflammatory process can be likened to a sprinkler system that prevents fire from spreading in a building. While the intention of the process—to limit damage and restore function—is positive, the response itself can cause significant harm. One undesirable consequence of inflammation, for example, is that some of the enzymes and toxic products contained within phagocytic cells are inevitably released, damaging tissues.

If inflammation is limited, such as in a response to a cut finger, the damage caused by the process is normally minimal. If the process occurs in a delicate system, however, such as the membranes that surrounds the brain and spinal cord, the consequences can be much more severe, even life threatening. Another serious situation occurs in the response to bloodstream infections, particularly those caused by Gram-negative bacteria. The lipopolysaccharide component of their outer membrane, referred to as endotoxin, causes a number of responses, includ

15.7 Inflammation—A Coordinated Response to Invasion or Damage 387

Skin ci irfanû

Skin ci irfanû

(a) Normal blood flow in the tissues as injury occurs.

• Microbial products

• Tissue damage

15.7 Inflammation—A Coordinated Response to Invasion or Damage 387

(b) Substances released cause dilation of small blood vessels and increased blood flow in the immediate area.

(d) The attraction of phagocytes causes them to move to the site of damage and inflammation. Collections of dead phagocytes and tissue debris make up the pus often found at sites of an active inflammatory response.

Figure 15.10 The Inflammatory Process This coordinated response to microbial invasion or tissue damage brings phagocytes and other leukocytes to the site.The role of inflammation is to contain a site of damage, localize the response, and restore tissue function.

(d) The attraction of phagocytes causes them to move to the site of damage and inflammation. Collections of dead phagocytes and tissue debris make up the pus often found at sites of an active inflammatory response.

Figure 15.10 The Inflammatory Process This coordinated response to microbial invasion or tissue damage brings phagocytes and other leukocytes to the site.The role of inflammation is to contain a site of damage, localize the response, and restore tissue function.

ing the release of pro-inflammatory cytokines by monocytes, activation of the complement cascade and activation of the clotting cascade. The net result is a rapid loss in blood pressure, leading to shock, extensive tissue damage, and widespread formation of clots that plug the capillaries, cutting off the blood supply; this manifestation of a bloodstream infection (sepsis) is called septic shock (see figure 28.3). The cell wall components of Gram-positive bacteria can also elicit septic shock. ■ meninges, p. 664 ■ endotoxin, p. 59 ■ Gram-negative sepsis, p. 719

Apoptosis—Controlled Cell Death that Circumvents the Inflammatory Process

The inflammatory response represents a potential problem for the host; that is, how to distinguish cell death caused by abnormal

Chapter 15 The Innate Immune Response

PERSPECTIVE 15.1 For Schistosoma, the Inflammatory Response Delivers

Just as our immune system has evolved to protect us from new and different invasions, it is not surprising that in the opportunistic and adaptable world of microbes, some would find ways to use our defenses to their advantage.The parasitic flatworms that cause schistosomiasis do not shy from the immune response when it comes to procreation; instead they appear to use it to deliver their ova to an environment where they might hatch. Adult females of Schistosoma species, which live in the bloodstream of infected hosts, lay their ova in veins near the intestine or bladder; they seem to rely on a robust inflammatory response to expel the ova, completing one portion of a complex life cycle.The ova released in feces or urine can hatch to form a larval form called a miracidium if untreated sewage reaches water.The miracidium then infects a specific freshwater snail host and undergoes asexual multiplication.The infected snail then releases large numbers of another larval form, cercariae, which swim about in search of a human host.

The parasite is acquired when a person wades or swims in contaminated water.The cercariae penetrate the skin by burrowing through it with the aid of digestive enzymes; schistosomes are rare among pathogens because they can actually penetrate intact skin.The larvae then proceed to enter the circulatory system where they can live for over a quarter of a century.Schisotosoma species have separate sexes and, remarkably, the male and female worms locate one another in the bloodstream.The male's body has a deep longitudinal groove in which he clasps his female partner to live in copulatory embrace (shisto-soma means "split-body,"referring to the long slit).The adult worms effectively mask themselves from the immune system by adsorbing various blood proteins; this provides them with a primitive stealth "cloaking device."

Depending on the species, the female worm migrates to the veins of either the intestine or bladder to lay hundreds of ova per day.The body responds vigorously to the highly antigenic eggs, ejecting them in manner that appears similar to what is experienced as a sliver in the skin works its way to the surface. Over half of the ova are not expelled, however, and many of these are instead swept away by the bloodstream to the liver.The inflammatory process and granuloma formation there gradually destroys liver cells, replacing the cells with scar tissue. Malfunction of the liver results in malnutrition and a buildup of pressure in the esophagus. Fluid accumulates in the abdominal cavity and hemorrhage occurs if the engorged esophageal veins rupture.

Despite their complex life cycle, Schistosoma species are highly successful. Not only are they adept at avoiding certain immune responses that would otherwise lead to their destruction, they have learned to exploit inflammation for their own dissemination. Over 200 million people worldwide are infected with these parasites, resulting in the death of over 500,000 people each year.

events, such as injury, from that caused by normal events such as tissue remodeling that render certain cells unnecessary or potentially harmful. The former merits an inflammatory response whereas the latter does not and, in fact, would be unnecessarily destructive to normal tissue. Apoptosis (Greek, apo for "falling"; ptosis for "off"), or programmed cell death, is a process that destroys self-cells without eliciting inflammation. During apoptosis, the dying cells undergo certain changes. For example, the shape of the cell changes, enzymes cut the DNA, and portions of the cell bud off, effectively shrinking the cell. Some changes appear to signal to macrophages that the remains of the cell are to be engulfed without the commotion associated with inflammation. For example, some parts of the membrane invert, exposing molecules that are generally restricted to the inner leaflet.

The mechanisms and events connected to apoptosis are currently the focus of a great deal of research. It is now recognized that the process is used to eliminate a wide range of cells from the body, including virally infected cells, as well as those lymphocytes whose function is rendered obsolete by the successful elimination of an antigen.

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