The inflammatory response is a dynamic sequence of events that can be acute (lasting from a few minutes or hours) to chronic (lasting for days, weeks, or years). Once the initial injury has occurred, a chain reaction takes place at the site of damaged tissue, summoning beneficial cells and fluids into the injured area. To envision this process in action, we start with an injury and observe the flow of major events at the microscopic level (process figure 1).
Process Figure 1 The major events in inflammation.
Vascular Changes: Early Inflammatory Events
Following an injury, some of the earliest changes occur in the vasculature (arterioles, capillaries, venules) in the vicinity of the damaged tissue. These changes are controlled by nervous stimulation, chemical mediators, and cytokines released by blood cells, tissue cells, and platelets in the injured area. Vasoactive mediators affect the smooth muscle cells surrounding veins and arteries, changing the flow of blood to the area by causing constriction or dilation of vessels. Others are chemotactic factors, also called chemokines, that affect white blood cells. Inflammatory mediators cause fever, stimulate lymphocytes, prevent infection spread, and cause allergic symptoms (14.1 Making Connections). Although the constriction of arterioles is stimulated first, it lasts for only a few seconds or minutes. Once a clot has formed to prevent blood loss, it is followed in quick succession by the opposite reaction, vasodilation. The overall effect of vasodilation is to increase the flow of blood into the area, which facilitates the influx of immune components and also causes redness and warmth (rubor and calor).
An Early Chemical Indicator of Inflammation
C-reactive protein (CRP) is a pattern recognition receptor that is an early indicator of inflammation. It is a large protein synthesized by the liver that circulates in the blood. CRP is released in response to cytokines produced by macrophages during infections and other pathologic conditions. It attaches to PAMPs and other receptors on dead or injured body cells and infectious agents, an action that increases phagocytosis and promotes the complement system (see next section). In this way it serves as another source of localized, immediate, innate protection. Because it can be detected within the first few hours of the onset of inflammation, it is an effective marker for inflammation and can be measured with blood tests. Elevated levels of CRP can also be found in cardiovascular disease, cancer, tissue injury, and necrosis, and are often used to diagnose risks for these conditions.
Postcapillary venules, small veins that drain blood from the capillary beds, are important in several aspects of inflammation. When they constrict, this causes a slowing of circulation and a pooling of extracellular fluid at the site. Some vasoactive substances cause the endothelial cells in the walls of these venules to separate and form gaps through which blood-borne components exude into the extracellular spaces. Capillaries also become leaky under the influence of cytokines. The plasma that escapes from small vessels into the tissues is called the exudate. Accumulation of this fluid gives rise to local swelling and hardness known as edema. The edematous exudate contains varying amounts of plasma proteins, such as globulins, albumin, the clotting protein fibrinogen, blood cells, and cellular debris. Depending upon its content, the exudate may be clear (called serous), or it may contain red blood cells or pus. Pus is composed mainly of white blood cells, microbes, and the debris generated by phagocytosis. In some types of edema, the fibrinogen is converted to fibrin threads that enmesh the injury site (figure 2). Within an hour, multitudes of neutrophils, responding chemotactically to special signaling molecules, converge on the injured site.
Fig2. Formation of a blood clot. After an injury, fibrinogen is converted to insoluble fibrin threads that ensnare red blood cells. White blood cells and platelets are also trapped, helping to stop bleeding (SEM 3250x). Science Photo Library/Alamy Stock Photo
Unique Dynamic Characteristics of White Blood Cells In or der for WBCs to leave the blood vessels and enter the tissues, they adhere to the inner walls of the smaller blood vessels such as capillaries and venules. From this position, they are poised to migrate out of the blood into the tissue spaces by a process called diapedesis.
Diapedesis, also known as transmigration, is aided by several related characteristics of WBCs. For example, they are actively motile and readily change shape. Their migration is assisted by the nature of the endothelial cells lining venules. Venules contain complex adhesive receptors that develop increased “stickiness” under the influence of inflammatory mediators. This causes WBCs to adhere or marginate at the endothelial cells. From this location, they can readily crawl into the extracellular spaces (figure 3).
Fig3. Diapedesis and chemotaxis of leukocytes. Cross section of a venule depicts white blood cells squeezing them selves between spaces in the vessel wall through diapedesis. This process also indicates how the pool of leukocytes adheres to receptors in the endothelial wall. From this site, they are poised to migrate out of the vessel into the tissue space and respond to chemotactic factors released as part of the generalized inflammatory process.
Another factor in the migratory habits of these WBCs is chemotaxis, defined as the tendency of cells to migrate in response to a specific chemical stimulus released at a site of injury or infection. Through this means, cells swarm from many compartments to the site of infection and remain there to perform general functions such as phagocytosis, repair, and specific immune reactions. These basic properties are absolutely essential for the sort of intercommunication and deployment of cells required for most immune reactions.
The Benefits of Edema and Chemotaxis The influx of fluids and the infiltration of neutrophils are physiologically beneficial activities. Fluids dilute toxic substances, and the fibrin clot can effectively trap microbes and prevent their further spread. The neutrophils that aggregate in the inflamed site are immediately involved in phagocytosing and destroying microbes, dead tissues, and particulate matter. In some types of inflammation, accumulated phagocytes contribute to pus. Certain bacteria (streptococci, staphylococci, gonococci, and meningococci) are especially powerful attractants for neutrophils and are thus termed pyogenic, or pus-forming, bacteria.
Late Reactions of Inflammation Sometimes a mild inflammation can be resolved by edema and phagocytosis. Inflammatory re actions that last more than a few days attract a collection of monocytes, lymphocytes, and macrophages to the reaction site. Clearance of pus, cellular debris, dead neutrophils, and damaged tissue is performed by macrophages, the only cells that can engulf and dispose of such large masses. At the same time, specific immune reactions of acquired immunity are brought into play. B lymphocytes react with foreign molecules and cells by producing specific antimicrobial proteins (antibodies), and T lymphocytes kill intruders directly. Late in the process, the tissue undergoes various levels of repair and may be replaced by connective tissue in the form of a scar (see process figure 1d). If the inflammation cannot be relieved or resolved in this way, it can become chronic and create long-term pathologic conditions discussed in 14.2 Making Connections, “The Downside of Inflammation.”
Fever: An Adjunct to Inflammation
An important systemic component of inflammation is fever, defined as an abnormally elevated body temperature. Although fever is a nearly universal symptom of infection, it is also associated with certain allergies, cancers, and other organic illnesses. Fevers whose causes are undiagnosed are called fevers of unknown origin, or FUOs.
The body temperature is normally maintained by a control center in the hypothalamus region of the brain. This thermostat regulates the body’s heat production and heat loss and sets the core temperature at around 37°C (98.6°F), with slight fluctuations (1°F) during a daily cycle. Fever is initiated when a circulating substance called pyrogen resets the hypothalamic thermostat to a higher set ting. This change signals the musculature to increase heat production and peripheral arterioles to decrease heat loss through vasoconstriction. Fevers range in severity from low-grade (37.7°C to 38.3°C, or 100°F to 101°F) to moderate (38.8°C to 39.4°C, or 102°F to 103°F) to high (40.0°C to 41.1°C, or 104°F to 106°F).
Pyrogens are described as exogenous (coming from outside the body) or endogenous (originating internally). Exogenous pyrogens are products of infectious agents such as viruses, bacteria, protozoans, and fungi. One well-characterized exogenous pyrogen is endo toxin, the lipopolysaccharide found in the cell walls of gram-negative bacteria. Blood, blood products, vaccines, or injectable solutions can also contain exogenous pyrogens. Endogenous pyrogens are liberated by monocytes, neutrophils, and macrophages during the process of phagocytosis and appear to be a natural part of the immune response. Two potent pyrogens released by macrophages are interleukin-1 (IL-1) and tumor necrosis factor (TNF).
Fever is usually accompanied by chills. What would cause a febrile (feverish) person to periodically feel cold and tremble uncontrollably? The explanation lies in how the brain reacts to pyrogen and the natural physiological interaction between the hypothalamus and the temperature of the blood. For example, if the thermostat has been reset (by pyrogen) at 102°F but the blood temperature is 99°F, the muscles are stimulated by the brain to contract involuntarily (shivering) as a means of producing more heat. In addition, the vessels in the skin constrict, creating a sensation of cold, and the piloerector muscles in the skin cause goose bumps to form.
Benefits and Treatment of Fever Medical experts have abundant evidence that fever serves an important biological function. Work with tissue cultures showed that increased temperatures stimulate the activities of T cells and increase the effectiveness of interferon. Artificially infected rabbits and pigs allowed to remain febrile survive at a higher rate than those given suppressant drugs. Fever appears to enhance phagocytosis of staphylococci by neutrophils in many mammalian species. The appearance of fever during infections strongly suggests that it is a normal and beneficial reaction to invading microbes. Some other effects of fever include:
● It inhibits multiplication of temperature-sensitive microorganisms, such as the poliovirus, cold viruses, herpes zoster virus, systemic and subcutaneous fungal pathogens, Mycobacterium species, and the syphilis spirochete.
● It impedes the nutrition of bacteria by reducing the availability of iron. Research has demonstrated that during fever, the macrophages stop releasing their iron stores, which could re tard several enzymatic reactions needed for pathogen growth.
● It increases metabolism and stimulates immune reactions and naturally protective physiological processes. It speeds up hematopoiesis, phagocytosis, and specific immune reactions.
Understanding that fever is possibly more beneficial than harmful, deciding whether to suppress it is an important medical question. Some advocates feel that a slight to moderate fever (99–101°F) in an otherwise healthy person should be allowed to run its course in light of its potential as an immune stimulant and its minimal side effects. All medical experts do agree that high and prolonged fevers or fevers in children or patients with cardiovascular disease, seizures, and respiratory ailments are risky and must be treated immediately with fever-suppressant drugs. The classic therapy for fever is an antipyretic drug such as aspirin or acetaminophen (Tylenol) that lowers the setting of the hypothalamic center and restores normal temperature. Any physical technique that increases heat loss (tepid baths, for example) can also help reduce the core temperature.
