complement components C3a, C4a, C2b, and C5a. C3a, C4a, and C5a act as anaphylatoxins that increase histamine and heparin release from mast cells and basophils, smooth muscle contraction, and vascular permeability. C5a and (to a lesser extent) C3a also act as potent chemokines (enhancing chemotaxis of phagocytes to the infection site).
The cytokine IL-6 released from macrophages and T cells stimulates the liver to increase production of transferrin (to sequester iron), complement components (to regenerate complement components used up during complement activation), LPS-binding proteins (to continue stimulation of cytokine production as long as bacteria are detected in the body), and two general opsonins—MBL, discussed above in the context of complement, and C-reactive protein (CRP). CRP is a pentameric protein produced in the liver whose expression and release into blood is greatly up-regulated in response to IL-6 during inflammation. CRP is also another PAMP recognition protein in that it binds to LTA of some bacterial species as well as to phosphocholine found on the surface of dead or dying bacterial cells. Phagocytes have receptors for CRP, which allows it to act as an opsonin by enhancing phagocytosis.
Septic Shock: The Dark Side of the Innate Defenses
Inappropriately functioning or over-stimulated host defenses can sometimes lead to disastrous consequences such as septic shock. Septic shock is a form of shock caused by bacterial infection (Figure 3-17), during which a massive release of cytokines (sometimes called a cytokine storm) leads to a subsequent overwhelming inflammatory response. Other causes of shock include massive crush injuries, burns, radiation poisoning, and exposure to toxins (toxic shock). In people with septic shock, vasodilation causes a dramatic drop in vascular resistance and blood pressure (hypotension) despite normal-to-high cardiac output. The heart rate and respiratory rate increase as the body tries to compensate for decreasing blood pressure and lack of oxygen. Septic shock is a serious condition because severely reduced levels of blood flow deprive essential organs of oxygen and nutrients (ischemia), causing them to malfunction. The consequent failure of multiple organs, such as the kidneys, heart, brain, and lungs, is the usual cause of death in septic shock patients.
Figure 3-17. Triggering of proinflammatory cytokine release by Gram-negative LPS and its role in septic shock. TNF-α, IL-1, IL-6, and IL-8 are proinflammatory cytokines.
Septicemia (bacteria infecting and growing in the bloodstream) is one of the leading causes of septic shock and occurs in 500,000 to 750,000 patients per year in the United States alone. Up to half of the patients with septicemia end up dying in the hospital. Even those who survive may have long-term aftereffects, such as stroke or permanent damage to lungs, kidneys, liver, or other organs. Indeed, statistics show that those who survive an episode of septic shock have a significantly greater risk of dying during the next five-year period than people with the same underlying conditions but no previous episode of shock. Septic shock is not only serious business for the patient, but it is also a seriously expensive business, as hospital administrators and insurance executives are quick to point out, with annual hospital costs of $5 to 10 billion.
The all-inclusive term sepsis has now been defined more precisely in an effort to aid diagnosis of the various stages of disease. The first stage of shock, called systemic inflammatory response syndrome (SIRS), is characterized by a temperature over 38°C or under 36°C, elevated heart rate, elevated respiratory rate, and an abnormally high or low neutrophil count. The second stage, termed sepsis, is SIRS with a culture-documented infection (i.e., laboratory results showing the presence of bacteria in the bloodstream). The third stage is severe sepsis, characterized by organ dysfunction and very low blood pressure (hypotension). The fourth stage is septic shock, which is characterized by low blood pressure despite intravenous fluid administration.
How does a bacterial infection of the bloodstream produce such a serious condition? Steps involved in septic shock are illustrated in more detail in Figure 3-18. From previous sections of this chapter, it should be evident that the body goes to great lengths to confine the inflammatory response to specific areas of the body. Septic shock is an example of what happens when an inflammatory response is triggered throughout the body. Shock occurs when bacteria or their products reach high enough levels in the bloodstream to trigger complement activation, cytokine release, and the coagulation cascade in many parts of the body. High levels of cytokines, especially TNF-α, IL-1, IL-6, IL-8, and IFN-γ, cause increased levels of PMNs in the blood and encourage these PMNs to leave the blood vessels throughout the body. This leads to massive leakage of fluids into surrounding tissue. PMNs and macrophages activated by IFN-γ also damage blood vessels directly, resulting in loss of fluid from these vessels.
Figure 3-18. Sources of hypotension, disseminated intravascular coagulation (DIC), and internal hemorrhages seen in cases of septic shock.
Activation of complement throughout the body further increases the transmigration of phagocytes. The vasodilating action of C3a, C5a, leukotrienes, and prostaglandins contributes to leakage of fluids from blood vessels and further reduces the ability of blood vessels to maintain blood pressure. Some cytokines cause inappropriate constriction and relaxation of blood vessels, an activity that undermines the ability of the circulatory system to maintain normal blood flow and blood pressure.
Another sign that is frequently associated with septic shock is disseminated intravascular coagulation (DIC), which can be seen as blackish or reddish skin lesions (petechiae). DIC results from widespread activation of blood clotting (coagulation system) in blood capillaries throughout the body. A mediator of DIC is the release of tissue factor (TF), a glycoprotein found on the surface of many cells, such as endothelial cells, monocytes, and macrophages. TF is released into the circulation in response to proinflammatory cytokines (IL-1 and TNF-α), as well as LPS-stimulated TLR4 signaling during sepsis from Gram-negative bacteria. As clots form, blood flow to organs is impaired and ischemia ensues, leading to the tissue damage seen in DIC. On the other hand, as clotting factors are consumed during the formation of multiple clots, bleeding results in other areas where vasodilation has occurred. In addition, activation of the clotting cascade releases excess thrombin, a protease that cleaves the zymogen plasminogen to plasmin, which in turn causes fibrinolysis (the breakdown of clots) and results in hemorrhaging (bleeding), a common symptom of DIC. Hemorrhages not only contribute to hypotension but also damage vital organs.
Once septic shock enters the phase in which organs start to fail, it is extremely difficult to treat successfully. The death rate for severe septic shock is 30–50%, but DIC worsens the prognosis to 70–80%. Treatment is most likely to be effective if it is started early in the infection; however, diagnosis of septic shock in its early stages is not straightforward, as the early symptoms of shock (fever, hypotension, and tachycardia) are very nonspecific. Also, the transition from the early stages to multiple organ failure can occur with frightening rapidity. Of the hundreds of thousands of cases of septic shock that occur in the United States each year, many occur in patients hospitalized with some underlying condition other than infectious disease, which complicates the treatment options for patients.
Accordingly, a massive effort has been made to develop new techniques for treating septic shock patients more successfully, especially in cases where the disease has reached the point at which treatment with antibacterial agents is no longer sufficient to avert disaster. Early efforts to combat septic shock have centered on the administration of glucocorticoids, which down-regulate cytokine production. Physicians have long believed that administration of steroids or ibuprofen would help shock victims because these compounds dampen various aspects of the inflammatory response, but there is now general agreement that glucocorticoid treatment is not effective in treating most types of shock. Indeed, clinical trials have now shown no significant effects from
