Inflammation and Inflammatory Response PDF

Inflammation and the Inflammatory Response The inflammatory response is a multistage process that involves vascular and cellular changes but may also include systemic changes. White blood cells (WBCs) are brought to the damaged area, and they secrete mediators that control the process from initial i...

Inflammation and the Inflammatory Response The inflammatory response is a multistage process that involves vascular and cellular changes but may also include systemic changes. White blood cells (WBCs) are brought to the damaged area, and they secrete mediators that control the process from initial injury to resolution or long-term inflammation. The inflammatory response is most efficient when it rids the body of injury, enhances healing processes, and resolves. In some disorders, such as rheumatoid arthritis (RA), tuberculosis (TB), and atherosclerosis, inflammation can persist and ultimately cause unremitting damaging effects on the body; these are considered chronic inflammatory conditions. See Box 9-1 for examples of inflammatory conditions. Inflammatory conditions can cause discomfort, organ dysfunction, and diminished quality of life. Cell biologists continue to uncover micromolecular-level mediators of inflammation, which could be precise targets for drugs. Our current knowledge base regarding inflammation is incomplete, but research continues to enhance our understanding of this complex physiological response. Types of Inflammation There are two types of inflammation: acute and chronic. Acute inflammation occurs rapidly in reaction to cell injury, rids the body of the offending agent, enhances healing, and terminates after a short period, either hours or a few days. Chronic inflammation occurs when the inflammatory reaction persists, inhibits healing, and causes continual cellular damage and organ dysfunction. Acute Inflammation Acute inflammation can be triggered by various injurious stimuli, such as infections, microbial toxins, physical injury, surgery, cancer, chemical agents, tissue necrosis, foreign bodies, and immune reactions. Regardless of etiology, all acute inflammatory reactions cause the same characteristic vascular, cellular, and systemic changes. These reactions are orchestrated by responses to various inflammatory mediators. The acute inflammatory reaction involves two main phases: Vascular phase: momentary vascular constriction followed by a long period of vascular permeability Cellular phase: attraction and rush of WBCs to area of injury Vascular Permeability. During the vascular phase, there is transient vasoconstriction followed by a prolonged period of vascular permeability. At a site of inflammation, inflammatory mediators such as histamine and bradykinin cause the blood vessels to dilate and become more permeable. Capillary pores open and allow fluids, WBCs, and platelets to travel to the site of injury or infection (Fig. 9-1). The increased fluid in the tissues dilutes the toxin and lowers the pH of the surrounding fluids so they are not conducive to microbial growth. The inflamed area immediately starts to become congested, warm, red, and swollen from the vasodilation and fluid extravasation into the tissues from the capillaries. These effects can occur internally within an organ or externally on the surface of the body, depending on where the cell injury and inflammation are occurring. CLINICAL CONCEPT The classic external signs of inflammation are known as the five cardinal signs: rubor (redness), tumor (swelling), calor (heat), dolor (pain), and loss of function (functio laesa). FIGURE 9-1. The vascular permeability phase of inflammation. Inflammation stimulates dilation of blood vessels and the opening of capillary pores. The capillary pores allow fluid and cells, such as WBCs and platelets, out to the area of injury. The fluid that leaves the capillaries is a protein-rich filtrate of blood that contains WBCs. As the WBCs perform defensive activities, the fluid increases within the tissue spaces and causes edema, or swelling. If the fluid is rich in protein from WBCs, microbial organisms, and cellular debris, it is called purulent exudate, or pus. An abscess is a localized, walled-off collection of purulent exudate within tissue. In contrast, fluid that contains little protein and is mainly a watery filtrate of blood is called transudate. Other types of exudates include serous (clear, watery fluid), sanguineous (blood), serosanguineous (bloody/watery fluid), or fibrinous (thick, fibrin-rich fluid). Any accumulation of fluid in a body cavity is called an effusion. An effusion can occur due to inflammatory or noninflammatory processes. CLINICAL CONCEPT An example of purulent exudate is the whitish-green drainage emitted from an infected wound. An example of a transudate is the clear fluid contained within a noninfected blister. Both are types of fluid that result from inflammation. Leukocytosis. During the cellular phase of inflammation, a chemical signal from microbial agents, endothelial cells, and WBCs attracts platelets and other WBCs to the site of injury. This is referred to as chemotaxis. During this phase, an increased number of leukocytes (WBCs) are released from the bone marrow into the bloodstream, a process known as leukocytosis. During inflammation, the WBC count in the blood commonly increases from a normal baseline of 4000 to 10,000 cells/mL to 15,000 to 20,000 cells/mL. The clinician can use the number of WBCs to determine the severity of the infectious process that the patient is experiencing. Once the WBCs arrive at the site of inflammation, they line up along the endothelium in the area of inflammation in a process called margination. At the site of injury, the leukocytes adhere to the endothelial lining of the blood vessels, held by adhesion molecules called selectins and integrins (Fig. 9-2). The term leukemoid reaction is used to describe an extreme, extraordinary elevation in the number of WBCs. Leukemoid reactions can raise the WBC count to 50,000 cells/microliter or more. These reactions can occur in conditions such as leukemia. CLINICAL CONCEPT Some genetic disorders such as severe combined immunodeficiency syndrome cause a deficiency in selectins and integrins, leading to immunodeficiency and increased risk of infection. FIGURE 9-2. Acute inflammation. After binding to the endothelial surfaces of the blood vessels, the WBCs then squeeze through pores in the capillaries to arrive at the tissues of injury. The type of WBC varies as time passes in the process of inflammation. During the first 6 to 24 hours, neutrophils predominate in the inflammatory infiltrate. Neutrophils undergo apoptosis and are gradually replaced by monocytes. Over the next 24 to 48 hours, monocytes change into macrophages. Macrophages then survive for long periods (weeks to months) and are the predominant type of WBC in persistent inflammatory reactions. There are some exceptions to this pattern. In certain infections—such as those caused by Pseudomonas bacteria—the cellular infiltrate is dominated by neutrophils for several days; in viral infections, lymphocytes dominate as the WBCs in the infiltrate. In allergic reactions, eosinophils are the dominant type of WBC in the infiltrate. Analysis of the type of WBC in the infiltrate can assist the clinician to determine the etiology of the inflammatory reaction. CLINICAL CONCEPT Some infections—such as typhoid fever and infections caused by Rickettsia, protozoa, and viruses—cause a decreased number of WBCs, termed leukopenia. WBCs and injured tissue release many different inflammatory mediators that act in various ways. Some mediators amplify the inflammatory process, recruiting more WBCs to the area of injury, and others attempt to stop the inflammatory process. Patho-Pharm Connection Tissue Injury and Inflammation Tissue injury stimulates inflammation reaction in the white blood cell. Injury stimulates the action of the phospholipase enzyme that breaks down phospholipids, which are key components of the white blood cell membrane. This enzymatic action yields arachidonic acid. [See how phospholipase is blocked by corticosteroids. Note the side effects of not producing “good PGs1”: decreased gastric mucus, kidney perfusion, and platelet aggregation.] NSAIDs stop arachidonic breakdown and inhibit both cyclooxygenase 1 and cyclooxygenase 2 pathways. This inhibition, in turn, inhibits production of both PG1 and PG2 prostaglandins. [Note that PG1 prostaglandins are “good PGs,” which enhance body processes such as production of gastric mucus, renal perfusion, and platelet aggregation/clot formation.] Cyclooxygenase 2 (COX-2) inhibitors block production of solely PG2 prostaglandins, which block the edema, inflammation, pain, and muscle spasms. TNF inhibitors and IL inhibitors block production of the cytokines, TNF alpha, and interleukins. These are released by white blood cells and promote the inflammation reaction. Blockade or inhibition of interleukins decreases inflammation. Mediators of Inflammation The mediators of inflammation are substances that promote or inhibit inflammatory reactions. These include interleukins (ILs) and tumor necrosis factor alpha (TNF-alpha). Inflammatory mediators are summarized in Table 9-1. Many anti-inflammatory pharmaceutical agents have been devised to counteract different types of inflammatory-promoting mediators (see Patho-Pharm Connection). Cytokines, Chemokines, and Acute Phase Proteins. Some of the inflammatory mediators released by WBCs are referred to as cytokines; the most common are tumor necrosis factor (TNF) alpha and interleukins (ILs). Cytokines modulate the inflammatory reaction by amplifying or deactivating the process. Simultaneously, they cause localized and systemic effects. Chemokines are proteins that attract leukocytes to the endothelium at the area of injury. Cytokines cause stimulation of the liver to release substances called acute phase proteins. Acute phase proteins include C-reactive protein (CRP), fibrinogen, serum amyloid A, and hepcidin. Acute phase proteins facilitate WBC phagocytosis of microbes and other foreign material and assist in the analysis of the inflammation process occurring in the body. CRP is a key acute phase protein that is integral to marking foreign material for phagocytosis; activating the complement system, which augments immunity; and stimulating other inflammatory cytokines. Elevation of CRP in the bloodstream indicates that active inflammation is occurring. Elevation of a specific type of CRP, identified by a laboratory test called high sensitivity CRP, is a marker for increased risk of myocardial infarction in patients with coronary artery disease. Fibrinogen binds to red blood cells (RBCs) and fixes them into stacks that precipitate rapidly in the blood through processes called rouleaux and sedimentation. This is the basis for a laboratory test called erythrocyte sedimentation rate (ESR) that, if elevated, indicates active inflammation. Elevated CRP, fibrinogen, and ESR alert the clinician that an active process of inflammation is occurring currently. Prolonged secretion of serum amyloid A causes a condition called amyloidosis, which indicates chronic inflammation and alerts the clinician that the patient has endured a long-term inflammatory process. Elevated hepcidin levels in the bloodstream indicate diminished iron storage in the body—a process that leads to anemia in chronic inflammatory conditions. TABLE 9-1. Major Proinflammatory Mediators Inflammatory Mediator​ Origin​ Effects Tumor necrosis factor-alpha Macrophages Fever, lack of appetite, raises metabolism to cause cachexia, hypotension Interleukins Macrophages Fever, stimulates platelet production, fatigue, anemia, headache Histamine Mast cells, basophils, platelets Vasodilation, increases vascular permeability, activates endothelium Kinins Liver, lungs, kidneys Increases vascular permeability, smooth muscle contraction, pain, natriuresis, hypotension Platelet-activating factor Platelets, leukocytes, mast cells Vasodilation, increases vascular permeability, platelet aggregation, angiogenesis (formation of new blood vessels), leukocyte adhesion to endothelium Prostaglandins Leukocytes Pain, fever, vasodilation, muscle spasm Leukotrienes Leukocytes, mast cells Bronchospasm, increased vascular permeability Substance P Neurons Pain, hypotension, enhances vascular permeability CLINICAL CONCEPT Laboratory tests that demonstrate elevated CRP, ESR, and fibrinogen levels in the bloodstream are indicators that the patient is enduring an active inflammatory process. Types of White Blood Cells. There are five basic types of WBCs: neutrophils, lymphocytes, eosinophils, basophils, and monocytes (see Fig. 9-3). CLINICAL CONCEPT Neutrophils are also referred to as polymorphonuclear leukocytes (PMNs); in their immature form, they are called bands or stabs. FIGURE 9-3. Types of WBCs. Neutrophils, basophils, and eosinophils are referred to as granulocytes because obvious cytoplasmic granules can be seen when examined under the microscope. These cytoplasmic granules contain important enzymes and antimicrobial proteins that support the inflammatory process and fight infection. Neutrophils have a short life span ranging from approximately 10 hours to a few days. Mature neutrophils have distinctive multisegmented nuclei and are sometimes known as segmented neutrophils (segs). As mature neutrophils die off and the supply becomes exhausted, the bone marrow responds with a rapid release of immature neutrophils (bands). Neutrophils begin the process of phagocytosis of the foreign matter immediately. Phagocytosis involves recognition and attachment of the leukocyte to the foreign matter, engulfment, and degradation or killing of the ingested matter (Fig. 9-4). During engulfment, extensions of the cytoplasm called pseudopods surround the foreign matter and pinch off, forming a phagosome. The phagosome then contains the foreign matter, and lysosomal and granular enzymes break it down. FIGURE 9-4. Phagocytosis. While the neutrophils are involved in phagocytosis of microbial organisms and cellular debris, there is a respiratory burst from the mitochondria. This burst releases free radicals (also called superoxides or reactive oxygen species) that disrupt microbial membranes, leading to their destruction. Free radicals contain a superoxide anion (O2), which is an oxygen molecule with a free electron that is drawn to elements in tissue. Using different terminology, free radicals oxidize microbial membranes and some of the surrounding host tissue cell membranes. However, host cells contain antioxidants that protect against extensive tissue damage. A genetic disorder called chronic granulomatous disease causes a deficiency of free radicals, which leads to immunodeficiency and increased risk of infections. CLINICAL CONCEPT Antioxidant vitamins A, C, E, and beta carotene can counteract collateral free radical oxidizing damage of healthy tissue in inflammatory processes. A laboratory test called a white blood cell (WBC) differential is used in the diagnosis of infection and inflammation. This test is part of a complete blood count (CBC) with differential, which quantifies RBCs and WBCs. A WBC with differential measures the total number of WBCs and calculates the percentages of specific types of WBCs within the total. The result of the laboratory test shows the predominant type of WBC responding to the infectious agent and can be used to indicate the etiology of inflammation. For example, a patient with pneumonia who has an elevated total WBC count of 16,000 with 90% neutrophils most likely has bacterial pneumonia, whereas a patient with pneumonia and an elevated WBC with 90% lymphocytes most likely has viral pneumonia. The WBC count with differential can also indicate an acute inflammatory reaction by quantifying the number of bands in the bloodstream. When a high number of bands are present, clinicians often use the phrase “shift to the left,” indicating an increase in newly formed neutrophils. An elevated WBC count with a “shift to the left” indicates that an acute inflammatory process is occurring. As inflammation resolves, immature neutrophils become less numerous and the WBC count returns to normal. Systemic Responses. Persons enduring acute inflammation experience symptoms throughout the whole body, such as fever, pain, lymphadenopathy (swollen lymph nodes), anorexia, sleepiness, lethargy, anemia, and weight loss. These are known as systemic responses. Inflammatory mediators such as prostaglandins (PGs), TNF-alpha, and ILs are responsible for many of these systemic effects. Studies also show that inflammatory mediators are elevated in older adults suffering from frailty. Progressive increases in frailty severity are correlated with inflammatory mediator concentrations, particularly IL and TNF. Fever. Fever, an increase in body temperature, is a common manifestation of inflammation and infection. Microbial organisms, bacterial products, and cytokines all act as pyrogens, which are substances that cause fever. Pyrogens activate PGs to reset the hypothalamic temperature-regulating center in the brain to a higher level. A higher body temperature is theorized to increase the efficiency of WBCs in their defense of the body against foreign invaders (see Fig. 9-5). CLINICAL CONCEPT Fever, although advantageous to the immune system, can reach levels high enough to cause seizures and brain damage. Therefore, it is recommended to keep fever below 102°F through the use of antipyretic medications such as aspirin, ibuprofen, or acetaminophen. These medications inhibit PG formation and thus reduce fever. ALERT! Never give children or adolescents aspirin or any salicylate-containing products to control a fever. Research has demonstrated a link between salicylate use and Reye’s syndrome in children and adolescents who have viral infections. Reye’s syndrome is a life-threatening disorder in which mitochondrial failure leads to liver failure and encephalopathy. The sensation of chills often accompanies fever. When the set point of the hypothalamic temperature-control center is suddenly changed from normal (98.6°F) to a higher temperature, it takes some time before the body reaches the new higher set point. Initially, the blood temperature is less than the new higher set point and the person has a sensation of being cold. The blood vessels constrict and the body attempts to conserve and generate heat. To reach the new hypothalamic temperature set point, the muscles shiver to generate body heat. The sensation of cold and muscle shivering are experienced as chills, which continue until the body reaches the higher hypothalamic temperature set point. When the stimulus for the fever resolves, pyrogens stop stimulating PGs and the hypothalamic temperature returns to normal levels. The feverish body must adapt to the new, lower hypothalamic set point. In response, vasodilation and intense sweating (diaphoresis) occur to dissipate the body heat. As body temperature declines, the patient appears flushed and diaphoretic because of widespread vasodilation. FIGURE 9-5. The fever response. Microorganisms enter the body and stimulate WBCs. Pyrogens are inflammatory mediators that are released by WBCs. Pyrogens reset the hypothalamic temperature center in the brain to create fever. Fever assists the WBCs in performing their activities in infection. Lymphadenopathy. Lymphadenopathy, or lymphadenitis, is a term used to describe the enlargement of lymph nodes because of inflammatory processes. Lymph nodes are small, bean-sized masses of tissue located in various regions of the body, including the neck, axillary regions, central thoracic region, inguinal areas, and gastrointestinal tract (Fig. 9-6). Lymphocytes mature within a lymph node, and during an inflammatory process, lymph nodes become enlarged. Because of the active proliferation of lymphocytes, lymph nodes enlarge, which stretches their capsule and causes tenderness. Lymphatic fluid or lymph circulates around body tissues and collects debris. The injurious agents that cause the inflammation can invade lymph and then spread to other lymph nodes. Histamine Release. Histamine, an inflammatory mediator released from basophils, platelets, and mast cells, has many systemic effects. It causes arteriolar vasodilation, large artery vasoconstriction, and increased permeability of venules. Mast cells, located in tissues adjacent to blood vessels, are the richest source of histamine. Physical injury, immune reactions, cytokines, and other inflammatory mediators stimulate histamine release. Commonly, sneezing, rhinorrhea (runny nose), eye tearing, sinus inflammation, and pharyngeal irritation are consequences of histamine released in the upper respiratory tract. FIGURE 9-6. Regions of the lymph nodes in the body. Effects of Prostaglandins, Leukotrienes, and Their Enzymatic Pathways. Prostaglandins (PGs) are released from WBCs and other cell membranes through a series of reactions. During inflammation, an enzyme called phospholipase is stimulated and acts on phospholipids, constituents of the WBC cell membrane. Phospholipids are broken down into arachidonic acid, which undergoes further enzymatic action by cyclooxygenase and lipoxygenase. The cyclooxygenase pathways produce PGs, and the lipoxygenase pathway produces leukotrienes. Some PGs perpetuate negative effects of inflammation, and other PGs are needed for protective bodily functions. Leukotrienes provoke bronchiole inflammation in asthma. Two different enzymes are involved in the formation of PGs from arachidonic acid: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Each pathway yields a different type of PG. The COX-1 pathway breaks down arachidonic acid enzymatically into helpful PGs, and the COX-2 pathway yields harmful PGs. The PGs formed from the COX-1 pathway stimulate gastric mucus production, enhance renal perfusion, and assist platelets to aggregate and form clots. The PGs formed by the COX-2 pathway perpetuate inflammation; cause pain, fever, swelling, and muscle contractions; and potentiate the effects of other inflammatory mediators (see Fig. 9-7). FIGURE 9-7. Prostaglandin and leukotriene synthesis pathways within the WBC. Injury stimulates inflammation, which attracts WBCs to the area of injury. Within the WBC, phospholipase acts upon phospholipids to yield arachidonic acid, which is then converted to PGs via the COX-1 or COX-2 pathway or to leukotrienes via the lipoxygenase pathway. The PGs created by the COX-1 pathway are needed to secrete gastric mucus and enhance renal perfusion and thrombus formation. The PGs created by the COX-2 pathway cause uncomfortable symptoms of inflammation, such as fever, edema, and pain. Leukotrienes cause bronchospasm and bronchiole edema. Systemic Effects of TNF-alpha and ILs. TNF-alpha, IL-1, and IL-6 are major cytokines produced by macrophages in the inflammation reaction and have been shown to induce fever, loss of appetite, and lethargy. TNF-alpha also promotes lipid and protein mobilization, which causes weight loss and cachexia, the wasting of lean body mass. TNF-alpha can enhance release of WBCs into the bloodstream and facilitate the release of pituitary corticotropin and adrenal corticosteroids in the body. In an infected bloodstream, a condition known as sepsis, TNF-alpha provokes hypotension, widespread vasodilation, increased heart rate, and decreased blood pH. CLINICAL CONCEPT In severe sepsis, large amounts of bacteria stimulate enormous quantities of cytokines, notably TNF and ILs, which cause shock, disseminated intravascular coagulation, and possible death. Outcomes of Acute Inflammation. Acute inflammation will result in one of three outcomes: Complete resolution Healing by connective tissue Chronic, persistent inflammation that does not recede Ideally, acute inflammation is a short-lived reaction that eliminates an injurious agent, allows little tissue destruction, and terminates by facilitating the regeneration of normal tissue. Resolution involves normalization of vascular permeability, deactivation of chemical mediators, elimination of cellular debris and edema, and apoptosis of WBCs. At times, severe tissue injury and a large acute inflammatory reaction preclude the regeneration of normal cells. This happens when inflammation involves tissues incapable of regenerating cells or when inflammatory exudates and cellular debris cannot be adequately cleared at the conclusion of the inflammatory reaction. At these times, resolution and healing occur through the proliferation of connective tissue. Cellular debris and exudates are reabsorbed, and fibrous scar tissue, rather than regenerated cells, replaces damaged cells. Finally, there are times when acute inflammation cannot be resolved because of persistence of the injurious agent or other interference with healing. In these cases, inflammation becomes a chronic, persistent condition with failure to resolve and extensive tissue damage. Chronic Inflammation An inflammatory reaction that persists for a prolonged time, from weeks to months, without resolution or healing is considered a chronic inflammatory disorder. Specific etiological agents are known to cause chronic inflammation, but a persistent, unremitting inflammatory reaction can also occur for unknown reasons. Etiologies of Chronic Inflammation Causes of chronic inflammation include: Persistent infection by microorganisms that are difficult to eradicate (e.g., Mycobacterium tuberculosis [TB]). Hypersensitivity disorders, which cause excessive activation of the immune system. Examples of these disorders include autoimmune diseases such as RA, multiple sclerosis (MS), or systemic lupus erythematosus (SLE).  Prolonged exposure to potentially toxic agents such as coal dust, which causes anthracosis (black lung). Atherosclerosis is also a chronic inflammatory disease affecting the arterial wall that is caused by agents that damage the endothelial cells. Some agents that cause endothelial injury include hypertension, free radicals (superoxide molecules), and high blood glucose. Some cancers, such as basal cell carcinoma—a type of skin cancer caused by excessive sun damage, are promoted by chronic inflammatory reactions. In contrast to acute inflammation, which is manifested by vascular permeability and neutrophil proliferation, chronic inflammation is characterized by the predominance of monocytes, lymphocytes, and macrophages. In acute inflammation, the products of activated macrophages eliminate injurious agents such as microbes and initiate the process of healing. In chronic inflammation, however, these same products, when constantly secreted by macrophages, cause tissue damage. The destructive macrophage products include free radicals, proteases, cytokines, angiogenesis growth factors, and fibroblast activators. Tissue is repeatedly damaged, healing is delayed, and connective tissue replaces injured cells. As tissue damage causes cell death, necrotic tissue stimulates an inflammatory reaction. As a result, tissues undergoing chronic inflammation can have regions demonstrating acute inflammation as well. T and B lymphocytes commonly amplify and perpetuate chronic inflammation. These are the cells found in chronic autoimmune disorders. T lymphocytes are particularly involved in chronic inflammatory conditions, as they produce ILs and interferon, which recruit macrophages. Chronic inflammation often causes a distinctive histological pattern of granulomatous changes. A granuloma is an area where macrophages have aggregated and are transformed into epithelial-like or epithelioid cells. The epithelioid cells are surrounded by lymphocytes, fibroblasts, and connective tissue. Frequently, the epithelioid cells fuse to form giant cells within the granuloma. TB is the prototypical granulomatous chronic inflammatory disease. On histological examination of the lungs, a TB granuloma is characterized by an aggregate of macrophages surrounding TB organisms. After acute infection, neutrophils and monocytes surround, but cannot kill, TB bacteria. The WBCs attracted to the area of infection can only wall off the bacteria. Eventually this region, infiltrated with macrophages, becomes a chronic inflammatory granuloma called a tubercle. The tubercle can be identified on histological examination and x-ray of the lungs (see Fig. 9-8).