Inflammation PDF

Inflammation By the end of the lesson, students will be able to: 1. Illustrate and describe the three stages of an acute inflammatory reaction including the processes that happen in each A. Increased vascular permeability I. momentary vascular constriction followed by a long p...

Inflammation By the end of the lesson, students will be able to: 1. Illustrate and describe the three stages of an acute inflammatory reaction including the processes that happen in each A. Increased vascular permeability I. momentary vascular constriction followed by a long period of vascular permeability II. Vasodilation III. Histamine and bradykinin: dilate vessels IV. Fluid, WBC's, platelet travel to injury V. Toxins diluted VI. WBC's phagocytize foreign matter and debris VII. Vasodilation and fluid extravasation into the tissues VIII. Abscess i. Localized, walled-off collection of purulent exudate IX. Effusion ii. Accumulation of fluid in a body cavity X. 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. XI. 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. B. Cellular chemotaxis XII. attraction and rush of WBCs to area of injury XIII. **Segmented (Mature) neutrophils-** they would predominate in the first 6-24hrs. XIV. **Monocytes/macrophages-** predominate within 24-48hrs XV. Chemical agents from WBC's, endothelial cells, microbial agents XVI. Chemotaxis iii. Chemical signals attract WBC's and platelets XVII. Margination iv. WBC's line up along endothelium v. Release inflammatory mediators XVIII. Leukocytosis vi. Increase in WBC number XIX. Leukemoid reactions vii. Extreme elevation in WBC XX. WBC Differential viii. Different types of WBC's XXI. 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. 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. 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. C. Systemic response XXII. **Fever and lymphadenopathy** XXIII. 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. 2. List the cardinal signs of inflammation D. Rubor (redness) E. Tumor (swelling) F. Calor (heat) G. Dolor (pain) H. Loss of function (function laesa) 3. Define phagocytosis, cytokines, acute phase proteins, pyrogens, and granuloma I. Phagocytosis XXIV. 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. XXV. 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. J. Cytokines XXVI. Released by WBC's XXVII. Tumor Necrosis Factor (TNF) alpha XXVIII. Interleukins (IL's) XXIX. 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. K. Acute phase proteins XXX. Liver produces in response to cytokines XXXI. C-reactive protein (CRP) ix. Marks foreign material for phagocytosis x. Activates complement system xi. Stimulates other inflammatory cytokines xii. Elevation indicates active inflammation xiii. High sensitivity CRP a. Marker for increased risk of myocardial infarction XXXII. Fibrinogen xiv. Binds to red blood cells and fixes them into stacks that precipitate xv. Processes called rouleaux and sedimentation xvi. Erythrocyte sedimentation rate (ESR) b. Active inflammation XXXIII. Serum amyloid A xvii. Amyloidosis c. Prolonged secretion which indicates chronic inflammation and alerts the clinician that the patient has endured a long-term inflammatory process XXXIV. Hepcidin xviii. Elevation indicates diminished iron storage in the body xix. Anemia with chronic inflammation XXXV. 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. L. Pyrogens XXXVI. 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 M. Granuloma XXXVII. 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 4. Differentiate between purulent exudate and transudate N. Purulent exudate (pus) XXXVIII. Proteins, microbes, cell debris XXXIX. White-green discharge O. Transudate XL. Watery, clear fluid XLI. *Example:* non-infected blister 5. Identify labs indicative of inflammation P. 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. Q. 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. R. 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. S. C-reactive protein (CRP)- 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. T. 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. 6. List the 5 basic types of white blood cells U. Granulocytes XLII. Neutrophils xx. begin the process of phagocytosis of the foreign matter immediately. xxi. Like macrophages, they are the first responders to an infection, stressful event, or inflammatory reaction. At the first sign of cell injury, neutrophils leave the circulation and enter the tissues, where they lyse (break down) bacteria by releasing enzymes stored in their granules. When a neutrophil phagocytizes an invading organism or cellular debris, it releases a respiratory burst of free radicals called superoxides \[O2--\] that contribute to injury of surrounding tissues XLIII. Basophils xxii. generated and released by the bone marrow in response to many inflammatory reactions, particularly parasitic infection. The mediators histamine and heparin assist in the migration of neutrophils to an inflammatory site. XLIV. Eosinophils xxiii. are generated by the bone marrow and released mainly during allergic reactions and parasitic infection. V. Agranulocytes XLV. Monocytes xxiv. When they leave the circulation and enter tissue, they mature into macrophages. their primary function, which is phagocytosis. In this process, the macrophage engulfs, ingests, and enzymatically destroys antigenic substances and cellular debris. Macrophages are a major component of the innate immune system and are the primary immunological response to a foreign invader, termed an antigen. Another important function of monocytes is their ability to synthesize and secrete cytokines, substances that enhance inflammation and stimulate function of other WBCs. XLVI. Lymphocytes xxv. The two main types of lymphocytes are B cells and T cells. Lymphocytes are part of the adaptive branch of the immune system. After exposure to an antigen, lymphocytes recognize, target, and have memory for specific antigens. The stimulus of an antigen transforms a B cell into a plasma cell, which produces immunoglobulins (Igs) that attack antigens. In contrast, the stimulus of an antigen activates a T cell to directly attack the antigen. B and T cells endow the body with long-term immunity 7. Describe the timing of neutrophils and monocytes/macrophages in a WBC response W. 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. 8. Identify the type of WBCs that dominate in a viral infection X. Viral infections XLVII. Lymphocytes dominate XLVIII. T and B lymphocytes commonly amplify and perpetuate chronic inflammation. 9. Illustrate the inflammation reaction inside a WBC, including the actions of the prostaglandins and leukotrienes Y. Prostaglandins XLIX. Pain, fever, vasodilation, muscle spasm Z. Leukotrienes L. Bronchospasm, increased vascular permeability A. 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. B. 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 10. Describe the benefits of fever C. **Fever** enhances immune cell activity (such as the action of lymphocytes) \[c\], interferes with pathogen replication \[d\] and increases the production of acute phase proteins, which are important components of the immune response \[f\]. D. **Fever inhibits** rather than enhances pathogen replication. E. **Fever** **increases** rather than decreases the metabolic rate and oxygen consumption. F. **Fever** **increases** rather than reduces the production of acute phase proteins, which are important components of the immune response. 11. Determine when anti-pyretic medications are indicated and which medications to avoid for certain age groups G. 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. H. 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. 12. List symptoms of a histamine reaction I. Vasodilation, increases vascular permeability, activates endothelium J. Commonly, sneezing, rhinorrhea (runny nose), eye tearing, sinus inflammation, and pharyngeal irritation are consequences of histamine released in the upper respiratory tract. 13. List possible outcomes of acute inflammation K. Complete resolution L. Healing by connective tissue M. Chronic, persistent inflammation that does not recede N. 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. O. 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. 14. Describe the 4 phases of wound healing P. Hemostasis Q. Inflammation R. Proliferation, granulation tissue formation, angiogenesis, and epithelialization S. Wound contraction and remodeling T. Hemostasis occurs shortly after injury as exposed collagen surfaces attract platelets. Platelets aggregate and secrete inflammatory mediators such as serotonin, histamine, and platelet-derived growth factor. Vasoactive amines such as epinephrine cause short-term vasoconstriction, which limits blood loss. U. Inflammation occurs next in the acute phase, after injury, and has been described previously. Vasodilation, increased vascular permeability, and chemotaxis occur during this phase. V. In the subsequent proliferation phase, granulation tissue forms. The fibroblast, a connective tissue cell that synthesizes collagen and provides the extracellular matrix in wound healing, is the key cell involved in this process. As early as 24 to 48 hours after injury, fibroblasts form the granulation tissue that serves as the foundation of scar tissue. Vascular endothelial cells create new blood vessels in a process called angiogenesis. The granulation tissue then secretes growth factors and cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), tissue growth factor-beta (TGF-beta), and IL-1. Also, during this phase, epithelial cells migrate and proliferate to form a new surface and fill in the gap between the wound edges. Fibroblasts produce collagen for days, weeks, or months, depending on the wound size. Approximately 3 weeks after injury, the remodeling phase begins, where the scar tissue is structurally refined and reshaped by fibroblasts and myofibroblasts 15. Discriminate between primary, secondary and tertiary intention W. Skin wounds heal by either of three processes: primary, secondary, or tertiary intention (see Fig. 9-10). The nature of the wound determines the process the body uses. Healing by primary intention, also called primary union, is the least complicated type of wound repair. The edges of the wound are clearly demarcated, cleanly lacerated, and easily brought together, and there is no missing tissue within the injured area. A surgical wound is the best example of this type of injury, which usually undergoes a simple, rapid healing process. Surgical wounds can be closed with sutures, staples, or adhesive. Sutures are the gold standard and can be made of absorbable or nonabsorbable material. Within 24 hours, WBCs congregate and a fibrin clot develops at the site. After 24 to 48 hours, simple epithelialization predominates as the major process that closes the wound. By day 5, granulation tissue progressively fills in the incision space and new blood vessel growth is maximal. During the second week, there is accumulation of collagen and proliferation of fibroblasts within the incisional scar. By the end of the first month, inflammation has subsided, and connective tissue covered by an intact epidermis makes up the wound site. X. When there is extensive loss of tissue within a wound, the repair process is more complex; in this case, secondary intention, also called secondary union, healing begins (see Fig. 9-10). Regeneration of the same cells to replace lost tissue is not possible. Abundant granulation and fibrous tissue are necessary to fill the defect and restore the original structure of tissue. The inflammation process within this type of wound is more intense and longer in duration. The formation of granulation tissue requires extensive time and support for the healing process. Y. The phase that differentiates primary from secondary intention is wound contraction. Wound contraction occurs because of myofibroblasts, which are connective tissue cells with smooth muscle characteristics. These specialized cells cause the contraction of the wound's edges to close the tissue gap. Substantial scar formation and thinning of the epidermis occurs. Wounds of this type are highly susceptible to infection, complications, and deformity. Z. In tertiary intention, also called tertiary union, the wound is missing a large amount of deep tissue and is contaminated. It is cleaned and left open for 4 to 5 days before closure. The wound may require temporary packing with sterile gauze and have extensive drainage that often requires insertion of a drainage tube. By the fifth day, WBC phagocytosis of contaminated tissues occurs and the processes of epithelialization, collagen deposition, and maturation take place. Foreign materials are walled off by macrophages and other types of leukocytes to form granulomas. There is prominent scarring with healing. This type of wound commonly requires a skin graft. A. Pressure injuries and severe burns are examples of wounds that require secondary and tertiary intention healing. These wounds have large areas of missing skin, dermis, and deeper tissue, which are replaced by scar tissue (see Fig. 9-11). B. Primary, secondary, and tertiary intention wounds do not regain full tensile strength of unwounded skin after healing is completed. Clinicians and patients need to be aware of the weakened integrity of the skin and underlying tissues. Careful support of the area to facilitate healing is necessary during the first few weeks after surgery. After sutures are removed, usually 1 to 2 weeks later, wounded skin is again in a vulnerable, weakened state. The healed wound builds to a maximal tensile strength of 70% to 80% after 3 months. C. Some wounds develop eschar tissue. Eschar is dead tissue that sheds or falls off from healthy skin. It is common in burn wounds and pressure injuries. Eschar is typically tan, brown, or black and often has a crusty top layer. 16. List factors that affect wound healing D.  Nutrition: Lack of adequate nutrients, particularly protein, decreases cellular regeneration and metabolic function. E.    Oxygenation: Oxygen is needed for neutrophil phagocytosis and collagen synthesis. F.    Circulation: Lack of adequate circulation predisposes the individual to ischemia, infarction, and consequent infection of necrotic tissue, also known as gangrene. G.    Immune strength: Diabetes, corticosteroid use, cancer, HIV, aging, and immunosuppressant agents diminish WBC activity, delay wound healing, and predispose to infection. H.    Contamination: Foreign bodies present in a wound diminish healing ability and predispose to infection. Foreign bodies include sutures that remain in place too long, surgically inserted devices such as pacemakers, heart valves, and orthopedic or prosthetic implants. I.    Mechanical factors: Includes increased localized pressure, torsion, and excessive fat tissue. J.    Age: The regeneration process of infants and young children is superior to that of adults. Studies show that fetal wounds heal without fibrosis or scarring. Older adults have the slowest healing process. 17. Differentiate between keloid, contractures, dehiscence, evisceration, fistula and adhesions K. Keloid: hyperplasia of scar tissue L. Contractures: inflexible shrinkage of wound tissue that pulls the edges toward the center of the wound M. Dehiscence: opening of a wound's suture line N. Evisceration: opening of wound with extrusion of tissue and organs O. Fistula: an abnormal connection between two epithelium-lined organs or vessels that normally do not connect (e.g., tracheoesophageal fistula) P. Adhesions: internal scar tissue between tissues or organs