Introduction to Pathology INFLAMMATION PDF

Introduction to Pathology INFLAMMATION Kenneth W. Hunter, Sc. D. OBJECTIVES FOR INFLAMMATION Following this lecture, you should be able to: 1. Recount the sequence of events in the inflammatory process from the recognition of pathogens and tissue injury, through the pathophysiologic changes in blood...

Introduction to Pathology INFLAMMATION Kenneth W. Hunter, Sc. D. OBJECTIVES FOR INFLAMMATION Following this lecture, you should be able to: 1. Recount the sequence of events in the inflammatory process from the recognition of pathogens and tissue injury, through the pathophysiologic changes in blood vessels and leukocytes, to eventual tissue repair and resolution. 2. List the hematopoietic and other cell types that participate in inflammation, including macrophages, dendritic cells, neutrophils, mast cells, platelets, and endothelial cells. 3. Describe the various microbial, physical, chemical, and biologic stimuli that induce inflammation, and the consequences of defective and excessive inflammation in health and disease. 4. Discuss how pattern recognition receptors on cell surfaces and in plasma recognize pathogen associated molecular patterns (PAMPs) and damage associated molecular pattern (DAMPs), and explain how they trigger inflammation. 5. Describe the role of blood vessels and endothelium in inflammation, including the processes of vasodilation and increased vascular permeability. 6. Explain the function of leukocytes in inflammation, including the processes of leukocyte recruitment (adhesion molecules), chemotaxis, activation, and phagocytosis. 7. Compare and contrast the distinctive features of acute and chronic inflammation. 8. Discuss the principal biochemical mediators of inflammation including: histamine and serotonin; arachidonic acid metabolites (e.g., prostaglandins and leukotrienes); cytokines and chemokines (e.g., TNF-a, CXCL8), reactive oxygen and nitrogen species (e.g., OH-, NO), and platelet activating factor. INFLAMMATION IS A TWO-EDGED SWORD This physiologic process is a component of the innate immune response to pathogenic microorganisms Also deals with the consequences of cell and tissue injury (e.g., necrotic cells and tissues) caused by microbes and other physical and chemical insults Without inflammation pathogenic microbes would overwhelm us, and injured tissues would never heal In the practice of medicine, understanding inflammation is important because it is sometimes inappropriately triggered or poorly controlled, and is thus the cause of tissue injury in many disorders Protective inflammatory response to Streptococcus pyogenes (impetigo) Harmful inflammatory response in rheumatoid arthritis INFLAMMATION WAS RECOGNIZED LONG AGO An accurate description of the clinical features of inflammation was found in an Egyptian papyrus dated around 3000 b.c. Celsus, Roman writer of the first century a.d., first listed the four cardinal signs of inflammation: rubor (redness), tumor (swelling), calor (heat), and dolor (pain) A fifth clinical sign, loss of function (functio laesa), was added by Rudolf Virchow in the 19th century Inflammatory response in bacterial cellulitis MANY HEMATOPOIETIC CELLS HAVE A ROLE IN INFLAMMATION Lymphoid Lineage Myeloid Lineage More Details in Block 6 THE INFLAMMATORY PROCESS Microbes or necrotic cells in extravascular tissues are recognized by sentinel cells These cells produce mediators that affect blood vessels Leukocytes and plasma proteins are recruited from the circulation Microbes and dead tissue are removed The reaction is regulated and terminated The damaged tissue is repaired The Five Rs of Inflammation WHAT ARE THE STIMULI FOR INFLAMMATION? Infections (bacterial, viral, fungal, parasitic) and microbial toxins Tissue necrosis from any cause, including: ischemia (e.g., myocardial infarct); trauma, physical, and chemical injury (e.g., thermal injury, irradiation, environmental chemicals, foreign bodies like splinters and sutures); and hypoxia Immune or hypersensitivity reactions (autoimmune or allergic) These various stimuli for inflammation are sensed by a variety of cellular receptors and molecules in plasma Tissue necrosis following a myocardial infarction (sterile inflammation) PATHOGENIC MICROORGANISMS ARE STRONG INDUCERS OF INFLAMMATION Inflammation can be triggered by “danger signals” from pathogens Phagocytic cells (e.g., macrophages) have many pattern recognition receptors (PRR) PRR bind to highly conserved molecular motifs on pathogens called pathogenassociated molecular patterns (PAMPs) Recognition of PAMPs triggers intracellular signaling pathways that activate the phagocytic cells Genes for numerous inflammatory mediators are expressed; orchestrate protective innate immune responses Pathogen with PAMP Recognition of PAMP by PRR on Phagocytic Cells Activaton of intracellular signaling pathway Production of inflammatory mediators INFLAMMATION Destruction of the Pathogen USMLE QUESTION An 11-year-old child falls and cuts his hand. The wound becomes infected. Bacteria extend into the extracellular matrix around capillaries. The injury is now red, swollen, warm, and painful. In the inflammatory response to this infection, which of the following cells removes the bacteria? A. B lymphocyte B. Fibroblast C. Macrophage D. Mast cell E. T lymphocyte PATTERN RECOGNITION RECEPTORS (PRR) ON PHAGOCYTIC CELLS Toll-Like Receptors (TLR) Other PRR PRR expressed on phagocytic cells recognize highly conserved PAMPs found on viruses, bacteria, fungi, and parasites Recognition often promotes phagocytosis of the pathogens, while simultaneously causing the production of inflammatory mediators More Details in Block 6 INFLAMMATION IS ALSO INDUCED BY CELL AND TISSUE INJURY (NECROSIS NOT APOPTOSIS) Inflammation triggered by “danger signals” from injured cells or dead cells that die by the process of necrosis Programmed cell death (apoptosis) does NOT trigger inflammation Cell injury or necrotic cell death promotes the release or expression of damage-associated molecular patterns (DAMPs) aka alarmins (e.g., ATP) Phagocytic cells have a variety of DAMP receptors Release of numerous mediators orchestrates the processes of tissue regeneration or repair Injured Cells Release or Express DAMPs Phagocytic Cells Recognize DAMPs Activaton of intracellular signaling pathway Production of inflammatory mediators INFLAMMATION Tissue Regeneration or Repair USMLE QUESTION A 17-year-old motocross rider presents with a severely bruised and swollen left arm resulting from a crash at the track an hour ago. This acute inflammatory response was triggered by the release of biological molecules from necrotic cells. What term below is used to describe these proinflammatory molecules? A. Inflammatory chemokines B. Apoptotic signaling molecules C. Damage-associated molecular patterns D. Arachidonic acid metabolites E. NADPH inhibitors INFLAMMATION CAN CAUSE COLLATERAL DAMAGE TO NORMAL TISSUES Normal tissues can be damaged by the inflammatory processes (collateral damage) When inappropriately directed against self tissues or not adequately controlled, inflammation becomes the cause of injury and disease Inflammatory reactions underlie common chronic diseases, such as rheumatoid arthritis, atherosclerosis, and COPD, as well as life-threatening hypersensitivity reactions to insect bites, drugs, and toxins As physicians, you will spend a large amount of time preventing or managing the collateral damage caused by inflammation (using anti-inflammatory drugs) INFLAMMATION IS CRITICAL TO TISSUE REPAIR The inflammatory response is closely aligned with the process of tissue repair (wound healing) Repair begins during inflammation but usually reaches completion after the injurious agent has been neutralized Injured tissue is replaced through regeneration of native parenchymal cells, by filling of the defect with fibrous tissue (scarring), or by a combination of these two processes PHYSIOLOGY OF THE INFLAMMATORY PROCESS Goal is to deliver leukocytes and plasma proteins (e.g., antibodies) to sites of infection or tissue injury Vasodilation increases the blood supply to tissues (hyperemia), but actually decreases blood flow (stasis) Increased vascular permeability results from structural changes in the endothelium that permit plasma proteins and leukocytes to leave the circulation (results in edema) Recruitment, adhesion, and transmigration of leukocytes across blood vessel endothelium Chemotaxis of leukocytes to site of infection or tissue injury Phagocytosis and destruction of pathogens or dead cells VASODILATION: THE FIRST MANIFESTATION OF INFLAMMATION Vasodilation is often preceded by a brief vasoconstriction (neurogenic) Specific mediators released from tissue phagocytic cells (mainly macrophages) Mediators like histamine and nitric oxide (NO) cause relaxation in smooth muscle surrounding the blood vessels Arterioles, capillaries, and venules dilate Dilation results in greater blood volume but slower blood flow (stasis) Upon observation, such tissue appears to show hyperemia MECHANISMS OF INCREASED VASCULAR PERMEABILITY Many mediators (e.g., histamine) cause vascular leakage by “retracting” endothelial cells; usually short-lived (15-30 minutes) Direct endothelial damage is encountered in severe injuries (e.g. burns) or by microbes that target endothelial cells; injury is rapid and can be long-lived (hours to days) Both mechanisms probably contribute in varying degrees in responses to many stimuli TRANSUDATES AND EXUDATES Transudate (A): fluid with low protein content and little or no cellular material. It is an ultrafiltrate of blood plasma resulting from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability Exudate (B): extravascular fluid that has a high protein concentration and contains cells and cellular debris. Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, is an inflammatory reaction A B edema Specific Gravity 1.020 USMLE QUESTION A 72-year-old man with severe emphysema has had worsening right ventricular failure for the past 5 years. For the past 4 days, he has had fever and increasing dyspnea. A chest radiograph shows an accumulation of fluid in the pleural spaces. Fluid obtained by thoracentesis has a specific gravity of 1.030 and contains degenerating neutrophils. The most likely cause of this fluid accumulation is due to changes in which of the following? A. Increased colloid osmotic pressure B. Leukocytic diapedesis C. Lymphatic pressure drop D. Renal sodium retention E. Increased vascular permeability LYMPHATIC VESSELS ALSO RESPOND TO INFLAMMATION Microbes may find their way into lymph The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis) Inflamed lymph nodes are often enlarged because of hyperplasia of lymphoid follicles and increased numbers of lymphocytes and macrophages Red streaks near a skin wound is a clinical sign of infection in the wound Follows the course of the lymphatic channels RECRUITMENT OF LEUKOCYTES TO SITE OF INFECTION OR INJURY Leukocyte recruitment (mainly neutrophils) to the site of injury is mediated by chemokines produced by macrophages (e.g., CXCL8) The movement of leukocytes from the vessel lumen to the interstitial tissue, is called extravasation The extravasation process involves margination, rolling, and then adhesion to endothelium In inflammation the endothelium is activated and can bind leukocytes via adhesion molecule interactions Migration across the endothelium and vessel wall is called diapedesis Migration in the tissues toward the inflammatory stimulus (chemotaxis) THE ROLE OF ADHESION MOLECULES Attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types Expression of adhesion molecules is enhanced by cytokines (e.g., TNF-a) that bind to receptors on endothelial cells Cytokines are secreted by cells in tissues (e.g., macrophages) in response to microbes and other injurious agents, thus ensuring that leukocytes are recruited to tissues where these stimuli are present There are four groups of adhesion molecules: selectins, vascular addressins, integrins, and immunoglobulin superfamily proteins LEUKOCYTE INTERACTION WITH ENDOTHELIUM Proteoglycan Matrix Basement Membrane Refer to movie USMLE QUESTION A small sliver of wood becomes embedded in the finger of a 25year-old man. He does not remove it, and over the next 3 days the area around the sliver becomes red, swollen, and tender. Neutrophils migrate into the injured tissue. Expression of which of the following substances on endothelial cells is most instrumental in promoting neutrophil accumulation in this inflammatory reaction? A. Interferon gamma B. Hageman factor C. Lysozyme D. E-selectin E. Prostacyclin LEUKOCYTE MIGRATION THROUGH ENDOTHELIUM Diapedesis of leukocytes occurs mainly in postcapillary venules Chemokines stimulate leukocytes to migrate through interendothelial spaces toward the site of injury or infection (e.g., CXCL8) Adhesion molecules present in the intercellular junctions between endothelial cells are involved in the migration of leukocytes (e.g. CD31 or PECAM-1) Leukocytes enter the extravascular tissue by secreting collagenases that break down basement membrane The cells then migrate up the chemokine gradient (chemotaxis) and accumulate in the extravascular site USMLE QUESTION An investigator was studying several drugs for their ability to promote the rapid movement of neutrophils between endothelial cells and into a site of tissue inflammation. Which of the following phenomena was he studying? A. Margination B. Diapedesis C. Rolling Adhesion D. Phagocytosis E. Hyperemia LEUKOCYTE CHEMOTAXIS Chemoattractants can be either endogenous and exogenous substances Endogenous chemoattractants include chemokines (e.g., CXCL8), components of the complement system (e.g., C5a), and leukotrienes (e.g., LTB4) The most common exogenous agents are bacterial products, including peptides that possess an Nformylmethionine terminal amino acid (f-met-leu-phe), and some lipids (see movie) PHAGOCYTOSIS: REMOVAL OF THE OFFENDING AGENTS After recruitment to the site of inflammation and activation, leukocytes recognize and remove pathogens and/or necrotic cells The predominant process is phagocytosis Phagocytosis involves three sequential steps: 1) recognition and attachment of the particle by the leukocyte; 2) engulfment of the particle into a phagosome; and 3) fusion of the phagosome with lysosomes to form phagolysosomes NADPH oxidase is a complex of proteins that assembles at the phagolysosome membrane and generates a hostile microenvironment that leads to killing and degradation of ingested materials Anti-inflammatory mediators terminate the acute inflammatory reaction when it is no longer needed More details in Block 6 INFLAMMATION MAY BE ACUTE OR CHRONIC Depending on the nature of the stimulus inflammation may be acute or chronic Acute inflammation is rapid in onset (minutes), and usually short in duration (hours or a few days) Chronic inflammation may follow acute inflammation or be insidious in onset. It is of longer duration (days to months or longer) Inflammation is usually terminated when the offending agent is eliminated. Mediators are rapidly broken down, and neutrophils are shortlived A host of anti-inflammatory mechanisms prevent excessive damage to the host Acute inflammatory response in sunburn Chronic inflammatory response in psoriasis ACUTE VS. CHRONIC INFLAMMATION Acute inflammation is characterized by vascular changes, edema, and a predominantly neutrophilic infiltration In contrast, chronic inflammation involves an monocytic infiltration, which include macrophages, lymphocytes, and plasma cells Tissue destruction, induced by the persistent offending agent or by the inflammatory cells, is common in chronic inflammation Chronic inflammation is characterized by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and fibrosis Acute Prostatitis Chronic Hypersensitivity Pneumonitis HISTOPATHOLOGY OF ACUTE INFLAMMATION Normal Lung Vascular Congestion and Stasis Leukocytic Infiltrate Normal lung shows thin blood vessels in the alveolar walls and no cells in the alveoli (A) The vascular component of acute inflammation is manifested by congested blood vessels (packed with erythrocytes), resulting from stasis (B) The cellular component of the response is manifested by large numbers of leukocytes (neutrophils) in the alveoli (C) MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION Serous inflammation is marked by the exudation of cell-poor fluid into spaces created by cell injury or into body cavities lined by the peritoneum, pleura, or pericardium (A) Fibrinous inflammation develops when vascular leaks are large or there is a local procoagulant stimulus (B) Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid (abscesses) (C) Examples will be shown in lab next week A B C USMLE QUESTION A 75-year-old woman touches a pot of boiling water. Within 2 hours, she has marked erythema of the skin of the fingers of her hand, and small blisters appear on the finger pads. This has led to which one of the following inflammatory responses? A. Fibrinous inflammation B. Granulomatous inflammation C. Purulent inflammation D. Serous inflammation E. Ulceration USMLE QUESTION A 45-year-old man has had a fever and dry cough for 3 days, and now has difficulty breathing and a cough productive of sputum. On physical examination his temperature is 38.5 C. Diffuse rales are auscultated over lower lung fields. A chest radiograph shows a right pleural effusion. A right thoracentesis is performed. The fluid obtained has a cloudy appearance with a cell count showing 15,500 leukocytes per microliter, 98% of which are neutrophils. Which of the following terms best describes his pleural process? A. Serous inflammation B. Purulent inflammation C. Fibrinous inflammation D. Chronic inflammation E. Granulomatous inflammation OUTCOMES OF ACUTE INFLAMMATION Resolution (limited tissue injury and return to normal function) Healing by fibrosis (significant tissue injury; loss of some function) Progression to chronic inflammation (continued tissue injury) STIMULI OF CHRONIC INFLAMMATION Pathogens such as mycobacteria, and certain viruses, fungi, and parasites cause persistent infections that are difficult to eradicate These organisms often evoke a chronic inflammatory reaction called delayed-type hypersensitivity Immune-mediated diseases, such as autoimmune diseases (e.g., rheumatoid arthritis and multiple sclerosis) and allergic diseases (e.g., asthma), are important causes of chronic inflammation Prolonged exposure to potentially toxic exogenous (e.g. particulate silica and silicosis) or endogenous (e.g., plasma lipids and atherosclerosis) agents can lead to chronic inflammation TB Skin Test Silicosis USMLE QUESTION A 37-year-old man has had midepigastric pain for the past 3 months. An upper gastrointestinal endoscopy shows a 2-cm, sharply demarcated, shallow ulceration of the gastric antrum. Microscopic examination of a biopsy from the ulcer base shows angiogenesis, fibrosis, and mononuclear cell infiltrates with lymphocytes, macrophages, and plasma cells. Which of the following terms best describes this pathologic process? A. Acute inflammation B. Chronic inflammation C. Fibrinous inflammation D. Granulomatous inflammation E. Serous inflammation The Tuberculous Granuloma Central (caseous) necrosis macrophages lymphocytes Epithelioid cells Multi-nucleated giant cells In contrast to acute inflammation with its predominant neutrophilic infiltrate, chronic infection with Mycobacterium tuberculosis results in a mononuclear infiltrate. Note also the presence of epithelioid cells and multi-nucleated giant cells USMLE QUESTION A 32-year-old woman has had a chronic cough with fever for the past month. On physical examination, her temperature is 37.5° C. A chest radiograph shows many small, ill-defined nodular opacities in all lung fields. A transbronchial biopsy specimen shows interstitial infiltrates with lymphocytes, plasma cells, and epithelioid macrophages. Which of the following infectious agents is the most likely cause of this appearance? A. Candida albicans B. Cytomegalovirus C. Enterobacter aerogenes D. Mycobacterium tuberculosis E. Plasmodium falciparum F. Staphylococcus aureus USMLE QUESTION A 40-year-old woman had bilateral silicone breast implants placed two years ago. Since that time, she has noted increased firmness with slight deformity of the breast on the left. The implants are removed, and there is evidence for leakage of the implant contents on the left. Histopathology is shown below. Which of the following cell types is most likely to be most characteristic of the inflammatory response in this situation? A. Mast cell B. Eosinophil C. Giant cell D. Neutrophil E. Plasma cell MACROPHAGES PLAY A PIVOTAL ROLE IN CHRONIC INFLAMMATION Blood monocytes emigrate into extravascular tissues in a manner similar to neutrophils Monocytes develop into tissue macrophages Macrophages are often the predominant cell type by 48 hours Macrophages may be activated by a variety of stimuli, including microbial products and cytokines (e.g., IFN-g) secreted by sensitized T lymphocytes and other cells Products of activated macrophages are responsible for much of the tissue injury in chronic inflammation, but also tissue repair CLASSICAL AND ALTERNATIVE MACROPHAGE ACTIVATION Monocytes/macrophages can develop into functionally distinct populations Classically activated macrophages (M1) are induced by microbial products and cytokines (e.g. IFN-g); they phagocytize and destroy microbes and dead tissues and can potentiate inflammatory reactions Alternatively activated macrophages (M2) induced by other cytokines (e.g. IL-4) and are important in tissue repair and the resolution of inflammation USMLE QUESTION A 9-year-old boy has had a chronic cough and fever for the past month. A chest radiograph shows enlargement of hilar lymph nodes and bilateral pulmonary nodular interstitial infiltrates. A sputum sample contains acid-fast bacilli. A transbronchial biopsy specimen shows granulomatous inflammation with epithelioid macrophages and Langhans giant cells. Which of the following mediators is most likely to contribute to giant cell formation? A. Complement C3b B. Interferon-γ C. Interleukin-1 (IL-1) D. Leukotriene B4 E. Tumor necrosis factor (TNF) SYSTEMIC EFFECTS OF INFLAMMATION Fever: cytokines (TNF-a, IL-1) stimulate production of prostaglandins (PGE2) in the hypothalamus Production of acute-phase proteins: Creactive protein, others; synthesis stimulated by cytokines (IL-6, others) acting on liver cells Leukocytosis: cytokines (colonystimulating factors) stimulate production of leukocytes from precursors in the bone marrow In some severe infections, septic shock: fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF-a and other cytokines Discussed in Block 7 MEDIATORS OF INFLAMMATION Active mediators are produced by cells or generated from plasma proteins in response to various stimuli (e.g., microbial products and substances released from necrotic cells) The requirement for microbes or dead tissues as the initiating stimuli ensures that inflammation is normally triggered only when and where it is needed Once activated and released from the cell, most of these mediators are short-lived, thus there is a system of checks and balances that regulates mediator actions PRINCIPAL INFLAMMATORY MEDIATORS, SOURCES, AND ACTIONS Note the redundance in physiologic actions among the various mediators THE COMPLEMENT SYSTEM Anaphylatoxins Discussed in Block 6 THE COAGULATION, FIBRINOLYTIC, AND KININ SYSTEMS Discussed in Block 7 THE ARACHIDONIC ACID PATHWAY Discussed in Block 7 THE VASOACTIVE AMINES: HISTAMINE AND SEROTONIN Stored in cellular granules as preformed molecules; among the first mediators to be released during inflammation (within minutes) Histamine is abundant in mast cells found in connective tissue adjacent to blood vessels It is also found in blood basophils and platelets (serotonin is mainly in platelets) Histamine is released by mast cell degranulation in response to stimuli such as antibodies bound to mast cells (allergic reactions), physical injury (trauma, thermal), complement anaphylatoxins (C3a and C5a), and cytokines (IL-1, CXCL8) Histamine binds to H1 receptors on microvascular endothelial cells causing dilation of arterioles and increased permeability of venules PLATELET ACTIVATING FACTOR (PAF) Phospholipid-derived mediator initially shown to induce platelet aggregation, but now known to have multiple inflammatory effects Produced by a variety of cells including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells Induces vasodilation and increased vascular permeability at extremely low concentrations (potency 100 to 10,000 times greater than histamine) PAF Histamine USMLE QUESTION A 15-year-old girl has had episodes of sneezing with watery eyes and runny nose for the past 2 weeks. On physical examination she has red, swollen nasal mucosal surfaces. She has had similar episodes each Spring and Summer when the amount of ragweed pollen in the air is high. Her symptoms are most likely to be mediated by the release of which of the following chemical mediators from mast cells? A. Complement C3b B. Tryptase C. Tumor necrosis factor a D. Histamine E. Immunoglobulin G NITRIC OXIDE (NO) Soluble gas produced by endothelial cells, macrophages, and some neurons in the brain In vivo half-life is only seconds, so NO acts only on nearby cells NO and its derivatives (e.g. peroxynitrite) are microbicidal Inducible nitric oxide synthetase (iNOS) is produced when macrophages and other cells are activated by cytokines (e.g.,TNF-a) or microbial products Promotes vasodilation, but also reduces platelet aggregation and adhesion, and inhibits leukocyte recruitment USMLE QUESTION A 77-year-old woman experiences a sudden loss of consciousness, with loss of movement on the right side of the body. Cerebral angiography shows an occlusion of the left middle cerebral artery. Elaboration of which of the following mediators will be most beneficial in preventing further ischemic injury to her cerebral cortex? A. Bradykinin B. Leukotriene E4 C. Nitric oxide D. Platelet-activating factor E. Thromboxane A2 PROINFLAMMATORY CYTOKINES Produced principally by activated lymphocytes and macrophages, but also endothelial, epithelial, and connective tissue cells); modulate the functions of other cell types TNF-a, interleukin 1 (IL-1), and IL-6, mediate inflammation; produced mainly by activated macrophages Secretion can be stimulated by microbial products, immune complexes, physical injury, and a variety of inflammatory stimuli Their most important local effects in inflammation are on endothelium, leukocytes, and fibroblasts, and they trigger systemic acute-phase reactions Discussed in Blocks 6 and 7 TNF-a MAJOR ROLES OF CYTOKINES IN ACUTE INFLAMMATION