Acute and Chronic Inflammation

Acute and Chronic Inflammation
Chapter 2 Lisa Stevens, D.O.

Background Inflammation Acute inflammation Acute or chronic
Depends on the nature of the stimulus Effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues Acute inflammation Rapid in onset (minutes) Short duration (hours or a few days) Exudation of fluid and plasma proteins (edema) Emigration of leukocytes (neutrophils)

Background Chronic inflammation May follow acute inflammation
May be insidious in onset Longer duration Presence of lymphocytes and macrophages Proliferation of blood vessels and fibrosis Tissue destruction

Historical Highlights
Clinical features of inflammation Egyptian papyrus dated around 3000 bc Celsus Roman writer of the first century ad First listed the four cardinal signs of inflammation Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Signs are typically more prominent in acute inflammation

Historical Highlights
Fifth clinical sign Loss of function (functio laesa) Added by Rudolf Virchow in the 19th century Sir Thomas Lewis Studied the inflammatory response in skin Chemical substances (histamine), mediate the vascular changes of inflammation

Acute Inflammation Rapid host response
Delivers leukocytes and plasma proteins Sites of infection or tissue injury Three major components Alterations in vascular caliber Structural changes in the microvasculature Emigration of the leukocytes

Figure 2-1 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth); (2) extravasation and extravascular deposition of plasma fluid and proteins (edema); (3) leukocyte emigration and accumulation in the site of injury.

Stimuli For Acute Inflammation
Infections (bacterial, viral, fungal, parasitic) and microbial toxins Most common and medically important causes Tissue necrosis Ischemia Trauma, Physical and chemical injury Foreign bodies Immune reactions

Definitions Exudate Transudate Inflammatory extravascular fluid
High protein concentration Specific gravity > 1.020 Usually due to  permeability Transudate Fluid with low protein concentration (albumin) Specific gravity < 1.012 Permeability usually not increased (due to a pressure response)

Definitions Edema Pus Excess interstitial fluid
Can be either an exudate or transudate Pus Purulent exudate Leukocytes (neutrophils) Debris of dead cells Microbes

Figure 2-2 Formation of transudates and exudates
Figure 2-2 Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. C, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces.

Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the alveolar spaces, along with PMN's. The series of events in the process of inflammation are: Vasodilation: leads to greater blood flow to the area of inflammation, resulting in redness and heat. Vascular permeability: endothelial cells become "leaky" from either direct endothelial cell injury or via chemical mediators. Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure intravascularly Vascular stasis: slowing of the blood in the bloodstream with vasodilation and fluid exudation to allow chemical mediators and inflammatory cells to collect and respond to the stimulus.

Vascular Changes Vasodilation
Earliest manifestations of acute inflammation Follows a transient constriction of arterioles Lasts a few seconds First involves the arterioles Leads to opening of new capillary beds Result is increased blood flow Cause of heat and redness (erythema) at the site of inflammation Induced by the action of several mediators Histamine and nitric oxide

Vascular Changes Vasodilation
Followed by increased permeability of the microvasculature Outpouring of protein-rich fluid into the extravascular tissues Loss of fluid and increased vessel diameter Leads to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood Changes result in dilation of small vessels Packed with slowly moving red cells Stasis

Vascular Changes As stasis progresses….
Leukocytes (neutrophils) accumulate along the vascular endothelium Endothelial cells are activated by mediators produced at sites of infection and tissue damage Express increased levels of adhesion molecules Leukocytes then adhere to the endothelium Migrate through the vascular wall into the interstitial tissue

Increased Vascular Permeability
Hallmark of acute inflammation Increased vascular permeability Leads to the escape of a protein-rich exudate into the extravascular tissue Causes edema

Mechanisms Contraction of endothelial cells Results in increased interendothelial spaces Most common mechanism of vascular leakage Elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other mediators Called the immediate transient response Occurs rapidly after exposure to the mediator Usually short-lived (15-30 minutes)

Mechanisms Endothelial injury Results in endothelial cell necrosis and detachment Direct damage to the endothelium Transcytosis Increased transport of fluids and proteins through the endothelial cell

Figure 2-3 Principal mechanisms of increased vascular permeability in inflammation, and their features and underlying causes. NO, nitric oxide; VEGF, vascular endothelial growth factor.

Responses of the Lymphatics
Lymphatics and lymph nodes Filters and polices the extravascular fluids Normally drain the small amount of extravascular fluid that leaked out of capillaries Inflammation Lymph flow is increased and helps drain edema fluid Accumulates due to increased vascular permeability Lymphatic vessels proliferate during inflammatory reactions Lymphatics may become secondarily inflamed (lymphangitis) Draining lymph nodes may become inflamed (lymphadenitis) Hyperplasia of the lymphoid follicles Increased numbers of lymphocytes and macrophages

Reactions of Leukocytes in Inflammation
Processes involving leukocytes in inflammation Recruitment from the blood into extravascular tissues Recognition of microbes and necrotic tissues Removal of the offending agent

Recruitment of Leukocytes to Sites of Infection and Injury
Extravasation Journey of leukocytes Vessel lumen to the interstitial tissue Lumen Margination, rolling, and adhesion to endothelium Migration across endothelium and vessel wall Migration in the tissues toward a chemotactic stimulus

Figure 2-4 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process-selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. Neutrophils express low levels of L-selectin; they bind to endothelial cells predom in antly via P- and E-selectins. ICAM-1, intercellular adhesion molecule 1; TNF, tumor necrosis factor.

Margination Blood flow slows early in inflammation (stasis) Hemodynamic conditions change (wall shear stress decreases) More white cells assume a peripheral position along the endothelial surface Rolling on the vessel wall Individual and then rows of leukocytes adhere transiently to the endothelium Detach and bind again

Adhere Cells finally come to rest at some point Firmly attach Resembling pebbles over which a stream runs without disturbing them

Leukocyte Migration through Endothelium Body
Migration of the leukocytes through the endothelium Transmigration or diapedesis Occurs mainly in post-capillary venules Chemokines act on the adherent leukocytes Stimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradient Toward the site of injury or infection where the chemokines are being produced

Leukocyte Migration through Endothelium Body
After traversing the endothelium Leukocytes pierce the basement membrane Enter the extravascular tissue Cells then migrate toward the chemotactic gradient Cells accumulate in the extravascular site

Chemotaxis of Leukocytes
After exiting the circulation Leukocytes emigrate in tissues toward the site of injury Chemotaxis Locomotion oriented along a chemical gradient Chemoattractants Exogenous substances Bacterial products Lipids Endogenous substances Chemical mediators Cytokines Components of the complement system Arachidonic acid (AA)

Chemotaxis of Leukocytes
Leukocyte movement Extending filopodia Pull the back of the cell in the direction of extension Example: Automobile with front-wheel drive is pulled by the wheels in front Migrate toward the inflammatory stimulus

Figure 2-6 Scanning electron micrograph of a moving leukocyte in culture showing a filopodium (upper left) and a trailing tail. (Courtesy of Dr. Morris J. Karnovsky, Harvard Medical School, Boston, MA.)

Leukocytic Infiltrate
Nature of the leukocyte infiltrate Varies with the age of the inflammatory response Varies with the type of stimulus Acute inflammation Neutrophils predominate in the inflammatory infiltrate During the first 6 to 24 hours Replaced by monocytes in 24 to 48 hours Survive longer May proliferate in the tissues Become the dominant population in chronic inflammatory reactions

Leukocytic Infiltrate
Exceptions Pseudomonas bacteria Cellular infiltrate is dominated by continuously recruited neutrophils for several days Viral infections Lymphocytes may be the first cells to arrive Hypersensitivity reactions Eosinophils may be the main cell type

Recognition of Microbes and Dead Tissues
Leukocyte recruitment to site of infection Must be activated to perform their functions Recognition of the offending agents Deliver signals Activate the leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction

Figure 2-7 Nature of leukocyte infiltrates in inflammatory reactions
Figure 2-7 Nature of leukocyte infiltrates in inflammatory reactions. The photomicrographs are representative of the early (neutrophilic) (A) and later (mononuclear) cellular infiltrates (B) seen in an inflammatory reaction in the myocardium following ischemic necrosis (infarction). The kinetics of edema and cellular infiltration (C) are approximations.

Removal of the Offending Agents
Leukocyte activation Results from signaling pathways Increases in cytosolic Ca2+ Activation of enzymes Protein kinase C Phospholipase A2 Functional responses that are most important for destruction of microbes Phagocytosis Intracellular killing

Phagocytosis Phagocytosis Involves three sequential steps
Recognition and attachment of the particle to be ingested by the leukocyte Its engulfment, with subsequent formation of a phagocytic vacuole Killing or degradation of the ingested material

Engulfment After a particle is bound to phagocyte receptors
Extensions of the cytoplasm (pseudopods) flow around it Plasma membrane pinches off to form a vesicle (phagosome) Encloses the particle Fuses with a lysosomal granule Discharge of the granule's contents into the phagolysosome

Killing and Degradation
Final step in the elimination of infectious agents and necrotic cells Occurs within neutrophils and macrophages Microbial killing is accomplished largely by reactive oxygen species and reactive nitrogen species

Microbial killing Can also occur through the action of other substances in leukocyte granules Granules contain many enzymes Elastase Defensins Cationic arginine-rich granule peptides that are toxic to microbes Cathelicidins Antimicrobial proteins found in neutrophils and other cells Lysozyme Hydrolyzes the muramic acid-N-acetylglucosamine bond, found in the glycopeptide coat of all bacteria

Microbial killing Leukocyte granules Granules contain many enzymes
Lactoferrin Iron-binding protein present in specific granules Major basic protein Cationic protein of eosinophils Limited bactericidal activity Cytotoxic to many parasites Bactericidal/permeability increasing protein Binds bacterial endotoxin Believed to be important in defense against some gram-negative bacteria

Functional Responses of Activated Leukocytes
Leukocytes play several other roles in host defense Produce a number of growth factors Stimulate the proliferation of endothelial cells and fibroblasts Stimulate the synthesis of collagen Stimulate enzymes that remodel connective tissues These products drive the process of repair after tissue injury

Release of Leukocyte Products and Leukocyte-Mediated Tissue Injury
Leukocytes are important causes of injury to normal cells and tissues under several circumstances Part of a normal defense reaction against infectious microbes Infections that are difficult to eradicate (TB) and certain viral diseases Prolonged host response contributes more to the pathology than does the microbe itself Inappropriately directed inflammatory response Against host tissues, as in certain autoimmune diseases Excessive host reaction Against usually harmless environmental substances Allergic diseases, including asthma

Defects in Leukocyte Function
Inherited and acquired Lead to increased vulnerability to infections Impairments of leukocyte function Inherited defects in leukocyte adhesion Inherited defects in phagolysosome function Chédiak-Higashi syndrome Autosomal recessive condition Characterized by defective fusion of phagosomes and lysosomes in phagocytes Causing susceptibility to infections

Impairments of leukocyte function Inherited defects in leukocyte adhesion Inherited defects in phagolysosome function Chédiak-Higashi syndrome Abnormalities in melanocytes (leading to albinism) Cells of the nervous system (associated with nerve defects) Platelets (causing bleeding disorders) Leukocyte abnormalities Neutropenia (decreased numbers of neutrophils) Defective degranulation Delayed microbial killing

Impairments of leukocyte function Inherited defects in microbicidal activity Chronic granulomatous disease (group of congenital diseases) Characterized by defects in bacterial killing Render patients susceptible to recurrent bacterial infection Inherited defects in the genes encoding components of phagocyte oxidase Name of this disease comes from the macrophage-rich chronic inflammatory reaction Tries to control the infection when the initial neutrophil defense is inadequate Leads to collections of activated macrophages that wall off the microbes Aggregates called granulomas

Impairments of leukocyte function Acquired deficiencies Most frequent cause of leukocyte defects Bone marrow suppression Decreased production of leukocytes Seen following therapies for cancer (radiation and chemotherapy) Seen when the marrow space is compromised by tumors Arise in the marrow Leukemias Metastatic from other sites

PART 2 Chapter 2 Lisa Stevens, D.O.

Mediators of Inflammation
Mediators are generated either from cells or from plasma proteins Cell-derived mediators Normally sequestered in intracellular granules Can be rapidly secreted by granule exocytosis Histamine in mast cell granules Synthesized de novo in response to a stimulus Prostaglandins, cytokines

Cells that produce mediators Platelets, neutrophils, monocytes/macrophages, and mast cells Mesenchymal cells (endothelium, smooth muscle, fibroblasts) Most epithelia Plasma-derived mediators Complement proteins, kinins Produced mainly in the liver Present in the circulation as inactive precursors Must be activated to acquire their biologic properties

Active mediators Produced in response to various stimuli Microbial products Substances released from necrotic cells Proteins of the complement, kinin, and coagulation systems Activated by microbes and damaged tissues Ensures that inflammation is normally triggered only when and where it is needed

Mediators are short-lived Once activated and released from the cell Quickly decay Arachidonic acid metabolites Inactivated by enzymes Kininase inactivates bradykinin Otherwise scavenged or inhibited Antioxidants scavenge toxic oxygen metabolites Inhibited: complement regulatory proteins break up and degrade activated complement components

Cell-Derived Mediators
Vasoactive amines Two major vasoactive amines Histamine and Serotonin Stored as preformed molecules in cells and are Among the first mediators to be released during inflammation

Histamine Richest sources Found in blood basophils and platelets
Mast cells Normally present in the connective tissue adjacent to blood vessels Found in blood basophils and platelets Present in mast cell granules

Histamine Released by mast cell degranulation in response to:
Physical injury such as trauma, cold, or heat Binding of antibodies to mast cells (allergic reactions) Fragments of complement called anaphylatoxins C3a and C5a Histamine-releasing proteins derived from leukocytes Neuropeptides (substance P) Cytokines (IL-1, IL-8)

Histamine Causes dilation of arterioles
Increases the permeability of venules Considered to be the principal mediator of the immediate transient phase of increased vascular permeability Producing interendothelial gaps in venules

Serotonin Preformed vasoactive mediator
Actions similar to those of histamine Present in platelets Stimulated when platelets aggregate After contact with collagen, thrombin, adenosine diphosphate, and antigen-antibody complexes Platelet release reaction Key component of coagulation Present in certain neuroendocrine cells Gastrointestinal tract

Arachidonic Acid (AA) Metabolites
Prostaglandins, Leukotrienes, and Lipoxins Arachidonic acid 20-carbon polyunsaturated fatty acid Derived from dietary sources Conversion from the essential fatty acid linoleic acid

Does not occur free in the cell Normally esterified in membrane phospholipids Mechanical, chemical, and physical stimuli Release AA from membrane phospholipids through the action of cellular phospholipases Phospholipase A2

AA-derived mediators (eicosanoids) Synthesized by two major classes of enzymes Cyclooxygenases Generate prostaglandins Lipoxygenases Produce leukotrienes and lipoxins Bind to G protein-coupled receptors on many cell types Can mediate virtually every step of inflammation

Prostaglandins Produced by mast cells, macrophages, endothelial cells, and many others Involved in the vascular and systemic reactions of inflammation Produced by the actions of two cyclooxgenases Constitutively expressed COX-1 Inducible enzyme COX-2

Prostaglandins Divided into series based on structural features
Coded by a letter PGD, PGE, PGF, PGG, and PGH Subscript numeral 1, 2 Indicates the number of double bonds in the compound

Prostaglandins Most important ones in inflammation Prostacyclin
PGE2, PGD2, PGF2α, PGI2 (prostacyclin), and TxA2 (thromboxane) Prostacyclin Vasodilator Potent inhibitor of platelet aggregation Markedly potentiates the permeability- increasing and chemotactic effects of other mediators

Prostaglandins PGD2 PGF2α Major prostaglandin made by mast cells
Along with PGE2 (which is more widely distributed) Causes vasodilation Increases the permeability of post-capillary venules Potentiating edema formation PGF2α Stimulates the contraction of uterine and bronchial smooth muscle and small arterioles

Prostaglandins PGD2 PGE2 Chemoattractant for neutrophils Hyperalgesic
Makes skin hypersensitive to painful stimuli Involved in cytokine-induced fever during infections

Leukotrienes Produced by lipoxygenase enzymes
Secreted mainly by leukocytes Chemoattractants for leukocytes Vascular effects

Leukotrienes Three different lipoxygenases 5-lipoxygenase
Predominant one in neutrophils Converts AA to 5-hydroxyeicosatetraenoic acid Chemotactic for neutrophils Precursor of the leukotrienes

Leukotrienes Three different lipoxygenases LTB4
Potent chemotactic agent and activator of neutrophils Causes aggregation and adhesion of the cells to venular endothelium Generation of ROS Releases lysosomal enzymes

Leukotrienes Three different lipoxygenases
Cysteinyl-containing leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4) Intense vasoconstriction, bronchospasm and increased vascular permeability

Lipoxins Generated from AA by the lipoxygenase pathway
Inhibitors of inflammation Two cell populations are required for their biosynthesis Leukocytes (esp. neutrophils) Produce intermediates in lipoxin synthesis Converted to lipoxins by platelets interacting with the leukocytes

Lipoxins Principal actions of lipoxins
Inhibit leukocyte recruitment and the cellular components of inflammation Inhibit neutrophil chemotaxis and adhesion to endothelium Inverse relationship between the production of lipoxin and leukotrienes Suggests that lipoxins may be endogenous negative regulators of leukotrienes May thus play a role in the resolution of inflammation

Inhibition of Eicosanoid Synthesis
Anti-inflammatory drugs work by inhibiting the synthesis of eicosanoids Cyclooxygenase inhibitors Aspirin Non-steroidal anti-inflammatory drugs Indomethacin Inhibit both COX-1 and COX-2 Inhibit prostaglandin synthesis

Lipoxygenase inhibitors 5-lipoxygenase is not affected by NSAIDs Inhibit leukotriene production (Zileuton) Block leukotriene receptors (Montelukast) Useful in the treatment of asthma Broad-spectrum inhibitors Corticosteroids Powerful anti-inflammatory agents Reduces the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF)

Modify the intake and content of dietary lipids Increasing the consumption of fish oil Polyunsaturated fatty acids in fish oil Serve as poor substrates for conversion to active metabolites Excellent substrates for the production of anti-inflammatory lipid products Resolvins and protectins

Platelet-Activating Factor (PAF)
Phospholipid-derived mediator Causes platelet aggregation Known to have multiple inflammatory effects Variety of cell types can elaborate PAF Platelets, basophils, mast cells, neutrophils, macrophages, and endothelial cells

Platelet-Activating Factor (PAF)
Causes vasoconstriction and bronchoconstriction At extremely low concentrations… Induces vasodilation Increased venular permeability Causes increased leukocyte adhesion, chemotaxis, degranulation, and the oxidative burst Boosts the synthesis of other mediators (eicosanoids)

Reactive Oxygen Species
Oxygen-derived free radicals May be released extracellularly from leukocytes After exposure to microbes, chemokines, and immune complexes Following a phagocytic challenge Production is dependent on the activation of the NADPH oxidase system Superoxide anion, hydrogen peroxide, and hydroxyl radical Major species produced within cells Combine with nitric oxide to form reactive nitrogen species

Reactive Oxygen Species
Implicated in responses in inflammation Endothelial cell damage, with resultant increased vascular permeability Injury to other cell types (parenchymal cells, red blood cells) Inactivation of antiproteases (α1-antitrypsin)

Antioxidants Superoxide dismutase Catalase Glutathione peroxidase
Found in or can be activated in a variety of cell types Catalase Detoxifies H2O2 Glutathione peroxidase Powerful H2O2 detoxifier Ceruloplasmin Copper-containing serum protein Serum transferrin Iron-free fraction

Nitric Oxide (NO) Discovered as a factor released from endothelial cells Caused vasodilation Called endothelium-derived relaxing factor Soluble gas Produced by endothelial cells, macrophages and some neurons Acts in a paracrine manner on target cells Relaxation of vascular smooth muscle cells In vivo half-life of NO is only seconds Gas acts only on cells in close proximity to where it is produced

Nitric Oxide (NO) Has dual actions in inflammation
Relaxes vascular smooth muscle Promotes vasodilation Inhibitor of the cellular component of inflammatory responses

Nitric Oxide (NO) Reduces platelet aggregation and adhesion
Inhibits several features of mast cell- induced inflammation Inhibits leukocyte recruitment NO and its derivatives are microbicidal NO is a mediator of host defense against infection

Figure 2-12 Functions of nitric oxide (NO) in blood vessels and macrophages. NO is produced by two NO synthase (NOS) enzymes. It causes vasodilation, and NO-derived free radicals are toxic to microbial and mammalian cells.

Cytokines and Chemokines
Proteins produced by many cell types Principally activated lymphocytes and macrophages Also endothelial, epithelial, and connective tissue cells Involved in cellular immune responses

Tumor Necrosis Factor and Interleukin-1 Major cytokines that mediate inflammation Produced mainly by activated macrophages Secretion of TNF and IL-1 Stimulated by endotoxin and other microbial products, immune complexes, physical injury, and a variety of inflammatory stimuli

Tumor Necrosis Factor and Interleukin-1 Endothelium Induce a spectrum of changes Referred to as endothelial activation Induce the expression of endothelial adhesion molecules Synthesis of chemical mediators, including other cytokines, chemokines, growth factors, eicosanoids, and NO Production of enzymes associated with matrix remodeling Increases in the surface thrombogenicity of the endothelium Augments responses of neutrophils to other stimuli Bacterial endotoxin

Figure 2-13 Principal local and systemic actions of tumor necrosis factor (TNF) and interleukin-1 (IL-1).

Tumor Necrosis Factor and IL-1
Induce the systemic acute-phase responses Associated with infection or injury Regulates energy balance by promoting lipid and protein mobilization and by suppressing appetite Sustained production contributes to cachexia Pathologic state characterized by weight loss and anorexia Accompanies some chronic infections and neoplastic diseases

Chemokines Family of small (8 to 10 kD) proteins
Act primarily as chemoattractants for specific types of leukocytes 40 different chemokines 20 different receptors Two main functions Stimulate leukocyte recruitment in inflammation Control the normal migration of cells through various tissues

Chemokines Classified into four major groups
According to the arrangement of the conserved cysteine (C) residues in the mature proteins C-X-C chemokines (α chemokines) One amino acid residue separating the first two conserved cysteine residues Act primarily on neutrophils IL-8 is typical of this group Secreted by activated macrophages, endothelial cells, and other cell types Causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils Most important inducers are microbial products and other cytokines, mainly IL-1 and TNF

Chemokines Classified into four major groups
C-C chemokines (β chemokines) First two conserved cysteine residues adjacent Generally attract monocytes, eosinophils, basophils, and lymphocytes but not neutrophils C chemokines (γ chemokines) Lack two (the first and third) of the four conserved cysteines Lymphotactin Relatively specific for lymphocytes

Chemokines Classified into four major groups CX3C chemokines
Contain three amino acids between the two cysteines Fractalkine Two forms Cell surface-bound protein Soluble form

Lysosomal Constituents of Leukocytes
Neutrophils and monocytes contain lysosomal granules Neutrophils have two main types of granules Smaller specific (or secondary) granules Contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase Larger azurophil (or primary) granules Contain myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases

Lysosomal Constituents of Leukocytes
Neutrophils have two main types of granules Both types of granules can fuse with phagocytic vacuoles containing engulfed material Granule contents can be released into the extracellular space

Neuropeptides Secreted by sensory nerves and various leukocytes
Play a role in the initiation and propagation of inflammation Substance P and neurokinin A Family of tachykinin neuropeptides Produced in the central and peripheral nervous systems Biologic functions Transmission of pain signals Regulation of blood pressure Stimulation of secretion by endocrine cells Increasing vascular permeability

Plasma Protein-Derived Mediators
Three interrelated systems: the complement, kinin, and clotting systems Complement System Consists of more than 20 proteins Numbered C1 through C9 Functions in both innate and adaptive immunity for defense against microbial pathogens Several cleavage products of complement proteins are elaborated Cause increased vascular permeability, chemotaxis, and opsonization Critical step in complement activation Proteolysis of the third (and most abundant) component, C3

Complement System Functionally divided into three general categories
Inflammation C3a, C5a, and, to a lesser extent, C4a are cleavage products of the corresponding complement Stimulate histamine release from mast cells Increase vascular permeability and cause vasodilation Called anaphylatoxins C5a Powerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophils Activates the lipoxygenase pathway of AA metabolism in neutrophils and monocytes Causes further release of inflammatory mediators

Complement System Functionally divided into three general categories
Phagocytosis C3b and its cleavage product iC3b (inactive C3b) When fixed to a microbial cell wall, act as opsonins Promote phagocytosis by neutrophils and macrophages Cell lysis Deposition of the MAC on cells Cells permeable to water and ions Results in death (lysis) of the cells

Complement System C3a and C5a Most important inflammatory mediators
Can be cleaved by several proteolytic enzymes present within the inflammatory exudate Include plasmin and lysosomal enzymes released from neutrophils Initiate a self-perpetuating cycle of neutrophil recruitment

Figure 2-14 The activation and functions of the complement system
Figure 2-14 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).

Coagulation and Kinin Systems
Culminate in the activation of thrombin and the formation of fibrin Intrinsic clotting pathway Series of plasma proteins Activated by Hageman factor (factor XII) Protein synthesized by the liver that circulates in an inactive form Activated upon contact with negatively charged surfaces

Kinins Vasoactive peptides Derived from plasma proteins (kininogens)
Action of specific proteases (kallikreins) Active form of factor XII (factor XIIa) Converts plasma prekallikrein into an active proteolytic form (kallikrein) Cleaves a plasma glycoprotein precursor high-molecular-weight kininogen, to produce bradykinin Bradykinin Increases vascular permeability Causes contraction of smooth muscle Dilation of blood vessels Pain when injected into the skin Short-lived---quickly inactivated by an enzyme called kininase

Kinins At the same time factor XIIa is inducing fibrin clot formation, it activates the fibrinolytic system Cascade counterbalances clotting by cleaving fibrin Solubilizing the clot Kallikrein Cleaves plasminogen Plasma protein that binds to the evolving fibrin clot to generate plasmin Multifunctional protease

Kinins Fibrinolytic system Primary function of plasmin
Lyse fibrin clots Cleaves the complement protein C3 to produce C3 fragments Degrades fibrin to form fibrin split products Activate Hageman factor Trigger multiple cascades

Figure 2-15 Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells. HMWK, high molecular weight kininogen.

Summary Bradykinin, C3a, and C5a C5a Thrombin
Mediators of increased vascular permeability C5a Mediator of chemotaxis Thrombin Effects on endothelial cells and many other cell types

Summary C3a and C5a Generated by several types of reactions
Immunologic reactions, involving antibodies and complement (the classical pathway) Activation of the alternative and lectin complement pathways by microbes, in the absence of antibodies Agents not directly related to immune responses Plasmin, kallikrein, and some serine proteases

Summary Activated Hageman factor (factor XIIa)
Initiates four systems (inflammatory response) Kinin system Produces vasoactive kinins Clotting system Induces formation of thrombin Fibrinolytic system Produces plasmin Degrades fibrin to produce fibrinopeptides Complement system Produces anaphylatoxins and other mediators

PART 3 Chapter 2 Lisa Stevens, D.O.

Outcomes of Acute Inflammation
Variables that may modify the basic process of inflammation Nature and intensity of the injury Site and tissue affected Responsiveness of the host

Inflammatory reactions--outcomes Complete resolution Restoration of site of acute inflammation to normal Usual outcome Injury is limited or short-lived Little tissue destruction and the damaged parenchymal cells can regenerate Removal of cellular debris and microbes by macrophages Resorption of edema fluid by lymphatics

Inflammatory reactions--outcomes Healing by connective tissue replacement Fibrosis Occurs after substantial tissue destruction Inflammatory injury involves tissues that are incapable of regeneration Abundant fibrin exudation in tissue or serous cavities that cannot be adequately cleared Connective tissue grows into the area of damage Converts it into a mass of fibrous tissue Organization

Inflammatory reactions--outcomes Progression of the response to chronic inflammation May follow acute inflammation Response may be chronic from the onset

Progression of the response to chronic inflammation Acute to chronic transition Acute inflammatory response cannot be resolved Persistence of injurious agent Interference with normal process of healing Bacterial infection of the lung Focus of acute inflammation (pneumonia) Extensive tissue destruction and formation of a cavity Chronic lung abscess

Figure 2-16 Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation. The components of the various reactions and their functional outcomes are listed.

Morphologic Patterns of Acute Inflammation
Morphologic hallmarks of acute inflammation Dilation of small blood vessels Slowing of blood flow Accumulation of leukocytes and fluid Extravascular tissue

Figure 2-17 The characteristic histopathology of acute inflammation
Figure 2-17 The characteristic histopathology of acute inflammation. A, Normal lung shows thin (virtually invisible) blood vessels in the alveolar walls and no cells in the alveoli. B, The vascular component of acute inflammation is manifested by congested blood vessels (packed with erythrocytes), resulting from stasis. C, The cellular component of the response is manifested by large numbers of leukocytes (neutrophils) in the alveoli.

Serous Inflammation Marked by outpouring of thin fluid
Derived from plasma/secretions of mesothelial cells Peritoneal, pleural, and pericardial cavities Accumulation of fluid in these cavities Effusion Skin blister Burn or viral infection Large accumulation of serous fluid

Figure 2-18 Serous inflammation
Figure 2-18 Serous inflammation. Low-power view of a cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion.

Serous effusion of the right pleural cavity

Serosanguineous effusion of bilateral pleural cavities

Chylous effusion of the peritoneal cavity

Fibrinous Inflammation
Fibrinous exudate Vascular leaks are large Local procoagulant stimulus (e.g., cancer cells) Characteristic of inflammation Lining of body cavities Meninges, pericardium and pleura

Fibrinous inflammation

Fibrinous exudate Microscopic examination Fibrin appears as an eosinophilic meshwork of threads Amorphous coagulum Removed by fibrinolysis and clearing of other debris by macrophages

Microscopic appearance of fibrinous inflammation

Fibrinous exudate If fibrin is not removed Stimulates ingrowth of fibroblasts and blood vessels Leads to scarring Conversion of the fibrinous exudate to scar tissue (organization) Pericardial sac Opaque fibrous thickening of the pericardium and epicardium Obliteration of the pericardial space

Figure 2-19 Fibrinous pericarditis
Figure 2-19 Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).

Suppurative Inflammation
Large amounts of purulent exudate Neutrophils, liquefactive necrosis, and edema fluid Bacteria (e.g., staphylococci) produce this localized suppuration Pyogenic (pus-producing) bacteria Example Acute appendicitis

Suppurative inflammation of the pericardial cavity

Suppurative inflammation of the meninges.

Suppurative inflammation of the peritoneum

Photomicrograph of suppurative inflammation within the alveolar spaces.

Photomicrograph of suppurative inflammation of the alveolar space.

Abscesses Localized collections of purulent inflammatory tissue Suppuration buried in a tissue, an organ, or a confined space Produced by deep seeding of pyogenic bacteria into a tissue

Abscesses of the lung.

Abscesses Central region Appears as mass of necrotic leukocytes and tissue cells Necrotic focus… Around it---zone of preserved neutrophils Outside it---vascular dilation and parenchymal and fibroblastic proliferation

Figure 2-20 Purulent inflammation
Figure 2-20 Purulent inflammation. A, Multiple bacterial abscesses in the lung, in a case of bronchopneumonia. B, The abscess contains neutrophils and cellular debris, and is surrounded by congested blood vessels.

Higher power view of the last photomicrograph---marked acute inflammation within the abscess cavity.

Ulcers Local defect, or excavation, of the surface of an organ or tissue Produced by the sloughing (shedding) of inflamed necrotic tissue Most commonly encountered Mucosa of the mouth, stomach, intestines, or genitourinary tract Skin and subcutaneous tissue of the lower extremities Older persons who have circulatory disturbances

Stomach ulcer.

Laryngeal ulceration.

Cutaneous ulceration.

“Gangrenous necrosis” with a large cutaneous ulceration.

Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer
Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the base

Esophageal ulceration secondary to a viral infection.

Summary of Inflammation
Vascular phenomena of acute inflammation Characterized by increased blood flow to the injured area Results mainly from arteriolar dilation and opening of capillary beds Induced by mediators such as histamine

Vascular phenomena of acute inflammation Increased vascular permeability Accumulation of protein-rich extravascular fluid (exudate) Plasma proteins leave the vessels (widened interendothelial cell junctions of the venules) Redness (rubor), warmth (calor), and swelling (tumor) Increased blood flow and edema

Vascular phenomena of acute inflammation Circulating leukocytes Adhere to the endothelium via adhesion molecules Traverse the endothelium Migrate to the site of injury under the influence of chemotactic agents Activated leukocytes release toxic metabolites and proteases extracellularly Causes tissue damage Prostaglandins, neuropeptides, and cytokines released Local symptom---pain (dolor)

Chronic Inflammation Inflammation of prolonged duration
Weeks or months May follow acute inflammation May begin insidiously

Causes of Chronic Inflammation
Persistent infections by microorganisms Mycobacteria, and certain viruses, fungi, and parasites Immune reaction (delayed-type hypersensitivity) Immune-mediated inflammatory diseases Autoimmune diseases Atherosclerosis Chronic inflammatory process of the arterial wall Induced by endogenous toxic plasma lipid components

Morphology of Chronic Inflammation
Infiltration with mononuclear cells Macrophages, lymphocytes, and plasma cells Tissue destruction Induced by the persistent offending agent or by the inflammatory cells Proliferation of small blood vessels Angiogenesis Fibrosis

Figure 2-22 A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.

Chronic inflammation as demonstrated by infiltrating lymphocytes and plasma cells.

Macrophages in Chronic Inflammation
Component of the mononuclear phagocyte system Also known as the reticuloendothelial system Consists of closely related cells of bone marrow origin Blood monocytes Tissue macrophages

Component of the mononuclear phagocyte system Tissue macrophages Diffusely scattered in the connective tissue Liver (Kupffer cells) Spleen Lymph nodes (sinus histiocytes) Lungs (alveolar macrophages) Central nervous system (microglia)

Mononuclear phagocytes Arise from a common precursor in the bone marrow Gives rise to blood monocytes From the blood, monocytes migrate into tissues Half-life of blood monocytes is about 1 day Differentiate into macrophages Life span of tissue macrophages is several months or years

Monocytes emigrate into extravascular tissues Early in acute inflammation Within 48 hours--predominant cell type When it reaches the extravascular tissue… Undergoes transformation into the macrophage Activated by a variety of stimuli Microbial products Cytokines Other chemical mediators

Products of activated macrophages Serve to eliminate injurious agents (microbes) Initiate the process of repair Responsible for tissue injury in chronic inflammation Activation of macrophages Increased levels of lysosomal enzymes and reactive oxygen and nitrogen species Production of cytokines, growth factors, and other mediators of inflammation Tissue destruction Hallmark of chronic inflammation

Macrophages with surrounding acute and chronic inflammation.

Figure 2-23 Maturation of mononuclear phagocytes
Figure 2-23 Maturation of mononuclear phagocytes. (From Abbas AK et al: Cellular and Molecular Immunology, 5th ed. Philadelphia, WB Saunders, 2003.)

Figure 2-24 The roles of activated macrophages in chronic inflammation
Figure 2-24 The roles of activated macrophages in chronic inflammation. Macrophages are activated by nonimmunologic stimuli such as endotoxin or by cytokines from immune-activated T cells (particularly IFN-γ). The products made by activated macrophages that cause tissue injury and fibrosis are indicated. AA, arachidonic acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; TGFβ, transforming growth factor β.

Other Cells in Chronic Inflammation
Lymphocytes Plasma cells Develop from activated B lymphocytes Produce antibodies Directed either against persistent foreign or self antigens

Eosinophils Abundant in immune reactions Mediated by IgE Parasitic infections Chemokine for eosinophil recruitment Eotaxin Granules that contain major basic protein Highly cationic protein that is toxic to parasites Causes lysis of mammalian epithelial cells Benefit in controlling parasitic infections Contribute to tissue damage in immune reactions Allergies

Mast cells Widely distributed in connective tissues Participate in acute and chronic inflammatory reactions Degranulation and release of mediators Histamine and prostaglandins Allergic reactions to foods, insect venom, or drugs Catastrophic results (e.g. anaphylactic shock)

Figure 2-25 Macrophage-lymphocyte interactions in chronic inflammation
Figure 2-25 Macrophage-lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines) and others that activate macrophages (IFNγ). Different subsets of T cells (called TH1 and TH17) may produce different sets of cytokines; these are described in Chapter 6. Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines (such as IL-12).

Figure 2-26 A focus of inflammation showing numerous eosinophils.

Granulomatous Inflammation
Distinctive pattern of chronic inflammation Cellular attempt to contain an offending agent that is difficult to eradicate Strong activation of T lymphocytes Leading to macrophage activation Cause injury to normal tissues

Granulomatous Inflammation
Most commonly seen Tuberculosis Sarcoidosis Cat-scratch disease Lymphogranuloma inguinale Leprosy Brucellosis Syphilis Mycotic infections Berylliosis

Granuloma Focus of chronic inflammation
Consists of a microscopic aggregation of macrophages Transformed into epithelium-like cells Surrounded by a collar of mononuclear leukocytes Lymphocytes and occasionally plasma cells

Gross photograph of granulomas.

Granulomas

Granuloma Epithelioid cells Pale pink granular cytoplasm
Indistinct cell boundaries Fuse to form giant cells Periphery or center of granulomas May attain diameters of 40 to 50 μm

Granuloma

Granuloma Two types of granulomas Foreign body granulomas
Incited by relatively inert foreign bodies Form around material Talc (IV drug abuse) Sutures Foreign material can be identified in the center of the granuloma Refractile

Foreign body giant cell reaction to aspirated vegetable matter.

Foreign body giant cell reaction to suture material.

Foreign body giant cell reaction to talc powder (heroin/IV drug user).

Granuloma Immune granulomas
Caused by a variety of agents that are capable of inducing a cell-mediated immune response Produces granulomas usually when the inciting agent is poorly degradable or particulate Prototype is caused by infection with Mycobacterium tuberculosis Granuloma is referred to as a tubercle Presence of central caseous necrosis rare in other granulomatous diseases

Figure 2-27 Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple Langhans-type giant cells, epithelioid cells, and lymphocytes

Non-caseating granulomas.

Systemic Effects of Inflammation
Collectively called the acute-phase response Also known as the systemic inflammatory response syndrome Reactions to cytokines whose production is stimulated by bacterial products Consists of several clinical and pathologic changes Fever Elevation of body temperature (1° to 4°C) One of the most prominent manifestations Produced in response to substances called pyrogens

Consists of several clinical and pathologic changes Acute-phase proteins Plasma proteins Synthesized in the liver Concentrate in the plasma in response to inflammatory stimuli Three best-known proteins C-reactive protein (CRP) Fibrinogen Serum amyloid A (SAA) protein

Consists of several clinical and pathologic changes Leukocytosis Common feature of inflammatory reactions Especially those induced by bacterial infections Leukocyte count usually climbs to 15,000 or 20,000 cells/μL

Consists of several clinical and pathologic changes Leukocytosis May reach extraordinarily high levels of 40,000 to 100,000 cells/μL Leukemoid reactions Similar to the white cell counts observed in leukemia Accelerated release of cells from the bone marrow Rise in the number of more immature neutrophils in the blood (shift to the left)

Consists of several clinical and pathologic changes Bacterial infections Increase in the blood neutrophil count (neutrophilia) Viral infections (infectious mono, mumps, and German measles) Absolute increase in the number of lymphocytes (lymphocytosis)

Consists of several clinical and pathologic changes Bronchial asthma, allergy, and parasitic infestations Increase in the absolute number of eosinophils (eosinophilia) Infections (typhoid fever and viruses, rickettsiae, and certain protozoa) Decreased number of circulating white cells (leukopenia)

Consists of several clinical and pathologic changes Increased pulse and blood pressure Decreased sweating Redirection of blood flow from cutaneous to deep vascular beds Minimizes heat loss through the skin Rigors (shivering) Chills (search for warmth) Anorexia Somnolence

Consequences of Defective or Excessive Inflammation
Defective inflammation Results in increased susceptibility to infections Associated with delayed wound healing Provides the necessary stimulus to get the repair process started Excessive inflammation Basis of many types of human disease Allergies Disorders in which the fundamental cause of tissue injury is inflammation

Acute and Chronic Inflammation

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