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

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

2 Background 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)

3 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

4 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

5 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

6 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

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8 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

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

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

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13 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

14 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

15 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

16 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

17 Increased Vascular Permeability 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)

18 Increased Vascular Permeability 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

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21 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

22 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

23 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

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25 Recruitment of Leukocytes to Sites of Infection and Injury 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

26 Recruitment of Leukocytes to Sites of Infection and Injury Adhere ◦ Cells finally come to rest at some point ◦ Firmly attach  Resembling pebbles over which a stream runs without disturbing them

27 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

28 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

29 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)

30 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

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32 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

33 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

34 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

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36 Removal of the Offending Agents Leukocyte activation ◦ Results from signaling pathways  Increases in cytosolic Ca 2+  Activation of enzymes  Protein kinase C  Phospholipase A 2 Functional responses that are most important for destruction of microbes ◦ Phagocytosis ◦ Intracellular killing

37 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

38 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

39 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

40 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

41 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

42 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

43 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

44 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

45 Defects in Leukocyte Function 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

46 Defects in Leukocyte Function 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

47 Defects in Leukocyte Function 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

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

49 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

50 Mediators of Inflammation 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

51 Mediators of Inflammation 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

52 Mediators of Inflammation 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

53 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

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

55 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)

56 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

57 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

58 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

59 Arachidonic Acid (AA) Metabolites Arachidonic 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 A 2

60 Arachidonic Acid (AA) Metabolites 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

61 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

62 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

63 Prostaglandins Most important ones in inflammation ◦ PGE 2, PGD 2, PGF 2 α, PGI 2 (prostacyclin), and TxA 2 (thromboxane) Prostacyclin ◦ Vasodilator ◦ Potent inhibitor of platelet aggregation ◦ Markedly potentiates the permeability- increasing and chemotactic effects of other mediators

64 Prostaglandins PGD 2 ◦ Major prostaglandin made by mast cells ◦ Along with PGE 2 (which is more widely distributed)  Causes vasodilation  Increases the permeability of post-capillary venules  Potentiating edema formation PGF 2 α ◦ Stimulates the contraction of uterine and bronchial smooth muscle and small arterioles

65 Prostaglandins PGD 2 ◦ Chemoattractant for neutrophils PGE 2 ◦ Hyperalgesic ◦ Makes skin hypersensitive to painful stimuli ◦ Involved in cytokine-induced fever during infections

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

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

68 Leukotrienes Three different lipoxygenases ◦ LTB 4  Potent chemotactic agent and activator of neutrophils  Causes aggregation and adhesion of the cells to venular endothelium  Generation of ROS  Releases lysosomal enzymes

69 Leukotrienes Three different lipoxygenases ◦ Cysteinyl-containing leukotrienes C 4, D 4, and E 4 (LTC 4, LTD 4, LTE 4 )  Intense vasoconstriction, bronchospasm and increased vascular permeability

70 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

71 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

72 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

73 Inhibition of Eicosanoid 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 A 2, pro-inflammatory cytokines (such as IL-1 and TNF)

74 Inhibition of Eicosanoid Synthesis 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

75 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

76 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)

77 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

78 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 ( α 1 -antitrypsin)

79 Antioxidants Superoxide dismutase ◦ Found in or can be activated in a variety of cell types Catalase ◦ Detoxifies H 2 O 2 Glutathione peroxidase ◦ Powerful H 2 O 2 detoxifier Ceruloplasmin ◦ Copper-containing serum protein Serum transferrin ◦ Iron-free fraction

80 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

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

82 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

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

85 Cytokines and Chemokines 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

86 Cytokines and Chemokines 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

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88 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

89 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

90 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

91 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

92 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

93 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

94 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

95 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

96 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

97 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

98 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

99 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

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101 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

102 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

103 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

104 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

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

107 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

108 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

109 Acute and Chronic Inflammation PART 3 Chapter 2 Lisa Stevens, D.O.

110 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

111 Outcomes of Acute Inflammation 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

112 Outcomes of Acute Inflammation 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

113 Outcomes of Acute Inflammation Inflammatory reactions--outcomes ◦ Progression of the response to chronic inflammation  May follow acute inflammation  Response may be chronic from the onset

114 Outcomes of Acute Inflammation 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

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116 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

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118 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

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124 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

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126 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

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128 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

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130 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

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136 Suppurative Inflammation 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

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139 Suppurative Inflammation 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

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142 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

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150 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

151 Summary of Inflammation 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

152 Summary of Inflammation 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)

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

154 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

155 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

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159 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

160 Macrophages in Chronic Inflammation 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)

161 Macrophages in Chronic Inflammation 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

162 Macrophages in Chronic Inflammation 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

163 Macrophages in Chronic Inflammation 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

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

168 Other Cells in Chronic Inflammation 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

169 Other Cells in Chronic Inflammation 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)

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172 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

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

174 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

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177 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 μ m

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179 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

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183 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

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186 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

187 Systemic Effects of Inflammation 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

188 Systemic Effects of Inflammation 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/ μ L

189 Systemic Effects of Inflammation Consists of several clinical and pathologic changes ◦ Leukocytosis  May reach extraordinarily high levels of 40,000 to 100,000 cells/ μ L  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)

190 Systemic Effects of Inflammation 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)

191 Systemic Effects of Inflammation 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)

192 Systemic Effects of Inflammation 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

193 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


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