Innate Immunity Inflammation Chapter 6 Elsevier items and

Innate Immunity: Inflammation Chapter 6 Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Immunity Innate resistance (1 st and 2 nd lines) First line of defense Ø Physical and mechanical barriers Second line of defense Ø Inflammation Third line of defense Ø Adaptive (acquired) immunity Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

First Line of Defense Physical and mechanical barriers Ø Skin Ø Linings of the gastrointestinal, genitourinary, and respiratory tracts • Sloughing off of cells • Coughing and sneezing • Flushing • Vomiting • Mucus and cilia Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

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First Line of Defense Biochemical barriers Ø Saliva, tears, ear wax, sweat, and mucus – trap bacteria and contain: Ø Lysozyme and antimicrobial peptides – produced by body cells, kill bacteria and other pathogens Ø Normal bacterial flora – symbiotic; help prevent growth of pathogens Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Second Line of Defense Overview of Inflammatory Response Ø Caused by a variety of stimuli • Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Ø Local manifestations • Redness, heat, swelling pain and loss of function Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Second Line of Defense Inflammatory response Ø Vascular response • Blood vessels dilate and become more permeable, allowing cells and fluid to enter site. • White blood cells adhere to the inner walls of the vessels and migrate across the vessel wall. • Fluid, inflammatory chemicals and cells can then dilute toxins and battle pathogens. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

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Inflammation Goals of Inflammation Ø Limit and control tissue damage Ø Prevent and limit infection Ø Initiate adaptive immune response Ø Initiate healing Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cellular Components of Inflammation Mast cells – primary mediators of inflammation Granulocytes (neutrophils & eosinophils), platelets, monocytes, and lymphocytes. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Inflammation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cells Cellular bags of granules located in the loose connective tissues close to blood vessels Ø Skin, digestive lining, and respiratory tract Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cells Mast Cell Activation: Caused by physical injury, burns, toxins, chemical agents, immunologic processes, etc. Chemical release in two ways Ø Degranulation and synthesis of lipidderived chemical mediators Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Degranulation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Degranulation Histamine Ø Vasoactive amine that causes temporary, rapid constriction of smooth muscle in the large blood vessels and the dilation of the postcapillary venules Ø Retraction of endothelial cells lining the capillaries and increased adherence of leukocytes Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Inflammation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Histamine • Histamine Receptors There are three types (See Chap. 8, Part 2 notes). The most common one is the: H 1 receptor • Proinflammatory • On nasal mucosa, conjunctiva, skin, bronchi, and the gastrointestinal tract. • Effects smooth muscle in blood vessels and bronchi, resulting in vasodilation and bronchoconstriction. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Histamine H 1 receptor (cont. ) Ø Increases capillary permeability by stimulating endothelial cells to retract, opening the spaces between cells, which allows cells and proteins to move out of the vessel and into the tissues (edema). Ø H 1 receptors located on white blood cells help to activate neutrophils (PMNs) and macrophages that provide the cellular inflammatory response. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Histamine Other types of histamine receptors perform different functions Located in the stomach lining and heart (H 2) and in the central nervous system (H 3). Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Degranulation Chemotactic factors Ø Neutrophil chemotactic factor • Attracts neutrophils Ø Eosinophil chemotactic factor of anaphylaxis (ECF-A) • Attracts eosinophils Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Synthesis of Mediators Results in slower, longer lasting effect than histamine Ø Leukotrienes Ø Prostaglandins Ø Platelet-activating factor Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Degranulation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Synthesis of Mediators Leukotrienes Ø Product of arachidonic acid from mast cell membranes Ø Similar effects to histamine in later stages Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Synthesis of Mediators Prostaglandins Ø Product of arachidonic acid from mast cell membranes Ø Cause increased vascular permeability, smooth muscle contraction, and induce pain and fever Ø Synthesis inhibited by NSAIDs (nonsteroidal anti-inflammatory drugs; aspirin, ibuprofen) Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Mast Cell Synthesis of Mediators Platelet-activating factor Ø Similar effect to leukotrienes Ø Cause platelet activation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

ACTIVITY 1. Why are antihistamines given to people suffering from an allergic inflammatory response? 2. Why is aspirin effective in lowering fever and reducing pain? Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Plasma Protein Systems Types of protein systems Ø Complement system Ø Coagulation system Ø Kinin system Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

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Plasma Protein Systems Characteristics: Made by liver All contain inactive enzymes (proenzymes) Sequentially activated (cascade) Ø First proenzyme is converted to an active enzyme Ø Substrate of the activated enzyme becomes the next component in the series Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Plasma Protein Systems Complement system Ø 10% of serum protein Ø Can destroy pathogens directly Ø Activates or collaborates with every other component of the inflammatory response Ø Three pathways, but all result in formation of MAC (membrane attack complex) • MAC creates pores in outer membranes of cells and bacteria which kills them. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Plasma Protein Systems Complement system Ø Roles of various components: • Opsonins – C 3 b coats bacteria and makes it easier for phagocytes to engulf them • Chemotactic factors – C 5 a attracts inflammatory cells • Anaphylatoxins – C 3 a and C 5 a induce rapid degranulation of mast cells Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Plasma Protein Systems Coagulation (clotting) system Ø Forms a fibrinous meshwork at an injured or inflamed site • Prevents the spread of infection • Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity • Forms a clot that stops bleeding • Provides a framework for repair and healing Ø Main substance is an insoluble protein called fibrin Ø Excess clotting is opposed by plasmin, which breaks down fibrin. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Plasma Protein Systems Kinin system Ø Functions to activate and assist inflammatory cells Ø Primary kinin is bradykinin Ø Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

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ACTIVITY 1. Why would a person with alcoholic cirrhosis of the liver have problems with blood clotting and fighting infections? 2. What two chemical substances have we mentioned that cause pain? Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cellular Components of Inflammation Neutrophils Ø Also referred to as polymorphonuclear neutrophils (PMNs) Ø Predominate in early inflammatory responses (6 -12 hours after injury) Ø Phagocytes - ingest bacteria, dead cells, and cellular debris Ø Cells are short lived and become a component of the purulent exudate Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Neutrophils Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cellular Components of Inflammation Monocytes and macrophages Ø Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Monocytes and Macrophages Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cellular Components of Inflammation Monocytes and macrophages Ø Macrophages typically arrive at the inflammatory site 24 hours or later (after neutrophils). Ø Can phagocytize larger particles. Ø More effective than neutrophils. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cellular Components of Inflammation Eosinophils Ø Defend against parasites and are mildly phagocytic. Ø Anti-inflammatory effects - regulate vascular mediators released by mast cells. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Eosinophils Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Other Cellular Components Natural killer (NK) cells Ø Function is to recognize and eliminate cells infected with viruses and some function in eliminating cancer cells Platelets Ø Activation results in degranulation and interaction with components of the coagulation system Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Phagocytosis Process by which a cell ingests and disposes of foreign material Attracted to site by production of adhesion molecules by vascular endothelium Margination (pavementing) Ø Adherence of leukocytes to endothelial cells Diapedesis Ø Emigration of cells through the endothelial junctions Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Phagocytosis Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Phagocytosis Opsonization Ø Molecules like C 3 b and antibodies bind and mark substances for phagocytosis. Steps in Phagocytosis Ø Adherence to target particle • Enhanced by opsonization Ø Engulfment Ø Phagosome formation and fusion with lysosomal granules → phagolysosome Ø Destruction of the target Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Phagocytosis Destruction of the target Ø Oxygen-dependent mechanisms – due to production of toxic free radicals by phagosome enzymes Ø Oxygen-independent mechanisms – various, including acidic p. H of phagosome, hydrolytic enzymes, lactic acid, and inhibiting bacterial growth by binding of free iron Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

ACTIVITY 1. How does the complement system aid the process of phagocytosis? 2. When macrophages die they break open and release their contents. How would this effect the surrounding tissue? Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cytokines Interleukins Ø Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cytokines Interleukins Ø Many types – examples: • IL-1 is a pro-inflammatory cytokine; causes fever • IL-10 is an anti-inflammatory cytokine; suppresses lymphocytes and cytokine production Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cytokines Interferon Ø Protects against viral infections Ø Produced and released by virally infected host cells in response to viral doublestranded RNA Ø Types • IFN-alpha and IFN-beta - induce production of antiviral proteins • IFN-gamma - increases microbiocidal activity of macrophages Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Interferon Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cytokines Tumor necrosis factor-alpha Ø Secreted by macrophages and mast cells • Induces fever by acting as an endogenous pyrogen • Increases synthesis of inflammatory serum proteins • Causes muscle wasting (cachexia) and intravascular thrombosis Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Cytokines Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Local Manifestations of Inflammation Results from vascular changes and corresponding leakage of circulating components into the tissue Heat - due to vasodilation Ø Redness- due to vasodilation Ø Edema (swelling) - due to increased vascular permeability Ø Pain - due to edema (puts pressure on nerve endings) & chemicals like prostaglandins & bradykinin Ø Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

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Exudative Fluids Serous exudate Ø Watery exudate: indicates early inflammation (blister) Fibrinous exudate Ø Thick, clotted exudate: indicates more advanced inflammation (pneumonia) Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Exudative Fluids Purulent exudate Ø Pus: indicates a bacterial infection Hemorrhagic exudate Ø Exudate contains blood: indicates bleeding Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

ACTIVITY 1. Identify at least one cell and one chemical that decrease or moderate inflammation. 2. Identify at least one cell and one chemical that combat viral infections. 3. Identify at least two substances that cause fever. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Systemic Manifestations of Inflammation Fever Ø Caused by exogenous and endogenous pyrogens Ø Act directly on the hypothalamus to raise the set point for body temperature Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Systemic Manifestations of Inflammation Leukocytosis Ø Increased numbers of circulating leukocytes Ø Neutrophilia (increased number of neutrophils) - seen in bacterial infections Ø Lymphocytosis (increased number of lymphocytes) - seen in viral infections Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Systemic Manifestations of Inflammation Increased plasma protein synthesis Ø Acute-phase reactants - C-reactive protein, fibrinogen, complement components, etc. • Elevated levels cause increased erythrocyte sedimentation (indicator of inflammation) • Elevated C-reactive protein is associated with increased risk of coronary heart disease Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Chronic Inflammation lasting 2 weeks or longer Often related to an unsuccessful acute inflammatory response Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Chronic Inflammation Other causes of chronic inflammation: Ø High lipid and wax content of a microorganism Ø Ability to survive inside the macrophage Ø Toxins Ø Chemicals, particulate matter, or physical irritants Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Chronic Inflammation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Chronic Inflammation Characteristics Ø Dense infiltration of lymphocytes and macrophages Ø Granuloma formation Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

Chronic Inflammation Ø Ø Ø Granulomas Form around areas of infection (ex. tuberculosis). Central area of caseous necrosis Surrounded by a zone of activated macrophages Outer layers of lymphocytes and fibroblasts A wall of fibrin is laid down around exterior Contents eventually breakdown and liquefy Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.

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Note Review information on Wound Healing at the end of the chapter. Elsevier items and derived items © 2008 by Mosby, Inc. , an affiliate of Elsevier Inc. Some material was previously published.