Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Innate Defenses: Inflammation Chapter 5

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  Physical and mechanical barriers  Second line of defense  Inflammation  Third line of defense  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  Skin  Linings of the gastrointestinal, genitourinary, and respiratory tracts Sloughing off of cells Sloughing off of cells Coughing and sneezing Coughing and sneezing Flushing Flushing Vomiting Vomiting Mucus and cilia Mucus and cilia

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. First Line of Defense  Biochemical barriers  Saliva, tears, ear wax, sweat, and mucus – trap bacteria and contain:  Lysozyme and antimicrobial peptides – produced by body cells, kill bacteria and other pathogens  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  Caused by a variety of stimuli Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc.  Local manifestations Redness, heat, swelling pain and loss of function 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  Vascular response Blood vessels dilate and become more permeable, allowing cells and fluid to enter site. 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. 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. 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.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Inflammation  Goals of Inflammation  Limit and control tissue damage  Prevent and limit infection  Initiate adaptive immune response  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  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  Degranulation and synthesis of lipid- derived 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  Vasoactive amine that causes temporary, rapid constriction of smooth muscle in the large blood vessels and the dilation of the postcapillary venules  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. 7, Part 2 notes). The most common one is the:  H1 receptor Proinflammatory Proinflammatory On nasal mucosa, conjunctiva, skin, bronchi, and the gastrointestinal tract. On nasal mucosa, conjunctiva, skin, bronchi, and the gastrointestinal tract. Effects smooth muscle in blood vessels and bronchi, resulting in vasodilation and bronchoconstriction. 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  H1 receptor (cont.)  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).  H1 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 (H2) and in the central nervous system (H3).

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mast Cell Degranulation  Chemotactic factors  Neutrophil chemotactic factor Attracts neutrophils Attracts neutrophils  Eosinophil chemotactic factor of anaphylaxis (ECF-A) Attracts eosinophils 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  Leukotrienes  Prostaglandins  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  Product of arachidonic acid from mast cell membranes  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  Product of arachidonic acid from mast cell membranes  Cause increased vascular permeability, smooth muscle contraction, and induce pain and fever  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  Similar effect to leukotrienes  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  Complement system  Coagulation system  Kinin system

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. Plasma Protein Systems Characteristics:  Made by liver  All contain inactive enzymes (proenzymes)  Sequentially activated (cascade)  First proenzyme is converted to an active enzyme  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  10% of serum protein  Can destroy pathogens directly  Activates or collaborates with every other component of the inflammatory response  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. 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  Roles of various components: Opsonins – C3b coats bacteria and makes it easier for phagocytes to engulf them Opsonins – C3b coats bacteria and makes it easier for phagocytes to engulf them Chemotactic factors – C5a attracts inflammatory cells Chemotactic factors – C5a attracts inflammatory cells Anaphylatoxins – C3a and C5a induce rapid degranulation of mast cells Anaphylatoxins – C3a and C5a 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  Forms a fibrinous meshwork at an injured or inflamed site Prevents the spread of infection Prevents the spread of infection Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity Forms a clot that stops bleeding Forms a clot that stops bleeding Provides a framework for repair and healing Provides a framework for repair and healing  Main substance is an insoluble protein called fibrin  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  Functions to activate and assist inflammatory cells  Primary kinin is bradykinin  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.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. 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  Also referred to as polymorphonuclear neutrophils (PMNs)  Predominate in early inflammatory responses (6-12 hours after injury)  Phagocytes - ingest bacteria, dead cells, and cellular debris  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  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  Macrophages typically arrive at the inflammatory site 24 hours or later (after neutrophils).  Can phagocytize larger particles.  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  Defend against parasites and are mildly phagocytic.  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  Function is to recognize and eliminate cells infected with viruses and some function in eliminating cancer cells  Platelets  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)  Adherence of leukocytes to endothelial cells  Diapedesis  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  Molecules like C3b and antibodies bind and mark substances for phagocytosis.  Steps in Phagocytosis  Adherence to target particle Enhanced by opsonization Enhanced by opsonization  Engulfment  Phagosome formation and fusion with lysosomal granules → phagolysosome  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  Oxygen-dependent mechanisms – due to production of toxic free radicals by phagosome enzymes  Oxygen-independent mechanisms – various, including acidic pH 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  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  Many types – examples: IL-1 is a pro-inflammatory cytokine; causes fever IL-1 is a pro-inflammatory cytokine; causes fever IL-10 is an anti-inflammatory cytokine; suppresses lymphocytes and cytokine production 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  Protects against viral infections  Produced and released by virally infected host cells in response to viral double- stranded RNA  Types IFN-alpha and IFN-beta - induce production of antiviral proteins IFN-alpha and IFN-beta - induce production of antiviral proteins IFN-gamma - increases microbiocidal activity of macrophages 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  Secreted by macrophages and mast cells Induces fever by acting as an endogenous pyrogen Induces fever by acting as an endogenous pyrogen Increases synthesis of inflammatory serum proteins Increases synthesis of inflammatory serum proteins Causes muscle wasting (cachexia) and intravascular thrombosis 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  Redness- due to vasodilation  Edema (swelling) - due to increased vascular permeability  Pain - due to edema (puts pressure on nerve endings) & chemicals like prostaglandins & bradykinin

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. Exudative Fluids  Serous exudate  Watery exudate: indicates early inflammation (blister)  Fibrinous exudate  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  Pus: indicates a bacterial infection  Hemorrhagic exudate  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  Caused by exogenous and endogenous pyrogens  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  Increased numbers of circulating leukocytes  Neutrophilia (increased number of neutrophils) - seen in bacterial infections  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  Acute-phase reactants - C-reactive protein, fibrinogen, complement components, etc. Elevated levels cause increased erythrocyte sedimentation (indicator of inflammation) Elevated levels cause increased erythrocyte sedimentation (indicator of inflammation) Elevated C-reactive protein is associated with increased risk of coronary heart disease 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  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:  High lipid and wax content of a microorganism  Ability to survive inside the macrophage  Toxins  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  Dense infiltration of lymphocytes and macrophages  Granuloma formation

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

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Note  Review information on Wound Healing (Resolution and Repair in 4 th ed.) at the end of the chapter.